Paul Peter Rosen

Sentinel Lymph Node Biopsy in Breast Cancer: Initial Experience at Memorial Sloan-Kettering Cancer Center

Abstract Background: Sentinel node biopsy (SNB) has emerged as a potential alternative to routine axillary dissection in clinically node-negative breast cancer. Study Design: From September 1995 to June 1996 at Memorial Sloan-Kettering Cancer Center, 60 patients with clinically node-negative cancer underwent SNB, which was immediately followed by standard axillary dissection. Both blue dye and radioisotope were used to identify the sentinel node. SNB was compared with standard axillary dissection for its ability to accurately reflect the final pathologic status of the axillary nodes. Results: The sentinel node was successfully identified by lymphoscintigraphy in 75% (42 of 56), by blue dye in 75% (44 of 59), by isotope in 88% (52 of 59), and by the combination of blue dye and isotope in 93% (55 of 59) of all 59 evaluable patients. Of the 55 patients in this study where sentinel nodes were identified, 20 (36%) were histologically positive. The sentinel node was falsely negative in three patients, yielding an accuracy of 95%. SNB was more accurate for T1 (98%) than for T2–T3 tumors (82%). Conclusions: Lymphatic mapping is technically feasible, reliably identifies a sentinel node in most cases, and appears more accurate for T1 tumors than for larger lesions. Blue dye and radioisotope are complementary techniques, and the overall success of the procedure is maximized when the two are used together.

Prediction of early relapse in patients with operable breast cancer by detection of occult bone marrow micrometastases.

We used monoclonal antibodies to identify occult micrometastases in the bone marrow of 49 patients with operable (stage I and II) breast carcinoma. Follow-up (mean, 29 months; median, 30 months) revealed that 12 patients recurred. The presence of bone marrow micrometastases (BMM) was significantly associated with early recurrence (P less than .04). The estimated 2-year recurrence rate for patients with no BMM detected (BMM-) was 3%; in patients with BMM, the 2-year recurrence rate was 33%. When BMM and axillary lymph node (LN) status were combined, groups of patients at low risk (LN-, BMM-; 2-year recurrence rate, 0%) and high risk (LN+, BMM+; 2-year recurrence rate, 42%) for early recurrence were identified. Bone marrow tumor burden was related to early recurrence. Among patients with BMM, those who did not recur had on average fewer extrinsic cells in their marrow than those who recurred (15 v 43 cells, respectively). Multivariate analysis comparing BMM, LN+ versus LN-, and tumor size (less than or equal to 2 cm v greater than 2 cm) revealed no factor independently associated with early recurrence. Peripheral tumor burden of BMM (0 or less than 10 extrinsic cells v greater than or equal to 10 extrinsic cells) was the only independent predictor of early recurrence (P less than .003). In conjunction with conventional prognostic factors, particularly axillary LN status, evaluation for BMM might be used to stratify patients for adjuvant treatment programs. Because this pilot study involved few patients with short-term follow-up, the results should be interpreted with caution. The examination of bone marrow for micrometastases remains an experimental procedure; the clinical usefulness of the test will be established through larger studies with long-term follow-up.

Lessons learned from 500 cases of lymphatic mapping for breast cancer.

OBJECTIVE To evaluate the factors affecting the identification and accuracy of the sentinel node in breast cancer in a single institutional experience. SUMMARY BACKGROUND DATA Few of the many published feasibility studies of lymphatic mapping for breast cancer have adequate numbers to assess in detail the factors affecting failed and falsely negative mapping procedures. METHODS Five hundred consecutive sentinel lymph node biopsies were performed using isosulfan blue dye and technetium-labeled sulfur colloid. A planned conventional axillary dissection was performed in 104 cases. RESULTS Sentinel nodes were identified in 458 of 492 (92%) evaluable cases. The mean number of sentinel nodes removed was 2.1. The sentinel node was successfully identified by blue dye in 80% (393/492), by isotope in 85% (419/492), and by the combination of blue dye and isotope in 93% (458/492) of patients. Success in locating the sentinel node was unrelated to tumor size, type, location, or multicentricity; the presence of lymphovascular invasion; histologic or nuclear grade; or a previous surgical biopsy. The false-negative rate of 10.6% (5/47) was calculated using only those 104 cases where a conventional axillary dissection was planned before surgery. CONCLUSIONS Sentinel node biopsy in patients with early breast cancer is a safe and effective alternative to routine axillary dissection for patients with negative nodes. Because of a small but definite rate of false-negative results, this procedure is most valuable in patients with a low risk of axillary nodal metastases. Both blue dye and radioisotope should be used to maximize the yield and accuracy of successful localizations.

