Lee K. Tan

A Nomogram for Predicting the Likelihood of Additional Nodal Metastases in Breast Cancer Patients With a Positive Sentinel Node Biopsy

AbstractBackground:The standard of care for breast cancer patients with sentinel lymph node (SLN) metastases includes complete axillary lymph node dissection (ALND). However, many question the need for complete ALND in every patient with detectable SLN metastases, particularly those perceived to have a low risk of non-SLN metastases. Accurate estimates of the likelihood of additional disease in the axilla could assist greatly in decision-making regarding further treatment. Methods:Pathological features of the primary tumor and SLN metastases of 702 patients who underwent complete ALND were assessed with multivariable logistic regression to predict the presence of additional disease in the non-SLNs of these patients. A nomogram was created using pathological size, tumor type and nuclear grade, lymphovascular invasion, multifocality, and estrogen-receptor status of the primary tumor; method of detection of SLN metastases; number of positive SLNs; and number of negative SLNs. The model was subsequently applied prospectively to 373 patients. Results:The nomogram for the retrospective population was accurate and discriminating, with an area under the receiver operating characteristic (ROC) curve of 0.76. When applied to the prospective group, the model accurately predicted likelihood of non-SLN disease (ROC, 0.77). Conclusions:We have developed a user-friendly nomogram that uses information commonly available to the surgeon to easily and accurately calculate the likelihood of having additional, non-SLN metastases for an individual patient.

Sentinel lymph node biopsy: is it indicated in patients with high-risk ductal carcinoma-in-situ and ductal carcinoma-in-situ with microinvasion?

Background: Axillary lymph node status is the strongest prognostic indicator of survival for women with breast cancer. The purpose of this study was to determine the incidence of sentinel node metastases in patients with high-risk ductal carcinoma-in-situ (DCIS) and DCIS with microinvasion (DCISM).Methods: From November 1997 to November 1999, all patients who underwent sentinel node biopsy for high-risk DCIS (n = 76) or DCISM (n = 31) were enrolled prospectively in our database. Patients with DCIS were considered high risk and were selected for sentinel lymph node biopsy if there was concern that an invasive component would be identified in the specimen obtained during the definitive surgery. Patients underwent intraoperative mapping that used both blue dye and radionuclide. Excised sentinel nodes were serially sectioned and were examined by hematoxylin and eosin and by immunohistochemistry.Results: Of 76 patients with high-risk DCIS, 9 (12%) had positive sentinel nodes; 7 of 9 patients were positive for micrometastases only. Of 31 patients with DCISM, 3 (10%) had positive sentinel nodes; 2 of 3 were positive for micrometastases only. Six of nine patients with DCIS and three of three with DCISM and positive sentinel nodes had completion axillary dissection; one patient with DCIS had an additional positive node detected by conventional histological analysis.Conclusions: This study documents a high incidence of lymph node micrometastases as detected by sentinel node biopsy in patients with high-risk DCIS and DCISM. Although the biological significance of breast cancer micrometastases remains unclear at this time, these findings suggest that sentinel node biopsy should be considered in patients with high-risk DCIS and DCISM.

Lymphovascular Invasion Enhances the Prediction of Non-Sentinel Node Metastases in Breast Cancer Patients with Positive Sentinel Nodes

Background:Fifty percent of patients with sentinel lymph node (SLN) metastases have no metastatic disease in non-SLNs on axillary lymph node dissection (ALND). The goal of this study is to determine which patients have metastatic disease limited to the SLN, and, therefore, may not require completion ALND.Methods:Of the first 1000 patients undergoing SLN biopsy at Memorial Sloan-Kettering Cancer Center, using a combined blue dye and isotope technique, 231 (26%) had positive SLN. Of these, 206 underwent completion ALND. They are the study group for this report.Results:The likelihood of non-SLN metastasis was inversely related to three clinicopathologic variables: tumor size ≤ 1.0 cm; absence of lymphovascular invasion (LVI); and SLN micrometastases (≤ 2 mm). None of 24 patients with all three predictive factors had non-SLN metastases, whereas 58% of patients with none of the factors had disease in the non-SLN.Conclusion:Patients with small breast cancers, no LVI, and SLN micrometastases have a low risk of non-SLN metastases, and may not require completion ALND.

