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Blog aimed at residents in surgery
 URL :  www.surgical-oncology.net             e mail surgoncnet@gmail.com
The Sentinel Node definition: updating.

Romeo Giuli MD, resident.
School of General and Emergency Surgery.
University of Siena.   Italy.



December 2001.     Review Article.     To previous article about sentinel node definition.

The development of SNL represents a major advance in the evaluation and management of solid tumors.
The improvements in cancer staging will improve both clinical decision-making and the accuracy and comparability of cancer clinical trials.
The use of SNL provides a minimally invasive way to detect nodal metastases, thus defining a group of node-negative patients who may be spared radical lymphadenectomy. Moreover it may provide earlier recognition of nodal metastases compared with clinical or radiological assessment and thus facilitate therapeutic lymphadenectomy because of lower volume of disease.
The staging accuracy and reproducibility of SNL creates a more homogeneous group of node-negative patients for entry onto new clinical trials and at the same time creates a group of microscopically node-positive patients who may have a prognosis that differs from patients who are macroscopically node positive.
The SNL technique facilitates a more accurate pathological staging and, as a consequence, contributes to a significant upstaging of patients. With serial sections and immunohistochemistry, there is an increase in node positive by as much as 50% due to improved staging, compared with the conventional method of examining a single section of a bivalved lymph node solely with routine staining. It is likely to improve the accuracy of staging, because of the opportunity to detect sentinel nodes located outside of conventionally defined lymph node basins.
Biologically, the use of this technology has given new insights into lymphatic drainage patterns and provides a new tool for the investigation of the biology of metastases.
However the need for ongoing study of the sentinel node technique and of associated clinical decision-making is clear. Widespread participation in current and future trials is essential for safe and rational integration of SNL into routine practice ( 1 ).

In addition studies have shown that radical tumor-draining regional lymph node dissections exert a markedly negative influence on the efficacy of postoperative immuno-therapy in animal models and humans. Certainly it would be an advantage to the patient to avoid such risks if there could be reasonable certaity that the axillary nodes were tumor-negative ( 2 ).

Glass reaffirms that is now established that the early lymphatic spread of malignant tumors occurs not just randomly to any nearby nodes, but instead to specific (sentinel) nodes that lie in the direct lymphatic drainage pathway from any individual tumor. Radionuclides provide an excellent method of determining these specific pathways of tumor drainage in an individual patient.
Essential to all sentinel node procedures are accurate localization and removal of the correct ( sentinel ) node. It is the responsibility of the nuclear medicine physician, before surgery, to identify both the relevant basins of drainage and the individual nodes within the basins.
Preoperative lymphoscintigraphy, not just intraoperative probe localization, is essential for this task for several reasons. Preoperative localization of the node and lymphatic basins can shorten and simplify surgical removal. The temporal sequence of nodal uptake must be known to distinguish which hot nodes are truly sentinel, and the probe alone cannot make this distinction. Anatomic proximity is not a reliable method for identifying sentinel nodes, and probes are not well suited for body surveys. Subsequently radiosensitive probes can enhance accuracy by providing operative guidance and confirmation of removal of the sentinel, or hot, node.
Most radiopharmaceuticals now used for lymphoscintigraphy are colloidal in nature and are labeled with 99m Tc. Desirable properties of radiopharmaceuticals include rapid migration, good retention in the first (sentinel) node, no egress from lymphatic vessels, minimal spillover into nonsentinel nodes, and low radiation dose to the patient.
Intradermal rather than subcutaneous injections are used for melanoma, and intraparenchimal injections are preferred for breast cancer. Imaging with a scintillation camera should begin immediately, to identify lymph channels and to identify the first (sentinel) nodes.
Because of the local retention of the interstitially injected doses, local radiation doses from lymphoscintigraphy are not trivial if the injection site is not excised ( 3 ).

Waddington et al stress that high sensitivity, reproducibility, and accuracy levels must be achieved in the identification and discrimination of the SLN if the extent and place of the standard lymph node diagnostic dissections can be challanged.
Successful detection of the SLN at operation depends on good technique for the detection of often occult radioactive foci in vivo ad on optimal detector performance. The detection task is simple but deceptively difficult to realize consistently in practice. If preoperative imaging is omitted, then the task is hampered significantly by the need to initiate detection from a blind, transcutaneous approach. Small, often weakly active foci must be precisely localized in vivo in an environment that is negligibly radioactive but frequently anatomically complex and in close proximity to an extensive injection site with significantly higher radioactive content. Imaging enables the SLN to be localized before surgery and permits the entire lymphatic basins to be studied comprehensively. However for the SLNs to distinguished with maximal specificity from second-echelon or spillover nodes or other foci for tracer retention, the draining lymphatic ducts must be visualized. Multimodality imaging instruments now exist. A dual-detector gamma camera has recently been developed onto which an x-ray computed tomography (CT ) tube is mounted to allow both x-ray CT transmission data and single photon emission tomography ( SPET ) data to be acquired in a single imaging session, without patient movement between scans. This hybrid imaging system offers sentinel node imaging the ability to localize anatomically the radiolabeled sentinel node with the excellent resolution characteristic of CT ( 4 ).

