Detecting Metastatic Disease in Breast Cancer Patients
Detecting Metastatic Disease in Breast Cancer Patients
The current standard of care for the surgical management of invasive breast cancer is the complete removal of the tumor, with documentation of negative margins by either mastectomy or lumpectomy followed by complete axillary lymph node dissection. However, lymphatic mapping of the breast has the potential of changing the standard of surgical care of the breast cancer patient. From April 1994 to April 1998, 700 patients presenting to the H. Lee Moffitt Cancer Center with breast cancer were enrolled in an Institutional Review Board-approved study that investigated lymphatic mapping and sentinel lymph node (SLN) biopsy.
Lymphatic mapping was performed using a combination of isosulfan blue dye and technetium Tc 99m sulfur colloid. Excised SLNs were examined using cytokeratin immunohistochemical stains in addition to the routine histologic evaluation. The SLNs were successfully identified in 665 (95.0%) of 700 patients. In 186 patients who underwent a complete lymph node dissection in addition to the SLN biopsy, 1 patient had skip metastasis. Blue dye identified SLNs in 533 (76.1%) of 665 patients and radiocolloid identified SLNs in 631 (90.1%) of 665 patients. Tumor size did not significantly affect lymphatic mapping, and the biopsy method only weakly correlated with lymphatic mapping.
We conclude that the technique of lymphatic mapping and SLN biopsy is a useful new tool in the surgical treatment of breast cancer, and that with adequate training and proper use it provides a safer, more cost-effective, and perhaps more accurate method of staging the axilla of the breast cancer patient.
The surgical approach to treating women with breast cancer is rapidly evolving. Some factors influencing these changes include altered disease demographics, advances in technology, governmental and reimbursement controls, and growing public expectations. As an increasing number of baby boomers reach 50 years of age, many more women will be at risk for breast cancer. A dramatic rise in the incidence of breast cancer is projected, from 185 000 cases to 420 000 annually during the next 20 years.
Since the time of Halsted, the status of the regional nodal basin has been the most important prognostic indicator of survival. During the past several years, factors such as tumor size, tumor grade, S-phase fraction, DNA index, tumor ploidy, estrogen and progesterone receptor status, and HER2/neu expression have been studied to determine their prognostic value. Although many of these factors are valuable in guiding the choice of adjuvant therapy, none reliably identifies metastatic potential of individual tumor cells. Thus, it remains important to identify those patients with nodal involvement to define their prognosis. Data suggest that removal of the axillary contents provides better local control of the disease but may not in itself offer a survival advantage. The current standard of care for the surgical management of invasive breast cancer is the complete removal of the tumor, with documentation of negative margins by either mastectomy or lumpectomy followed by complete axillary lymph node dissection (ALND). Lymphatic mapping of the breast is clearly changing this long-held paradigm and has the potential of changing the standard of surgical care of the breast cancer patient.
The concept of the sentinel lymph node (SLN) as the first lymph node(s) in the direct drainage pathway from the primary tumor was first developed in melanoma patients with the pioneering work of Morton and colleagues at the John Wayne Cancer Institute. Several investigators have since demonstrated that the concept of lymphatic mapping and SLN biopsy applies equally well to breast cancer. SLN biopsy offers its foremost advantage in nodal staging by allowing a more focused examination of the lymph node at greatest risk for metastatic disease. The pathologist can perform a more detailed examination of the SLN by serially sectioning and applying immunohistochemical (IHC) stains to the specimens, thereby enhancing the detection of nodal metastatic disease. In addition, molecular biology techniques such as reverse-transcriptase polymerase chain reactions (RT-PCR) may further enhance the detection of "submicroscopic" disease.
The importance of serially sectioning SLNs and performing IHC staining of these lymph nodes cannot be underestimated. The current research work focusing on the sensitivity and specificity of detecting micrometastatic nodal disease will become the springboard for the next decade of breast cancer research.
