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10.1245/ASO.2004.11.913
Annals of Surgical Oncology 11:236S-241 (2004)
© 2004 Society of Surgical Oncology
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SUPPLEMENT

Minimal Residual Disease Assessment in Sentinel Nodes of Breast and Gastrointestinal Cancer: A Plea for Standardization

Fania S. Doekhie, MD, Koen C. M. J. Peeters, MD, Rob A. E. M. Tollenaar, MD, PhD and Cornelis J. H. van de Velde, MD, PhD

From the Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.

Correspondence: Address correspondence and reprint requests to: Cornelis J. H. Van de Velde, MD, PhD, FRCS, FRCPS, Department of Surgery K6-R, Leiden University Medical Center, P. O. Box 9600, 2300 RC, Leiden, The Netherlands; Fax: 31-71-5266750; E-mail: c.j.h.van_de_velde{at}lumc.nl

ABSTRACT

Lymph node dissection plays an important role in staging and treatment of solid cancers. Sentinel node biopsy (SNB) has been introduced to minimize the extent of surgery and to enable assessment of minimal residual disease (MRD) without compromising accurate staging or survival. This review addresses the variation in technical aspects and outcome of SNB and MRD assessment in patients with breast and gastrointestinal cancer. Quality control leading to standardization of SNB and pathological examination will enable reliable comparison of studies, which is necessary for consensus of diagnostic and therapeutic strategies.

Key Words: Breast cancer • Colorectal cancer • Gastric cancer • Micrometastases • Minimal residual disease • Sentinel node

The histological status of lymph nodes is one of the most important prognostic indicators in patients with cancer originating from solid tumors. Staging cancer to determine the need for adjuvant therapy presently occurs through lymphadenectomy. Lymphadenectomy is a staging tool that may also have therapeutic value, even in patients without nodal involvement by standard pathological methods.1,2 In colorectal cancer patients without nodal involvement, overall survival improves with increasing number of lymph nodes recovered.3 Also, in invasive bladder cancer, both node-negative and node-positive patients had prolonged overall survival with an increasing number of lymph nodes examined.4 This benefit is possibly due to the presence of minimal residual disease (MRD) in hematoxylin and eosin (H&E)-negative lymph nodes.

Lymphadenectomy may be associated with considerable morbidity, especially in breast cancer and melanoma patients. To minimize the extent of lymphadenectomy without compromising accurate staging and survival, sentinel node biopsy (SNB) has been introduced. Sentinel nodes are the first possible sites of metastasis along the route of lymphatic drainage from a primary tumor. The histopathological state of the sentinel node is presumed to reflect that of all regional lymph nodes. SNB can be performed by injecting a vital dye, a radioactive colloid, or both around the primary tumor. Techniques vary substantially between institutions and researchers, however, which complicates reliable assessment of the role of SNB.

An advantage of SNB is the lower number of lymph nodes that have to be examined compared with regional lymph node dissection. Laborious and expensive focused examination techniques like immunohistochemistry (IHC) and reverse transcriptase polymerase chain reaction (RT-PCR) can therefore be applied in a limited number of sentinel nodes to detect the presence of so-called minimal residual disease, comprising micrometastases and isolated tumor cells. Micrometastases are defined as a cohesive cluster of malignant cells, from 0.2 mm to 2.0 mm in diameter. Micrometastases and isolated tumor cells are usually not detected with conventional pathological examination techniques. The prognostic significance of micrometastases and the therapeutic consequences of upstaging by MRD assessment, however, are far from clear. Nevertheless, in some countries treatment decisions are already based on MRD assessment, implying possible overtreatment. This review addresses the role of SNB and MRD in (sentinel) lymph nodes in breast, gastric, and colorectal carcinoma and pleads for standardized and randomized trials in this field.

BREAST CANCER

Axillary lymph node dissection (ALND) contributes to both treatment and staging. Overgaard et al.5 reported large differences in local recurrence rates in a trial investigating the efficacy of radiotherapy following total mastectomy. There were clear variations in the extent and quality of surgery, because more than half of the local recurrences appeared on the chest wall. It was concluded that radiotherapy after surgery improved local control. However, if surgical procedures improve, the benefits of standard radiotherapy might be questionable. It is clear that the quality of surgery dictates the value of adjuvant treatment. This stresses the need for standardized and quality-controlled SNB, because staging and treatment decisions depend on removing and investigating only one or a few sentinel nodes. Currently, most centers use a combination of radioactive tracer and blue dye, which improves the identification of multiple sentinel lymph nodes in comparison with the use of one tracer alone.6 Table 1 highlights studies published since 1998 on SNB in breast cancer patients; each study included more than 100 patients. Most centers use the combination of blue dye and radioactive colloid to detect sentinel nodes. Considerable variation in the volume of tracer used and the technique for examination of resected sentinel nodes might explain different success and false-negative rates. The site of injection is often inaccurately reported, and it remains unclear whether massage has been performed.