Cochran et al affirm that the SN is the first lymph node on the direct lymphatic drainage path from the primary tumor. This node is uniquely immune-modulated by the primary tumor and is the node most likely to contain the earliest stages of metastases. Accurate assessment of the SN requires careful evaluation of multiple sections removed from the areas of the node most likely to contain tumor. These sections are stained with hematoxilyn and eosin and by immunohistochemistry with antibodies directed to tumor-associated markers ( S-100, HMB-45, and Melan- A/MART-1) in the case of melanoma and to cytokeratins for breast cancer.
The authors use formalin-fixed and paraffin-embedded permanent sections. The interpretation of frozen sections and rapid immunohistochemistry was always less accurate than opinions based on sections cut from well-fixed tissue.
If immunohistology is not used at least 12% of tumor-positive SNs will be understaged. A major problem in evaluating H&E-stained SNs is the presence of melanized and nonmelanized macrophages that may quite closely resemble melanoma cells. Immunohistology is of great value in making this separation.
Approximately 20% of melanoma patients who undergo an SN procedure will have a tumor-positive SN. These patients usually undergo complete lymphadenectomy. However this may represent overtreatment for a majority of patients because only one third of patients with a positive SN have additional melanoma in the nodes removed at complete node dissection. There is therefore considerably interest in developing techniques that will identify, before complete lymphadenectomy, those patients who are likely to have tumor extension beyond the SN. Such an assessment might spare many patients an unnecessary operation that carries significant morbidity.
Moreover sentinel node technique have allowed them to focus on the nodes most susceptible to tumor influence. The SNs are profoundly downregulated, as evidenced by a significant reduction in the area of the node occupied by T lymphocytes , the area of node occupied by IDCs, the density of IDCs, and the proportion of IDCs that express long and complex dendrites. Reduction in antigen presentation to na´ve T lymphocytes is likely to lead to a dearth in T lymphocytes specifically sensitized to tumor-associated antigens. A reduction in these critical and often cytotoxic cells may permit enhanced growth of the primary tumor and the establishment and progression of metastases.
Study are in progress to determine whether molecular biology techniques will detect additional nodes that contain truly occult tumor deposits ( 5 ).

Cytokeratins (CK) are integral components of the cytoskeleton of epithelial cells, and they are reliably expressed by tumor cells. CK can be clearly identified in individual carcinoma cells by means of specific monoclonal antibodies. Although the prognostic significance of immunocytochemical assays has been confirmed in prospective clinical studies, the techniques used in these studies differ considerably in terms of reproducibility. It is therefore necessary to define critical variables of the immunocytochemical assays and to introduce standardization that will allow a reproducible and more precise determination of the cancer cell count.
In contrast to immunohistochemistry, molecular markers allow analysis of the entire lymph node in one reaction, thus reducing the time needed for screening. Recent preliminary studies of a small number of patients with colorectal cancer demonstrated an increase in the detection of lymph node micrometastases using reverse transcription-polymerase chain reaction ( RT-PCR) assays for carcinoembryonic antigen (CEA) or CK20 messenger RNAs (mRNAs). The presence of lymph node micrometastases was significantly correlated to reduced overall survival. However because the detection of these markers is based on molecular methods using amplification of mRNA, the specificity might be reduced by illegitimate expression of the respective marker gene from normal lymph node cells ( 6 ).

References

1) Charles M Balch and Julie R Lange. Lymphatic mapping and sentinel node lymphadenectomy for cancer: an overview. Annals of Surgical Oncology 2001, 8 ( 9S ): 1-4.

2) Patrick A Treseler et al. Pathologic analysis of the sentinel lymph node. Surgical Clinics of North America Volume 80, Number 6, December 2000: 1695-1719.

3) Edwin C Glass. Nuclear medicine in the detection of the Sentinel Node. Annals of Surgical Oncology 2001, 8 ( 9S ): 5-8.

4) W A Waddington, et al. Optimal nuclear medicine support in sentinel node detection. Annals of Surgical Oncology 2001, 8 ( 9S ): 9-12.

5) Alistair J Cochran et al. Current practice and future directions in pathology and laboratory evaluation of the sentinel node. Annals of Surgical Oncology 2001, 8 ( 9S ): 13-17.

6) Klaus Pantel, Stefan B Hosch. Molecular profiling of micrometastatic cancer cells. Annals of Surgical Oncology 2001, 8 (9S): 18-21.



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