For lymphatic mapping and SLN biopsy to maximally affect the management of breast cancer patients, the following observations must be widely accepted:
The surgical management of breast cancer has evolved dramatically during the 20th century. In the early 1900s, Halsted proved the feasibility and the utility of radical and ultraradical surgery in the treatment of invasive breast cancer. Studies by Patey and coworkers and subsequently by Veronesi and colleagues and Fisher and associates in the middle to late 1900s have caused the pendulum to swing toward less invasive surgical procedures. The continued interest in less extensive surgery, the need for faster recovery, and the increasing demand for outpatient treatment have brought the value of ALND into close scrutiny.
Not only does ALND have the potential for producing a wide spectrum of complications, such as paresthesia due to costobrachial nerve injury, wound infection, seroma, drain complications, and acute and chronic lymphedema, it also may result in acute treatment delays. Historically, approximately 40% of patients treated with complete ALND (defined as a dissection of all nodes in levels I, II, and III) develop acute lymphedema, and approximately 5% to 10% of patients experience chronic lymphedema. New data suggest that although limiting axillary dissection to levels I and II only has not changed the 40% incidence of acute lymphedema, the incidence of chronic lymphedema has decreased to 5%. The increased scrutiny given to axillary dissection is due, in part, to the lack of an effective treatment for chronic lymphedema. Interestingly, the most significant complaint by patients following breast cancer surgery is the morbidity associated with axillary dissection.
Controversy now rages over the current role of axillary dissection in the management of operable breast cancer. Indeed, trials are under way to eliminate ALND in patients with small (< 1 cm) invasive primary breast cancers who are at a less than 10% risk for axillary nodal metastases. Advocates of axillary dissection stress that the status of the regional nodal basin remains the most important independent variable of predicting prognosis. They also contend that the procedure benefits patients by producing regional control of axillary disease. Proponents also argue that surgical removal of microscopic nodal metastases is often curative without adjuvant chemotherapy in certain patient populations.
Critics of axillary dissection maintain that overall survival depends on the development of distant metastases and is not influenced by axillary dissection in most patients. They contend that patients with microscopic axillary metastases may be cured with adjuvant chemotherapy with or without nodal irradiation in the absence of axillary dissection. Many have even advocated the abandonment of axillary dissection in early breast cancer. Adding fuel to the debate is the fact that the procedure of axillary sampling has been notoriously unreliable, giving a high rate of false-negative sampling.
These controversies notwithstanding, the status of the regional nodal basin remains the most important independent prognostic factor of survival for breast cancer patients. Therefore, eliminating ALND poses some serious concerns for the diagnosis, staging, and treatment planning of breast cancer patients. First, cancer stage defines outcomes. Abandonment of the statistically most defining criteria of outcome (ie, nodal metastases) defies historical logic. The disregard of surgical staging, combined with the use of adjuvant therapies in all patients, may result in greater long-term morbidity (eg, leukemia and heart failure) in the entire population of patients and thus generate significantly greater costs for the health care system. Second, the assertion that micrometastatic disease carries no therapeutic significance has been shown to be false. Excellent studies have clearly demonstrated outcome differences when micrometastatic disease is detected. Lymphatic mapping and sentinel node evaluation now provide effective tools for more efficiently defining the subset of patients with micrometastatic disease and therefore may redefine the role of adjuvant chemotherapy. Finally, outcomes are not rapidly known in breast cancer management. Therefore, proposed radical alterations in treatment, such as the elimination of ALND, should be eschewed in favor of more prudent changes, such as the substitution of a less morbid procedure, ie, SLN mapping.
The following describes our lymphatic mapping experience at the H. Lee Moffitt Cancer Center and Research Institute with 700 breast cancer patients.
The current standard of care for the surgical management of invasive breast cancer is the complete removal of the tumor, with documentation of negative margins by either mastectomy or lumpectomy followed by complete axillary lymph node dissection. However, lymphatic mapping of the breast has the potential of changing the standard of surgical care of the breast cancer patient. From April 1994 to April 1998, 700 patients presenting to the H. Lee Moffitt Cancer Center with breast cancer were enrolled in an Institutional Review Board-approved study that investigated lymphatic mapping and sentinel lymph node (SLN) biopsy.