Is Routine Intraoperative Frozen-Section Examination of Sentinel Lymph Nodes in Breast Cancer Worthwhile?

Background: Routine intraoperative frozen section (FS) of sentinel lymph nodes (SLN) can detect metastatic disease, allowing immediate axillary dissection and avoiding the need for reoperation. Routine FS is also costly, increases operative time, and is subject to false-negative results. We examined the benefit of routine intraoperative FS among the first 1000 patients at Memorial Sloan Kettering Cancer Center who had SLN biopsy for breast cancer.Methods: We performed SLN biopsy with intraoperative FS in 890 consecutive breast cancer patients, none of whom had a back-up axillary dissection planned in advance. Serial sections and immunohistochemical staining for cytokeratins were performed on all SLN that proved negative on FS. The sensitivity of FS was determined as a function of (1) tumor size and (2) volume of metastatic disease in the SLN, and the benefit of FS was defined as the avoidance of a reoperative axillary dissection.Results: The sensitivity of FS ranged from 40% for patients with T1a to 76% for patients with T2 cancers. The volume of SLN metastasis was highly correlated with tumor size, and FS was far more effective in detecting macrometastatic disease (sensitivity 92%) than micrometastases (sensitivity 17%). The benefit of FS in avoiding reoperative axillary dissection ranged from 4% for T1a (6 of 143) to 38% for T2 (45 of 119) cancers.Conclusions: In breast cancer patients having SLN biopsy, the failure of routine intraoperative FS is largely the failure to detect micrometastatic disease. The benefit of routine intraoperative FS increases with tumor size. Routine FS may not be indicated in patients with the smallest invasive cancers.

The accuracy of sentinel lymph node biopsy in multicentric and multifocal invasive breast cancers

BACKGROUND Sentinel lymph node biopsy (SLNB) has proved to be an accurate alternative to complete axillary lymph node dissection (ALND) in clinically node-negative breast cancer patients. Multicentric (MC) and multifocal (MF) invasive breast cancers are considered to be relative contraindications to SLNB. We examine the accuracy of SLNB in patients with MC and MF invasive breast cancers. STUDY DESIGN From September 1996 to August 2001, a total of 3,501 patients with clinically node-negative breast cancer underwent SLNB using both blue dye and radioisotope at our institution. A total of 70 patients had MC or MF invasive breast cancer, a successful SLNB, and mastectomy for local control. All had >/=10 axillary nodes excised (including the SLN) in a planned ALND. Exclusion criteria included MC and MF in situ carcinoma; breast conservation; previous breast irradiation, ALND, or SLNB; recurrent breast cancer; neoadjuvant chemotherapy; or ALND based solely on SLNB pathologic examination. RESULTS; The incidence of axillary metastases was 54% (38 of 70). SLNB accuracy was 96% (67 of 70), sensitivity 92% (35 of 38), and false-negative rate 8% (3 of 38). All patients with an inaccurate SLNB had a dominant invasive tumor >5 cm and one patient had palpable axillary disease intraoperatively. The SLN was the only site of axillary metastasis in 37% (14 of 38). Results were compared with those of published SLNB validation studies, most of which reflect experience with single-site invasive breast cancers. No statistically significant difference was noted for accuracy, sensitivity, or false-negative rate. CONCLUSIONS SLNB accuracy in MC and MF disease is comparable with that of published validation studies. MC and MF patients with a dominant T3 tumor (>5 cm) or axillary disease palpable intraoperatively should have a concurrent formal ALND. Our retrospective data suggest SLNB may be used as a reliable alternative to conventional ALND in selected patients with MC or MF disease. Further studies in this patient population are warranted.