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  		TABLE 1. An overview of the sentinel node (SN) biopsy studies in breast cancer
 
In focused-examination studies of H&E-negative lymph nodes, there is considerable variation in the technique, marker, or antibody used and in the data analysis. Dowlatshahi7,8 showed upstaging by serial sectioning and immunohistochemistry of 9% to 33%. The clinical relevance of MRD assessment is debatable. Studies that showed a survival disadvantage due to the presence of micrometastases had larger populations (range, 147 to 921 patients) and longer follow-up (at least 6 years) than studies that did not show any survival difference. Moreover, most studies did not consider the size of the micrometastases, even though the size of nodal metastases linearly correlates with survival.8 Also, the role of isolated tumor cells in lymph nodes has not been determined.9 It might be difficult to distinguish isolated tumor cells from mesenchymal cells, mesothelial cells, and contamination by benign or malignant epithelium. These technical difficulties are probably common but are infrequently reported.

MRD assessment in sentinel nodes with immunohistochemistry and serial sectioning reveals a higher detection rate of micrometastases in sentinel nodes than in the regional lymph nodes.10 This is in line with the sentinel node hypothesis. An overview study showed that in 38% to 67% of patients with breast cancer the sentinel node is the only involved lymph node.11 When the sentinel node is the only involved lymph node it can be argued that ALND is not necessary. In the AMAROS (After Mapping of the Axilla Radiotherapy Or Surgery) Trial, coordinated by the European Organization for Research and Treatment of Cancer, patients with positive sentinel nodes are randomized to ALND or axillary radiotherapy. The presence of any tumor deposit, detected with either H&E staining or IHC, has consequences for the local treatment of the axilla (i.e., surgery or radiotherapy) but not for systemic treatment. Recently, concern has been expressed that many pathology laboratories have adopted IHC techniques and many oncologists recommend adjuvant chemotherapy upon IHC-detected metastases only.12 Giving patients a toxic and often expensive treatment with possibly limited benefits, on the basis of IHC findings alone, is not supported by the literature and should therefore not be encouraged.

It can be concluded that SNB for breast cancer is presently performed with acceptable success rates and low false-negative rates despite considerable variation in SNB techniques. Special techniques to detect micrometastases can lead to upstaging in a considerable number of patients, but it remains unclear whether these findings should affect the choice of adjuvant treatment.

GASTRIC CANCER

The widespread use of gastroscopy has increased identification of gastric cancer at an early stage. Nodal involvement occurs in only 2% to 18% of T1 tumors and in about 50% of T2 tumors.13 This means that a larger-than-necessary lymphadenectomy is performed in a substantial number of patients. The debate on the benefits of D1 compared with D2 lymph node dissection is still ongoing. Furthermore, the value of adjuvant therapy in relation to the extent of surgery is intensely discussed.14 An extended lymphadenectomy is associated with considerable postoperative morbidity and mortality, especially in Western countries.15,16 However, reliable tools are lacking to predict nodal involvement. SNB might minimize the surgical procedure and predict the status of nonsentinel nodes.

The studies on feasibility of SNB in gastric cancer are rather limited. Table 2 shows that different types of tracers are being used and different numbers of SNs are retrieved. Moreover, IHC was applied in only one of these SNB studies.17 Endoscopic submucosal injection is feasible for administration of a radioactive tracer or a dye. Identification of the sentinel node by means of a radiolabeled colloid and perioperative detection with a gamma probe has the drawback of detecting radiation not only from lymph nodes but also from the adjacent injection site. Therefore, most experience has been gained with the application of dyes. All the displayed studies, initiated in the Far East, showed acceptable feasibility in early-stage disease (i.e., T1 or T2). In Western countries, however, gastric cancer is often diagnosed at an advanced stage, potentially limiting the role of SNB in these patients.


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  		TABLE 2. An overview of the sentinel node (SN) biopsy studies in gastric cancer
 
In Table 3, three of five IHC studies using anticytokeratin antibodies showed an adverse effect of micrometastases on survival. There are remarkable differences in the antibodies used, the number of resected lymph nodes, and the proportion of patients upstaged. Noguchi et al.18 reported that RT-PCR with keratin 19 was more sensitive than histological examination for the detection of gastric micrometastases in lymph nodes. However, the prognostic significance of micrometastases detected with this technique was not addressed.


