Solange Pendas

Guidelines for sentinel node biopsy and lymphatic mapping of patients with breast cancer.

OBJECTIVE To define preliminary guidelines for the use of lymphatic mapping techniques in patients with breast cancer. SUMMARY BACKGROUND DATA Lymphatic mapping techniques have the potential of changing the standard of surgical care of patients with breast cancer. METHODS Four hundred sixty-six consecutive patients with newly diagnosed breast cancer underwent a prospective trial of intraoperative lymphatic mapping using a combination of vital blue dye and filtered technetium-labeled sulfur colloid. A sentinel lymph node (SLN) was defined as a blue node and/or a hot node with a 10:1 ex vivo gamma probe ratio of SLN to non-SLN. All SLNs were bivalved, step-sectioned, and examined with routine hematoxylin and eosin (H&E) stains and immunohistochemical stains for cytokeratin. A cytokeratin-positive SLN was defined as any SLN with a defined cluster of positive-staining cells that could be confirmed histologically on H&E sections. RESULTS Fine-needle aspiration (FNA) or stereotactic core biopsy was used to diagnose 195 of the 422 patients (46.2%) with breast cancer; 227 of 422 patients (53.8%) were diagnosed by excisional biopsy. The SLN was successfully identified in 440 of 466 patients (94.4%). Failure to identify an SLN to the axilla intraoperatively occurred in 26 of 466 patients (5.6%). In all patients who failed lymphatic mappings, a complete axillary dissection was performed, and metastatic disease was documented in 4 of 26 (15.4%) of these patients. Of the 26 patients who failed lymphatic mapping, 11 of 227 (4.8%) were diagnosed by excisional biopsy and 15 of 195 (7.7%) were diagnosed by FNA or stereotactic core biopsy. Of interest, there was only one skip metastasis (defined as a negative SLN with higher nodes in the chain being positive) in a patient with prior excisional biopsy. A mean of 1.92 SLNs were harvested per patient. Twenty percent of the SLNs removed were positive for metastatic disease in 105 of 440 (23.8%) of the patients. Descriptive information on 844 SLNs was evaluated: 339 of 844 (40.2%) were hot, 272 of 844 (32.2%) were blue, and 233 of 844 (27.6%) were both hot and blue. At least one positive SLN was found in 4 of 87 patients (4.6%) with noninvasive (ductal carcinoma in situ) tumors. A greater incidence of positive SLNs was found in patients who had invasive tumors of increasing size: 18 of 112 patients (16%) with tumor size between 0.1 mm and 1 cm had positive SLNs. However, a significantly greater percentage of patients (43 of 131 [32.8%] with tumor size between 1 and 2 cm and 31 of 76 [40.8%] with tumor size between 2 and 5 cm) had positive SLNs. The highest incidence of positive SLNs was seen with patients of tumor size greater than 5 cm; in this group, 9 of 12 (75%) had a positive SLN (p < 0.001). CONCLUSIONS This study demonstrates that accurate SLN identification was obtained when all blue and hot lymph nodes were harvested as SLNs. Therefore, lymphatic mapping and SLN biopsy is most effective when a combination of vital blue dye and radiolabeled sulfur colloid is used. Furthermore, these data demonstrate that patients with ductal carcinoma in situ or small tumors exhibit a low but significant incidence of metastatic disease to the axillary lymph nodes and may benefit most from selective lymphadenectomy, avoiding the unnecessary complications of a complete axillary lymph node dissection.

The role of sentinel lymph node biopsy in patients with ductal carcinoma in situ or with locally advanced breast cancer receiving neoadjuvant chemotherapy