Medullary carcinoma of the breast: a clinicopathologic study with 10 year follow-up.

Primary breast carcinomas from 192 patients treated between 1955 and 1965 for medullary carcinoma or duct carcinoma with medullary features were reviewed and reclassified using strictly defined pathologic criteria. Tumors that fulfilled requirements for medullary carcinoma were identified in 57 patients. Another 79 tumors that varied slightly from these criteria were termed “atypical” medullary carcinoma and 56 were characterized as nonmedullary carcinoma. When compared with the patients with nonmedullary infiltrating duct carcinoma, patients with medullary carcinoma had a significantly higher survival rate at 10 years, (84% vs. 63%), similar frequency of axillary lymph node metastases, and a more favorable prognosis when nodal metastases were present. Within the medullary carcinoma group, patients had a significantly better survival rate if their primary tumors were smaller than 3 cm in diameter. The average size of medullary carcinomas was 2.9 cm and that of nonmedullary carcinomas, 4.0 cm. Bilaterality was not more common in patients with medullary carcinoma, but the interval between diagnosis of the tumors was twice as long when one lesion was medullary (8.8 years) than when both were infiltrating duct carcinomas (4.6 years). Bilaterality was significantly more common among patients with medullary carcinoma who had a positive family history. The medullary lesion was most often the second one to be diagnosed. The 79 patients with atypical medullary carcinoma had a 10‐year survival rate of 74%. Patients in this group whose tumors had a sparse lymphoid infiltrate had a relatively poor prognosis. Intraductal carcinoma at the periphery of the lesion was not associated with a less favorable prognosis. It was concluded that intraductal carcinoma was consistent with the diagnosis of medullary carcinoma if all other criteria for the diagnosis were satisfied. With these exceptions we were unable to draw any firm conclusions about favorable or unfavorable effects of other morphologic features on survival in the group with atypical medullary carcinoma. Until further study of this group reveals that some or all of the lesions form a distinct clinicopathologic entity they are best included under the heading of infiltrating duct carcinoma. When the criteria described in this report were used, medullary carcinoma proved to be a specific lesion associated with a significantly better prognosis than ordinary infiltrating duct carcinoma.

Lobular carcinoma in situ of the breast Detailed analysis of 99 patients with average follow-up of 24 years

Ninety-nine patients with in situ lobular carcinoma (LCIS) of the breast, not treated by mastectomy, were identified in a review of consecutive breast biopsies performed at Memorial Hospital between 1940 and 1950. Follow-up for an average of 24 years was obtained in order to determine the frequency of subsequent breast carcinoma. Detailed analysis of important clinical and pathologic features was undertaken to identify predictive factors that would serve to distinguish between patients with the greatest and least risk for subsequent carcinoma. Thirty-nine breast carcinomas other than the original LCIS were diagnosed in 32 patients. Half of the carcinomas occurred in the same and half in the opposite breast. The hazard rate for subsequent carcinoma increased with increasing length of follow-up and increasing age.When compared with general population data, the frequency of subsequent breast carcinoma was nine times greater than expected and deaths due to breast carcinoma were 11 times more frequent than expected. None of the currently recommended choices for therapy is entirely satisfactory. Follow-up without further surgery should be considered an investigative procedure until more information is available. This recommendation should be made only if the patient and physician are prepared to accept the responsibility of lifetime surveillance. At present, we consider it prudent in most cases to recommend ipsilateral mastectomy with low axillary dissection and concurrent biopsy of the opposite breast. Contralateral mastectomy is most appropriate when carcinoma is detected in the biopsy.

