Regional node dissection for melanoma: techniques and indication.

Because virtually all microscopic nodal disease left untreated in melanoma patients will progress to clinically apparent macroscopic nodal disease, there is worse prognosis with macroscopic nodal disease, and ineffective systemic treatment currently exists, one must be cautious in favoring an observation approach to the regional basin in patients with a positive sentinel lymph node (SLN) in the hopes of avoiding the potential morbidity of a therapeutic node dissection. In the few patients with untreated microscopic nodal disease, the prognosis will be significantly worsened. Until further data are available, melanoma patients with a positive SLN by H&E analysis should proceed to a complete lymph node dissection.

Worldwide experience with lymphatic mapping for invasive breast cancer.

Lymphatic mapping and sentinel lymph node (SLN) biopsy have changed the standard of surgical care for women with invasive breast cancer. The rate of successful axillary SLN identification varies from 90% to 99%. Recurrence rates after a negative SLN biopsy have been remarkably low. Internal mammary node drainage has been noted in 8% to 22% of cases, but whether to harvest these extra-axillary sites of drainage remains controversial. Because of the low morbidity associated with the lymphatic mapping procedure, all women with invasive breast cancer should be considered as candidates for this more accurate staging technique.

National trials involving lymphatic mapping for melanoma: the Multicenter Selective Lymphadenectomy Trial, the Sunbelt Melanoma Trial, and the Florida Melanoma Trial.

Radioguided surgery and lymphatic mapping provide more accurate staging and a less morbid operation for the patient with malignant melanoma. It has rapidly become the standard of care for the nodal staging of this disease. Regional and national trials have been designed to address various questions that concern the application of this technique. The Multicenter Selective Lymphadenectomy Trial (MSLT), being performed by Donald Morton at the John Wayne Cancer Institute, is a national trial that will address whether this surgical strategy provides a survival benefit for patients. The national, industry-sponsored SunBelt Melanoma Trial (SBMT), with Kelly McMasters from the University of Louiville as the principle investigator, will determine the role of molecular staging in patients who undergo sentinel lymph node (SLN) harvest. In another arm of the study, the role of adjuvant interferon alfa (IFN) will be examined in patients with minimal disease in the regional basin, those patients with just one microscopically positive SLN. Finally, the Florida Melanoma Trial (FMT), with the central office and laboratory located at the Lakeland Regional Cancer Center, is a regional, industry-sponsored trial that will determine whether all patients with a positive SLN need to undergo a complete lymph node dissection (CLND) of the affected basin. Clinicians await the results of these three trials to help to determine the final role of radioguided surgery in patients with malignant melanoma.

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.

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.

Current status of sentinel lymph node mapping and biopsy: facts and controversies.

Lymphatic mapping and sentinel lymph node biopsy were first reported in 1977 by Cabanas for penile cancer. Since that time, the technique has become rapidly assimilated into clinical practice. Morton first described the application of lymphatic mapping for melanoma only a decade ago, and this technique is now accepted as the standard of care. The application for lymphatic mapping and sentinel lymph node biopsy in breast cancer remains approximately 5 years behind its utilization in melanoma. This technique has the potential to be utilized in all solid tumors. The rapid assent of this technique in clinical practice is the result of multiple factors, including accuracy, decreased morbidity, and supplying the pathologist with only a few nodes to allow a more focused and sensitive pathologic evaluation. Despite the success and acceptance of lymphatic mapping, many controversies remain. We have attempted to clearly highlight these controversies in this review.

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.

CTLA-4 blockade enhances the therapeutic effect of an attenuated poxvirus vaccine targeting p53 in an established murine tumor model.

p53 is overexpressed by half of all cancers, and is an attractive target for a vaccine approach to immunotherapy. p53 overexpression is frequently the result of point mutations, which leaves the majority of the protein in its wild-type form. Therefore, the majority of p53 sequence is wild type, making it a self-protein for which tolerance plays a role in limiting immune responses. To overcome tolerance to p53, we have expressed wild-type murine p53 in the nonpathogenic attenuated poxvirus, modified vaccinia virus Ankara (recombinant modified vaccinia virus Ankara expressing wild-type murine p53 (rMVAp53)). Mice immunized with rMVAp53 vaccine developed vigorous p53-specific CTL responses. rMVAp53 vaccine was evaluated for its ability to inhibit the outgrowth of the syngeneic murine sarcoma Meth A, which overexpresses mutant p53. Mice were inoculated with a lethal dose (5 x 10(5) cells injected s.c.) of Meth A tumor cells and vaccinated by i.p. injection 3 days later with 5 x 10(7) PFU of rMVAp53. The majority of mice remained tumor free and resistant to rechallenge with Meth A tumor cells. We wished to determine whether rMVAp53 immunization could effect the rejection of an established, palpable Meth A tumor. In subsequent experiments, mice were injected with 10(6) Meth A tumor cells, and treated 6 days later with anti-CTLA-4 Ab (9H10) and rMVAp53. The majority of treated mice had complete tumor regression along with lasting tumor immunity. In vivo Ab depletion confirmed that the antitumor effect was primarily CD8 and to a lesser extent CD4 dependent. These experiments demonstrate the potential of a novel cell-free vaccine targeting p53 in malignancy.