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  		TABLE 3. Immunohistochemistry studies on H&E-negative lymph nodes in gastric cancer
 
The majority of the reports on gastric carcinoma originate from specialized centers that have gained experience with the technically demanding procedure in a patient population less prone to postoperative morbidity and mortality than in Europe and the United States.

In conclusion, the initial and limited experience indicates that SNB has potential value in staging and treating gastric cancer. However, only patients with early-stage disease, a patient category not very often encountered in Western populations, may benefit from SNB. Moreover, the existing variation in technical aspects of SNB and MRD assessment hampers the introduction of treatment decisions based on MRD assessment.

COLORECTAL CANCER

The treatment of node-negative colorectal cancer consists of surgical resection of the primary tumor without adjuvant therapy. However, up to 30% of these patients will develop metastases, possibly due to micrometastases in the regional lymph nodes. We showed that patients with carcinoembryonic antigen (CEA) RT-PCR–negative lymph nodes had a significantly better five-year disease-free survival than patients with positive lymph nodes (91% versus 50%; P = .02).19 Three other RT-PCR studies20–22 also showed an adverse effect on prognosis, whereas only three of 10 immunohistochemistry studies showed an adverse effect.22,23 Again, the IHC studies show clear variation in the number of resected lymph nodes, the use of serial sectioning and antibodies, and the degree of upstaging, which ranges from 10% to 76%.22,24–32

Noura et al.22 studied the same paraffin-embedded lymph nodes with CEA RT-PCR and cytokeratin immunohistochemistry and showed that CEA RT-PCR had prognostic value, whereas immunohistochemistry did not.

SNB in colorectal cancer patients is still under development. In contrast to breast cancer, SNB is not performed in colorectal cancer to avoid unnecessary lymphadenectomy but to enable focused examination of a few lymph nodes. An important consequence of intraoperative SNB in colorectal cancer patients is the identification of aberrant lymphatic drainage patterns in up to 14% of the patients, leading to an adjustment of the initial surgical resection plan.33,34 Table 4 summarizes studies that examined SNB in more than 25 patients with colorectal cancer. Blue dye was used in most of the studies, with moderate variations in volume and site of injection. However, there is a wide range in the number of detected SNs. Success rates, false-negative rates, and upstaging techniques vary and are influenced by disease stage. In rectal cancer, the dye method is limited by restricted visibility of the dye as it moves into the SNs.35


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  		TABLE 4. An overview of the sentinel lymph node (SLN) biopsy studies in colorectal cancer
 
In summary, SNB in colorectal cancer patients is a technically demanding procedure with variable success rates. Although MRD assessment can lead to profound upstaging, there is no clear evidence that it should affect adjuvant treatment decisions. Still, in some countries colorectal cancer patients with sentinel node micrometastases are receiving systemic adjuvant therapy. Optimization of SNB and MRD assessment techniques may lead to more tailored adjuvant treatment.

CONCLUSION

Limiting the extent of surgery in the treatment of solid tumors through SNB is technically feasible. However, comparison of the studies reveals variations in patient selection and in the type, volume, and injection site of tracers. These variations complicate trial comparison, which hampers application of SNB in daily practice. Minimal residual disease assessment by serial sectioning, immunohistochemistry, and RT-PCR is possible and may lead to considerable upstaging. The results from studies addressing the prognostic role of micrometastases are often contradictory, which might be due to the use of different examination techniques, markers, antibodies and differences in sample size and length of follow-up. This variation in techniques of SNB and MRD assessment will delay the development of evidence-based diagnostic and therapeutic guidelines in the near future. Quality control leading to standardization of SNB and MRD assessment is necessary to enable reliable comparison of different studies. Only in this way can we determine the prognostic role of MRD and tailor adjuvant treatment on the basis of MRD assessment of lymph nodes retrieved after limited surgery.

ACKNOWLEDGMENTS

Koen C. M. J. Peeters, MD, is a EORTC Medical Research Fellow and is financially supported by the EORTC.

The acknowledgments are available online in the fulltext version at www.annalssurgicaloncology.org. They are not available in the PDF version.

FOOTNOTES

This review addresses the variation in technical aspects and outcome of sentinel node biopsy (SNB) and minimal residual disease assessment in patients with breast and gastrointestinal cancer. Quality control leading to standardization of SNB and pathological examination will enable reliable comparison of studies, which is necessary for consensus of diagnostic and therapeutic strategies.

Received for publication October 28, 2003. Accepted for publication November 17, 2003.

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