Occult Axillary Node Metastases in Breast Cancer Are Prognostically Significant: Results in 368 Node-Negative Patients With 20-Year Follow-Up

PURPOSE In breast cancer, sentinel lymph node (SLN) biopsy allows the routine performance of serial sections and/or immunohistochemical (IHC) staining to detect occult metastases missed by conventional techniques. However, there is no consensus regarding the optimal method for pathologic examination of SLN, or the prognostic significance of SLN micrometastases. PATIENTS AND METHODS In 368 patients with axillary node-negative invasive breast cancer, treated between 1976 and 1978 by mastectomy, axillary dissection, and no systemic therapy, we reexamined the axillary tissue blocks following our current pathologic protocol for SLN. Occult lymph node metastases were categorized by pattern of staining (immunohistochemically positive or negative [IHC+/-], hematoxylin-eosin staining positive or negative [H & E +/-]), number of positive nodes (0, 1, > 1), number of metastatic cells (0, 1 to 20, 21 to 100, > 100), and largest cluster size (<or= 0.2 mm [pN0(i+)], 0.3 to 2.0 mm [pN1(mi)], > 2.0 mm [pN1a]). We report 20-year results as overall survival (OS), disease-free survival (DFS), and disease-specific death (DSD). RESULTS A total of 23% of patients (83 of 368) were converted to node-positive. Of these, 73% were <or= 0.2 mm in size (pN0(i+)), 20% were 0.3 to 2.0 mm (pN1(mi)), and 6% were more than 2 mm (pN1a). On univariate and multivariate analysis, pattern of staining, number of positive nodes, number of metastatic cells, and cluster size were all significantly related to both DFS and DSD. On multivariate analysis, each of these measures had significance comparable to, or greater than, tumor size, grade or lymphovascular invasion. CONCLUSION In breast cancer patients staged node-negative by conventional single-section pathology, occult axillary node metastases detected by our current pathologic protocol for SLN are prognostically significant.

Expression of WT1, CA 125, and GCDFP-15 as useful markers in the differential diagnosis of primary ovarian carcinomas versus metastatic breast cancer to the ovary.

Metastatic breast carcinoma to the ovary is sometimes difficult to differentiate from primary ovarian carcinoma. This problem is often encountered in breast carcinoma patients who develop adnexal masses. ER and PR can be positive in a high percentage of breast and ovarian carcinomas, and therefore cannot be used in the differential diagnosis of these entities. WT1 and CA125 have been identified as possible markers for ovarian cancer. However, no studies have been done that specifically compare the immunophenotype of breast carcinoma metastatic to ovary with that of primary ovarian cancer. Thirty-nine cases of metastatic breast carcinoma to the ovary, 36 primary breast carcinomas, and 42 primary ovarian carcinomas were examined immunohistochemically for the expression of WT1, CA125, carcinoembryonic antigen, MUC2, MUC1, and GCDFP. The percentage of cells stained and the intensity of staining were recorded. Thirty-two ovarian carcinomas (76%) were positive for WT1, including 31 of 33 (94%) serous carcinomas. Most of them had strong and diffuse staining. None of the breast cancers either primary or metastatic to the ovary expressed WT1. Thirty-eight (90%) ovarian carcinomas were positive for CA125, most of them with strong and diffuse staining. Most breast carcinomas were negative for CA125, with only 6 (16%) of the primary ones and 5 (12%) of the metastatic showing weak and focal positivity. All ovarian carcinomas were negative for GCDFP. Five primary breast cancers (14%) and 17 (43%) metastatic to the ovary were positive for GCDFP. Nine (21%) ovarian carcinomas, 8 (22%) primary breast carcinomas, and 13 (33%) metastatic to the ovary were positive for carcinoembryonic antigen. Almost all tumors examined were positive for MUC1 (100% ovarian carcinomas, 100% primary breast carcinomas, and 95% metastatic breast carcinomas to ovary). MUC2 was positive in 10 (24%) ovarian carcinomas, 3 (8%) primary breast cancers, and 12 (30%) metastases to the ovary. The presence of immunoreactivity for WT1 and CA125 in a carcinoma involving ovary strongly favors a primary lesion. Most ovarian carcinomas are positive for both markers, whereas the majority of metastatic breast carcinomas to the ovary are negative. GCDFP can be complementary in this differential diagnosis.