BACKGROUND A significant number of patients who are initially diagnosed with pure DCIS will harbor missed or occult invasive disease at their definitive surgery. To provide more accurate staging information and to avoid a second operation, some investigators believe that SLN mapping should be performed in DCIS patients. The role of SLN biopsy after neoadjuvant chemotherapy in patients with advanced breast cancer is controversial. METHODS A review of the literature was performed to determine the role of SLN biopsy in patients with DCIS or advanced breast cancer receiving neoadjuvant chemotherapy. The success rate of SLN biopsy after neoadjuvant chemotherapy was investigated as well as the percentage of positive SLNs in patients with DCIS. RESULTS Two consecutive studies revealed metastatic disease to the regional lymph nodes in up to 13% of DCIS patients. In addition, 10% of DCIS patients were upstaged to infiltrating ductal carcinoma at their definitive therapy. The ability of the SLN to predict the status of the remaining non-SLNs after neoadjuvant chemotherapy is unknown. False-negative rates range from 0% to 33%. The success rate for SLN identification for the combined series varies from 84% to 97%. CONCLUSIONS SLN biopsy is a minimally invasive technique that can be used to evaluate the regional nodal status of DCIS patients. Performing a SLN biopsy during the initial surgical procedure may avoid a second operation in some DCIS patients who are diagnosed with invasive disease at their definitive operation. The success rate of sentinel node identification does not seem to be altered after neoadjuvant therapy. However, the ability of the SLN to predict the pathologic status of the adjacent non-SLNs remains unknown. Therefore, until further prospective randomized trials are conducted, it cannot be assumed that all the regional nodes have the same biologic response to chemotherapy as the SLN.

Lymphatic mapping in breast cancer

The most accurate predictor of survival in breast cancer is the presence or absence of lymph node metastases. Lymphatic mapping with sentinel node biopsy is a new technique that provides more accurate nodal staging compared with routine histology for women with breast cancer, but without the morbidity of a complete lymph node dissection. Sentinel lymph node (SLN) biopsy is a more conservative approach to the axilla that requires close collaboration from the surgical team, nuclear medicine, and pathology. National trials are investigating the clinical relevance of the upstaging that occurs with a more intense examination of the SLN. As is the case with breast preservation as a viable alternative to mastectomy for the definitive treatment of the primary node, selective lymphadenectomy has the ability to decrease morbidity without compromising patient care.

The staging of malignant melanoma and the florida melanoma trial

Lymphatic mapping and sentinel lymph node (SLN) biopsy have changed the standard of care for patients with malignant melanoma, by providing a less morbid procedure to obtain the nodal staging information that is critical for therapeutic decisions. Detailed examination of the SLN identifies patients who have an increased risk for recurrence and death. Patients whose melanoma is upstaged with very sensitive assays based on reverse transcriptase polymerase chain reaction technology are better targeted for clinical trials or surgical or adjuvant therapies. In the future, melanoma may be “ultrastaged” by examining the SLNs, peripheral blood, and bone marrow. This may improve identification of patients who are surgically cured of their disease and therefore can be spared the side effects of more radical surgery or the toxicities of adjuvant therapy. The lymphatic mapping procedure is the most accurate way to determine the tumor status of the regional lymph nodes.

Molecular staging for patients with malignant melanoma.

Molecular staging of cancers hold the promise of being more accurate compared with routine histology, particularly with regard to determining regional-nodal status. With newer reverse transcriptase-PCR (RT-PCR)-based assays, sensitivities reported are as high as identifying one cancer cell in a background of a million normal cells. Although this sensitivity is 100-times what the human eye can differentiate under the microscope, the new challenge becomes determining the relevance of this low-volume disease in the regional basin, in particular, the sentinel lymph node (SLN). Patients with melanomas greater than 0.75 mm in tumor thickness participated in a research study that examined their SLNs with routine histology, immunhistochemical staining and a RT-PCR assay based on the tyrosinase probe. A total of 311 patients were involved in the study and patients whose SLN were negative from all three assays for metastatic disease had a good survival, with a 92% disease-free survival (DFS) and a 97% overall survival (OS) regardless of the tumor thickness or the ulceration status of the primary melanoma. Patients upstaged with the RT-PCR assay had a significantly decreased DFS and OS compared with patients who were SLN negative. Patients who had enough tumor burden in the SLN that allowed their metastatic disease to be identified with routine histology had a 48% recurrence rate at 5 years. A recently published meta-analysis confirmed that molecular staging of the SLN in melanoma contains important prognostic information. Micrometastatic disease missed by routine histology in the SLN in melanoma patients is clinically relevant disease. Molecular staging has the potential of providing a more accurate staging in the SLN, for prognostication and directing adjuvant therapies.