Lymphatic mapping was performed using a combination of isosulfan blue dye and technetium Tc 99m sulfur colloid. Excised SLNs were examined using cytokeratin immunohistochemical stains in addition to the routine histologic evaluation. The SLNs were successfully identified in 665 (95.0%) of 700 patients. In 186 patients who underwent a complete lymph node dissection in addition to the SLN biopsy, 1 patient had skip metastasis. Blue dye identified SLNs in 533 (76.1%) of 665 patients and radiocolloid identified SLNs in 631 (90.1%) of 665 patients. Tumor size did not significantly affect lymphatic mapping, and the biopsy method only weakly correlated with lymphatic mapping.
We conclude that the technique of lymphatic mapping and SLN biopsy is a useful new tool in the surgical treatment of breast cancer, and that with adequate training and proper use it provides a safer, more cost-effective, and perhaps more accurate method of staging the axilla of the breast cancer patient.
The surgical approach to treating women with breast cancer is rapidly evolving. Some factors influencing these changes include altered disease demographics, advances in technology, governmental and reimbursement controls, and growing public expectations. As an increasing number of baby boomers reach 50 years of age, many more women will be at risk for breast cancer. A dramatic rise in the incidence of breast cancer is projected, from 185 000 cases to 420 000 annually during the next 20 years.
Since the time of Halsted, the status of the regional nodal basin has been the most important prognostic indicator of survival. During the past several years, factors such as tumor size, tumor grade, S-phase fraction, DNA index, tumor ploidy, estrogen and progesterone receptor status, and HER2/neu expression have been studied to determine their prognostic value. Although many of these factors are valuable in guiding the choice of adjuvant therapy, none reliably identifies metastatic potential of individual tumor cells. Thus, it remains important to identify those patients with nodal involvement to define their prognosis. Data suggest that removal of the axillary contents provides better local control of the disease but may not in itself offer a survival advantage. The current standard of care for the surgical management of invasive breast cancer is the complete removal of the tumor, with documentation of negative margins by either mastectomy or lumpectomy followed by complete axillary lymph node dissection (ALND). Lymphatic mapping of the breast is clearly changing this long-held paradigm and has the potential of changing the standard of surgical care of the breast cancer patient.
The concept of the sentinel lymph node (SLN) as the first lymph node(s) in the direct drainage pathway from the primary tumor was first developed in melanoma patients with the pioneering work of Morton and colleagues at the John Wayne Cancer Institute. Several investigators have since demonstrated that the concept of lymphatic mapping and SLN biopsy applies equally well to breast cancer. SLN biopsy offers its foremost advantage in nodal staging by allowing a more focused examination of the lymph node at greatest risk for metastatic disease. The pathologist can perform a more detailed examination of the SLN by serially sectioning and applying immunohistochemical (IHC) stains to the specimens, thereby enhancing the detection of nodal metastatic disease. In addition, molecular biology techniques such as reverse-transcriptase polymerase chain reactions (RT-PCR) may further enhance the detection of "submicroscopic" disease.
The importance of serially sectioning SLNs and performing IHC staining of these lymph nodes cannot be underestimated. The current research work focusing on the sensitivity and specificity of detecting micrometastatic nodal disease will become the springboard for the next decade of breast cancer research.
For lymphatic mapping and SLN biopsy to maximally affect the management of breast cancer patients, the following observations must be widely accepted:
Refinements in micrometastatic detection of nodal disease have already been developed and tested in the solid tumor system of melanoma; the trials need not be repeated for breast cancer.
Lymphatic mapping of breast cancer is sensitive and specific for identifying the specific node(s) at risk for micrometastases.