The Results of Frozen Section, Touch Preparation, and Cytological Smear Are Comparable for Intraoperative Examination of Sentinel Lymph Nodes: A Study in 133 Breast Cancer Patients

BackgroundThe goal of intraoperative sentinel lymph node (SLN) examination is to avoid reoperation for a positive SLN, but the ideal method of intraoperative SLN examination remains unclear, and published results vary widely.MethodsWe evaluated the sensitivity of intraoperative frozen section (FS), touch preparation (TP), and cytological smear (CS) in 305 SLNs from 133 breast cancer patients. Each SLN was received fresh and cut into 2- to 3-mm slices; TP and CS from each cut surface and an FS of the entire SLN were obtained. Postoperative evaluation of the SLN consisted of 1 hematoxylin and eosin–stained section and of one hematoxylin and eosin–stained and one immunohistochemically stained section for cytokeratin from each of two levels 50 μm apart. Tumor cells found by any method, including immunohistochemistry, identified a positive SLN. Three pathologists blinded to the final SLN diagnosis reviewed all TP, CS, and FS; the consensus diagnosis (concordance of two or more) was used for the study.ResultsFS, TP, and CS had comparable sensitivities (59%, 57%, and 59%, respectively). Each method was more sensitive in detecting macrometastases (>2 mm; 96%, 93%, and 93%, respectively) than micrometastases (≤2 mm; 27%, 27%, and 30%, respectively). The combination of methods only marginally improved the intraoperative sensitivity. TP and CS were each responsible for a single false-positive result.ConclusionsFS, TP, and CS are comparable for the intraoperative detection of SLN metastases, and each method is substantially better at detecting micrometastases than micrometastases. The combination of two or more techniques only marginally improves the sensitivity over that achieved by a single method.

Stage IA uterine serous carcinoma: a study of 13 cases.

Although in endometrioid type endometrial carcinoma depth of invasion is a powerful predictor of extrauterine disease and survival, in serous carcinoma its importance is unclear. Recurrences and death in patients with serous tumors confined to the endometrium or an endometrial polyp have been reported. In other studies, however, the absence of myometrial invasion was correlated with a more favorable course. In an attempt to clarify this issue, we reviewed 13 completely staged, stage IA serous carcinomas with follow-up from 10 to 93 months (median 38), in which extensive histologic examination had been performed. Serous carcinoma was identified in an endometrial polyp in six cases, in an endometrial polyp and associated endometrium in four, and solely in the endometrium in three cases. No other histologic types of endometrial carcinoma were present, and there was no myometrial invasion. Multifocal serous intraepithelial carcinoma was also seen in 12 cases. Two of the patients died of disease with intraabdominal carcinomatosis at 10 and 14 months after presentation. The overall estimated survival was 83%, showing a relatively favorable prognosis. In conclusion, although the absence of histologically detected myometrial invasion may be associated with recurrences and death in serous carcinoma, an accurately assessed stage based on a careful histologic examination appears to be, at present, the most reliable predictor of survival.

A phase II trial of imatinib mesylate monotherapy in patients with metastatic breast cancer.

Background. Imatinib mesylate is a potent inhibitor of Abl, KIT, and PDGFR tyrosine kinases. Breast cancer has variable expression of KIT and PDGFR therefore we conducted a phase II trial to evaluate the safety and efficacy of imatinib in patients with metastatic breast cancer (MBC).Patients and methods. Eligible patients had measurable and progressive MBC, with no limits on prior chemo- or hormonal therapy. Imatinib was initially administered at a dose of 400 mg orally twice a day with provisions for dose reductions based on toxicities. The primary endpoint was clinical benefit based on RECIST criteria. Tumor specimens were tested for expression of KIT and PDGFR tyrosine kinases.Results. Sixteen patients were enrolled and treated. Median age was 55 years (range: 35–73); median number of prior chemotherapy regimens for MBC was 4 (range 1–8). The main non-hematologic toxicities were (Grades 1/2; Grade 3): fatigue (56%; 6%), edema (38%; 19%), nausea (31%; 19%), vomiting (38%; 0%), anorexia (38%; 0%), diarrhea (19%; 6%), and rash (25%; 6%). Grade 3/4 hematologic and biochemical abnormalities were minimal. There was no evidence of clinical benefit. The median duration of therapy on trial was 28 days (range 2–71). Of the 13 testable cases: 1 was KIT positive and 4 were PDGFR positive.Conclusion. Imatinib therapy at doses of 800 mg/day was associated with significant toxicity in patients with heavily pre-treated MBC. Our results do not indicate activity for imatinib monotherapy in these unselected patients.