Molecular Staging of Melanoma

Two papers published in this issue of the Annals of Surgical Oncology involved the emerging field of molecular staging of cancers. For many years investigators have wondered why some patients with melanoma, despite being node negative, recur and die of their disease. Is this due to hematogenous spread from the primary site or perhaps missed micrometastatic disease when the regional basin is sampled? The manuscript by Gradilone and colleagues1 from the University of Rome would suggest that at least some component of these recurrences and deaths are due to missed micrometastatic disease and inaccurate staging in the regional basin. The paper by Ruka et al.,2 from the Skfodouska-Curie Memorial Cancer Center and Institute of Oncology in Poland examined the afferent lymphatic flow into the regional basin after a therapeutic lymph node dissection in patients with melanoma and discovered that some patients shed tumor cells after this operation and those patients are identified to have a worse prognosis. Both groups used the RT-PCR technology, a technology that has the sensitivity of identifying 1 cancer cell in a background of a million normal cells. This sensitivity cannot be matched by routine histology and the human eye under the microscope, which is on the magnitude of being able to identify 1 cancer cell in a background of 10,000 normal lymphocytes. The field of molecular staging for melanoma got its start in 1991 when Smith et al.3 identified circulating tumor cells with a very sensitive RT-PCR assay for tyrosinase. Tyrosinase is an enzyme that catalyzes the first two steps of the biosynthetic pathway of melanin synthesis. All cells in the body have the gene for tyrosinase but only cells that produce pigment, such as melanocytes and melanoma cells, will express the mRNA for this gene. If this gene product is found in the sentinel lymph node (SLN) or afferent lymphatic flow, that is good evidence that metastatic disease exits. The challenge has been to show clinical correlation. In other words, does finding evidence of metastatic disease with RT-PCR assays portend the patient to have a poorer prognosis. Heller and colleagues from the University of South Florida were the first to recognize that routine histologic examination of the regional basin can miss micrometastatic disease.4 Using a simple lymph node culture technique, this group showed that malignant melanoma cells could be grown from lymph nodes called histologic negative by the pathologist. This missed micrometastatic disease was found to be clinically relevant in that these patients up-staged with the method had a significantly higher recurrence rate and poorer survival.5 The tissue culture method proved cumbersome and inefficient in that results were not available for a number of weeks. A more sensitive RT-PCR assay was developed for metastatic melanoma in the SLN6 and approximately 40% of the so-called histologic negative patients were found to have evidence of metastatic disease in their regional basin. Again this missed micrometastasis disease, now termed “submicroscopic disease”, was found to be clinically important in that patients up-staged with the technique had a significantly worse outcome. In multivariate regression analysis that included known prognostic factors for melanoma, including tumor thickness and ulceration, it was the status of the SLN, either determined by routine histology or the RT-PCR assay that was the most important predictor of recurrence and death.7 This finding has now been supported by 6 different laboratories and one national trial throughout the world,8–16 including the recent publication from the University of Rome group. September 10, 2004; September 22, 2004. From the Cutaneous Oncology Program, Lakeland Regional Cancer Center, Lakeland, Florida. Douglas S. Reintgen, MD, Lakeland Regional Cancer Center, 3525 Lakeland Hills Boulevard, PO Box 91057, Lakeland, FL; Fax: 863904-1802; E-mail: doug.reintgen@lrmc.com.

A case report of invasive ductal adenocarcinoma identified in a lymphatic channel: a staging controversy.

A 65-year-old woman underwent core biopsy of a palpable left breast mass. This was a Nottingham grade II invasive ductal carcinoma with lymphovascular invasion. The tumor was ER/PR positive and Her-2/neu negative. The patient agreed to participate in the American College of Surgeon’s Oncology Group Z00100 trial. Two weeks later, the patient underwent a left breast lumpectomy, sentinel lymph node (SLN) biopsy, and bone marrow biopsy. Lymphatic mapping and SLN biopsy were performed utilizing a combination mapping agent technique. Manual intermittent breast massage was performed for 5 minutes after injection of the mapping agents. A single SLN was identified that was both blue and “hot.”