Pathological prognostic factors in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma: a study of 644 patients with median follow-up of 18 years.

Prognostic factors have been examined in 644 patients with tumor-node-metastasis (TNM) stage T1 breast carcinoma treated by mastectomy and followed for a median of 18.2 years. Overall, 148 patients (23%) died of recurrent breast carcinoma. Eighteen (3%) were alive with recurrent disease and 478 (74%) were alive or died of other causes without recurrence. Unfavorable clinicopathologic features were larger tumor size (1.1 to 2.0 cm v less than or equal to 1 cm), perimenopausal menstrual status, the number of axillary lymph node metastases, poorly differentiated grade, presence of lymphatic tumor emboli (LI) in breast tissue near the primary tumor, blood vessel invasion (BVI), and an intense lymphoplasmacytic reaction around the tumor. Median survival after recurrence for the entire series was 2 years. This was not significantly influenced by tumor size, the number of axillary nodal metastases, the type of treatment for recurrence, or the interval to recurrence. The proportions surviving 5 and 10 years after recurrence were 17% and 5%, respectively. Among T1N0M0 cases, the chance of a local recurrence was 2.8% within 20 years. Median survival of T1N0M0 cases after local recurrence (4.5 years) was significantly longer than after systemic recurrence (1.5 years). A similar trend (3.7 v 2.0 years), not statistically significant, was seen in T1N1M0 patients, who had a 6.5% chance of local recurrence within 20 years. Median survival following systemic recurrence detected 10 or more years after diagnosis in T1N0M0 and in T1N1M0 patients was significantly longer than the median survival for systemic recurrences found in the first decade of follow-up. This difference did not apply following local recurrence in either T1N0M0 or T1N1M0 cases. It is evident that patients with T1 breast carcinoma can be subdivided into differing prognostic groups and this must be taken into account when considering the role of adjuvant chemotherapy for stage I disease. Systemic adjuvant treatment may prove to be beneficial for patients with unfavorable prognostic factors, while women with an especially low risk for recurrence (eg, T1N0M0 tumor 1.0 cm or less) might be spared such treatment.

The clinical significance of pre‐invasive breast carcinoma

Improvements in mammography in the past 25 years have made it possible to detect before surgery many lesions with a high probability of being pre‐invasive carcinoma. Because these cancers are virtually all cured by mastectomy, there has been considerable interest in alternative types of treatment. Retrospective studies of pre‐invasive carcinoma treated by biopsy only revealed subsequent carcinoma in 30 to 40% of patients. Among women with lobular carcinoma in situ (LCIS), the frequency of subsequent carcinoma was nine times the expected rate, and mortality due to the disease was 11 times greater than expected. The risk of later invasive carcinoma appeared to involve both breasts equally when LCIS was present and to be largely limited to the breast that harbored intraductal carcinoma (IDC). When mastectomy was performed for pre‐invasive carcinoma, unsuspected invasion was found in 4% of patients with LCIS and 6% with IDC.

BRCA-associated breast cancer in young women.

