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Sentinel Lymph Node Procedure in Squamous Cell Carcinoma of the Vulva

Brown University School of Medicine, Women and Infants Hospital, Providence, RI

THE EXCELLENT STUDY by de Hullu et al¹ is the largest so far reported of sentinel node biopsy in vulvar carcinoma. Because of the high morbidity of groin dissections in vulvar carcinoma (and other malignancies), it would be extremely useful to have a reliable surrogate for the status of the node basin that could be analyzed in a preliminary fashion to discover patients who have negative or only micrometastatic nodes and do not require a groin dissection. The authors have demonstrated that the sentinel node biopsy in 59 patients was highly accurate and, most important, had a false-negative rate of zero and thus a negative predictive value of 100%. Interestingly, the authors note such consistent and clear lymphatic anatomy that cancers defined as midline lesions only because they approached but did not actually extend to the midline all had ipsilateral, not contralateral, sentinel nodes identified. The reliability of this midline separation of lymphatic drainage is quite different from data regarding melanoma of the trunk at approximately the level of the low abdomen.²

The 59 patients included in the study by de Hullu et al¹ had 107 groin dissections, which identified sentinel nodes in 95 (89%), with a total of 139 sentinel nodes (1.5 sentinel nodes per patient). The vast majority had only one or two sentinel nodes. All sentinel nodes were "hot" from the radiocolloid dermal injection, but only 60% were colored by the patent blue dye injected. There apparently were no blue "cold" sentinel nodes identified. Thus, in vulvar carcinoma, radiocolloid alone could be used reliably, which would avoid complications from blue dye (allergic reactions, permanent staining, false oximeter readings). In the 95 groins with 139 identified sentinel nodes, there were 1,077 other lymph nodes identified (12 per groin dissection) and analyzed by routine single-section examination.

After routine single-section hematoxylin/eosin-stained histologic examination, 37 (27%) of 139 nodes were positive in 20 (34%) of 59 patients who were subjected to 27 groin dissection (seven bilateral). There were 1.9 positive sentinel nodes per patient and 1.4 per groin dissected. The remaining 102 sentinel nodes, negative by initial routine examination, were then subjected to more intensive histologic examination. with extra sections and immunohistochemistry staining. Four additional positive sentinel nodes were found, three of which were in patients whose nodes were negative on routine examination and one in a patient with another positive sentinel node. The authors calculated the sensitivity of routine examination versus further step sectioning to be 93% for sentinel nodes or 87% regarding patients. After step sectioning of sentinel nodes, there were no positive lymph nodes in the 1,077 other nodes examined routinely in the 95 groin dissections if the sentinel nodes were negative. Thus there were no false-negative sentinel nodes. The negative predictive value was 100% after sentinel node biopsy analyzed by multiple sections.

This report highlights the significant advantages that can be achieved using sentinel node biopsy in a variety of cancers. The particular objective, of course, is to avoid the morbidity of routine regional node dissection, which so often yields negative lymph nodes yet produces significant morbidity. The overall rate of positive lymph nodes in invasive breast cancer today is less than 33%,³ and the overall rate of lymph node metastases in melanomas is similar.⁴ In this series of vulvar carcinomas, 66% of patients had entirely negative nodes, all of whom could be spared the morbidity of groin dissection. Removing negative lymph nodes has no therapeutic value whatsoever in the management of any cancer.

The authors note that because of the reliable lymphatic anatomy in the vulva, the learning curve for surgeons can be as few as 10 cases for which groin dissection arbitrarily needs to be completed after sampling sentinel nodes. It would be hoped that the sentinel node biopsy technique would be adopted rapidly by gynecologic oncologists, with dramatic improvement in patient comfort and quality of life and ease of surgical management via reductions in morbidity and complications that are so common after even superficial groin dissection.