The sensitivity of nodal detection of micrometastases in breast cancer is of paramount importance because the follow-up required for clinical detection of any nodal recurrence is extremely lengthy and may carry a high morbidity if left undetected.
Micrometastatic disease of lymph nodes in breast cancer has clinical significance for survival.
The RT-PCR technology may further refine the ability to detect the patients at risk for metastatic disease, thereby affecting which patients are subjected to adjuvant therapies.
The surgical management of breast cancer has evolved dramatically during the 20th century. In the early 1900s, Halsted proved the feasibility and the utility of radical and ultraradical surgery in the treatment of invasive breast cancer. Studies by Patey and coworkers and subsequently by Veronesi and colleagues and Fisher and associates in the middle to late 1900s have caused the pendulum to swing toward less invasive surgical procedures. The continued interest in less extensive surgery, the need for faster recovery, and the increasing demand for outpatient treatment have brought the value of ALND into close scrutiny.
Not only does ALND have the potential for producing a wide spectrum of complications, such as paresthesia due to costobrachial nerve injury, wound infection, seroma, drain complications, and acute and chronic lymphedema, it also may result in acute treatment delays. Historically, approximately 40% of patients treated with complete ALND (defined as a dissection of all nodes in levels I, II, and III) develop acute lymphedema, and approximately 5% to 10% of patients experience chronic lymphedema. New data suggest that although limiting axillary dissection to levels I and II only has not changed the 40% incidence of acute lymphedema, the incidence of chronic lymphedema has decreased to 5%. The increased scrutiny given to axillary dissection is due, in part, to the lack of an effective treatment for chronic lymphedema. Interestingly, the most significant complaint by patients following breast cancer surgery is the morbidity associated with axillary dissection.
Controversy now rages over the current role of axillary dissection in the management of operable breast cancer. Indeed, trials are under way to eliminate ALND in patients with small (< 1 cm) invasive primary breast cancers who are at a less than 10% risk for axillary nodal metastases. Advocates of axillary dissection stress that the status of the regional nodal basin remains the most important independent variable of predicting prognosis. They also contend that the procedure benefits patients by producing regional control of axillary disease. Proponents also argue that surgical removal of microscopic nodal metastases is often curative without adjuvant chemotherapy in certain patient populations.
Critics of axillary dissection maintain that overall survival depends on the development of distant metastases and is not influenced by axillary dissection in most patients. They contend that patients with microscopic axillary metastases may be cured with adjuvant chemotherapy with or without nodal irradiation in the absence of axillary dissection. Many have even advocated the abandonment of axillary dissection in early breast cancer. Adding fuel to the debate is the fact that the procedure of axillary sampling has been notoriously unreliable, giving a high rate of false-negative sampling.
These controversies notwithstanding, the status of the regional nodal basin remains the most important independent prognostic factor of survival for breast cancer patients. Therefore, eliminating ALND poses some serious concerns for the diagnosis, staging, and treatment planning of breast cancer patients. First, cancer stage defines outcomes. Abandonment of the statistically most defining criteria of outcome (ie, nodal metastases) defies historical logic. The disregard of surgical staging, combined with the use of adjuvant therapies in all patients, may result in greater long-term morbidity (eg, leukemia and heart failure) in the entire population of patients and thus generate significantly greater costs for the health care system. Second, the assertion that micrometastatic disease carries no therapeutic significance has been shown to be false. Excellent studies have clearly demonstrated outcome differences when micrometastatic disease is detected. Lymphatic mapping and sentinel node evaluation now provide effective tools for more efficiently defining the subset of patients with micrometastatic disease and therefore may redefine the role of adjuvant chemotherapy. Finally, outcomes are not rapidly known in breast cancer management. Therefore, proposed radical alterations in treatment, such as the elimination of ALND, should be eschewed in favor of more prudent changes, such as the substitution of a less morbid procedure, ie, SLN mapping.
The following describes our lymphatic mapping experience at the H. Lee Moffitt Cancer Center and Research Institute with 700 breast cancer patients.
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