PURPOSE To delineate the clinical characteristics and outcomes of breast cancer that arises in the setting of a germline BRCA mutation and to compare BRCA-associated breast cancers (BABC) with those that arise in women without mutations. PATIENTS AND METHODS We reviewed the clinical records of 91 Ashkenazi Jewish women ascertained during studies of the genetics of early-onset breast cancer. All women underwent testing for the BRCA1 mutations 185delAG and 5382insC. After the discovery of BRCA2, 79 women were also tested for the BRCA2 mutation 6174delT. RESULTS Mutations were identified in 30 women (33%). BABC were less likely to present with stage I disease than cases in women without mutations (27% v 46%), more likely to have axillary nodal involvement (54% v46%), and more likely to have extensive axillary involvement (25% v 17%). These differences were not statistically significant. BABC were significantly more likely to be histologic grade III (100% v 59%, P=.04) and to be estrogen receptor-negative (70% v 34%, P=.04). In the entire cohort, there were no significant differences between BABC and non-BRCA-associated cancers in 5-year relapse-free survival (65% v 69%, P=not significant [NS]), 5-year event-free survival (57% v 68%, P=NS), or 5-year overall survival. However, among cases diagnosed within 2 years of study entry, there was a trend toward shorter event-free survival in BRCA heterozygotes, but not relapse-free survival. Women with germline BRCA mutations were significantly more likely to develop contralateral breast cancer at 5 years (31% v 4%, P=.0007). CONCLUSION BABC present with adverse clinical and histopathologic features when compared with cases not associated with BRCA mutations. However, the prognosis of BABC appears to be similar to that of nonassociated cancer. Further studies of incident cases are necessary to define the independent prognostic significance of germline BRCA mutations.

Factors influencing prognosis in node-negative breast carcinoma: analysis of 767 T1N0M0/T2N0M0 patients with long-term follow-up.

PURPOSE This study was undertaken to define prognostically favorable and unfavorable subgroups of node-negative breast carcinoma patients by employing conventional pathologic data. PATIENTS AND METHODS Seven hundred sixty-seven women with T1N0M0/T2N0M0 breast carcinoma treated consecutively from 1964 through 1970 by modified or radical mastectomy without systemic adjuvant therapy were analyzed at a median follow-up duration of 18 years. RESULTS Size and histologic type of the carcinoma were crucial discriminants of prognosis. We defined a prognostically favorable group of 219 patients (29%) with infiltrating duct or lobular carcinoma < or = 1.0 cm in diameter or special tumor types < or = 3.0 cm. This group had a relapse-free survival rate of 91% at 10 years and 87% at 20 years. The less favorable group (548 patients, 71%) with infiltrating duct or lobular carcinoma greater than 1.0 cm and special tumor types greater than 3.0 cm had relapse-free survival rates of 73% and 68% at 10 and 20 years, respectively. The frequency of nonmammary malignant neoplasms (NMMN) was similar to that of contralateral carcinoma. Deaths due to NMMN were seven times more frequent than deaths due to contralateral carcinoma. CONCLUSION Nearly 30% of these node-negative patients, identified on the basis of tumor size and type, had an extremely favorable prognosis. There is insufficient evidence to warrant the routine use of adjuvant therapy in this group unless new forms of treatment prove to be less toxic and/or more effective in enhancing relapse-free survival. Early detection of NMMN should be an important part of the follow-up of node-negative breast carcinoma patients.

Pseudoangiomatous hyperplasia of mammary stroma

Grossly circumscribed, nonhemorrhagic breast masses consisting of mammary stromal proliferations that simulated vascular lesions were studied in nine women. Histologically, a striking pattern, which appeared to consist of complex inter-anastomosing channels lined by slender spindle cells, was present in the mammary parenchyma. The importance of this benign lesion, referred to as pseudoangiomatous hyperplasia of mammary stroma, is its distinction from angiosarcoma. The patients ranged in age from 22 to 52 years; all were premenopausal. Each presented with a palpable unilateral mass, measuring up to 7 cm in diameter. The patients were treated by excisional biopsy and remained well for up to 2.5 years after excision. One patient had two local recurrences within one year of the original excision, and a second patient had a local recurrence at 14 months. No patient had another concurrent or metachronous malignant tumor of the breast or other organ, and no abnormal hormonal status was found. Complete local excision appears to be adequate treatment. It remains to be determined whether this is a neoplastic process. However, there is no evidence that it is a precursor of angiosarcoma, and ultrastructural observations demonstrate that the spaces found in the lesion are not true vascular channels. Rather, they appear to arise by a process that involves disruption and separation of stromal collagen fibers. Since small foci of this change are common in hyperplastic breast tissue from premenopausal women, it is likely that the development of a discrete tumor with this pattern represents an exaggerated form of stromal hyperplasia.