It is to be appreciated that lymph node metastases, by all of the studies reported, are indicators, not governors, of outcome.⁵ Overall, in studies of melanoma,⁴ breast cancer,⁶ stomach cancer,^7,8 and colorectal cancer,⁹ greater or lesser lymphatic resections do not change prognosis. In breast cancer⁶ and melanoma,⁴ protocols that initially observe regional nodes without resection, using delayed node dissections in the minority of cases that later develop clinical regional node metastases, show no overall decrease in survival. Reports of the use of the sentinel node procedure in breast cancer indicate that the false-negative rate is low¹⁰ (usually less than 5%), and when special histologic studies of the sentinel node are performed, the rate is less than 1%, as reported at the H. Lee Moffitt Cancer Center in more than 1,000 patients.¹¹ Thus it is clear that a negative sentinel node biopsy in breast cancer,¹¹ melanoma,¹² some skin cancers,¹³ and now vulvar carcinoma¹ is a reliable surrogate for the absence of any regional lymph node metastasis. Furthermore, in a significant proportion of breast¹¹ and melanoma¹² cases, and as reported here in vulvar carcinoma,¹ the sentinel nodes, when positive, are the only positive nodes. In 15 (56%) of the 27 groins that had positive sentinel nodes, there were no other positive nodes in the subsequent groin dissection as reported by de Hullu et al.¹ When the primary lesions are small (T1a and T1b) in breast cancer, there is only one sentinel node metastasis in 50% of node-positive patients, and many of these are only micrometastases.¹¹

This report also brings up the issue of the meaning of micrometastases and the need to separate true micrometastatic disease from isolated tumor cells or isolated tumor cell clusters in lymph nodes. Isolated tumor cell clusters may have little or no biologic consequence, as noted by Hermanek et al¹⁴ and Page et al¹⁵ in recent articles supporting modification of the American Joint Committee on Cancer Staging System.

The authors are to be congratulated for expanding and extending our knowledge of the usefulness of sentinel lymph node analysis to yet another organ site and for illustrating lymphatic anatomy and physiology generally. They provide a strong stimulus for adaptation of preliminary sentinel node biopsy, either unilateral or bilateral, in vulvar carcinoma. Increasingly, we are realizing that sentinel node analysis provides a reliable surrogate for the entire regional node basin because it is highly accurate, anatomically based, and physiologically useful. Indeed, it can be argued that sentinel node biopsy is the preferred technique for analyzing lymph node metastases, because more careful analysis of a few sentinel nodes with multiple histologic step sectioning is more diagnostically accurate than single histologic sections through many nodes retrieved by a regional node dissection. In trunk locations of melanoma, the technique of radiocolloid display of sentinel nodes illustrates a direct lymphatic channel to the retroperitoneum, which would escape any reasonable attempt to use sentinel node biopsy.¹⁶ Otherwise, however, in the vast majority of patients, a radionuclide injection in the skin adjacent to the melanoma, over the breast cancer, or at the site of the vulvar carcinoma reliably demonstrates the sentinel node or nodes in the appropriate node basin. These sentinel nodes can be obtained with minimal morbidity and provide conclusive evidence of negative regional lymph nodes that do not require subsequent surgical resection. This, in itself, will have a major impact in the treatment of breast, skin, and vulvar cancers, and melanoma, by rationalizing and simplifying lymph node surgery. The concept of sentinel node biopsy may be useful when extended to colorectal cancers as well.

The issue of what to do if sentinel lymph nodes display metastatic disease remains less well defined. If only isolated tumor cells or tumor cell clusters are found, or only micrometastasis, it is unlikely that other positive nodes will be found if the primary cancer is small or early and the regional nodes probably do not need to be dissected.¹¹ If nodal metastases are the only prognostic indicators for use of systemic adjuvant therapy, then complete dissection need not be performed. If regional lymph node metastases (particularly if macrometastatic) or extensive involvement are sites of further metastatic cell dissemination or are associated with frequent regional failure that would become inoperable, then regional nodes should be removed. However, evidence for these eventualities is scant.¹⁷ If the exact number of metastatic nodes is necessary for research or therapeutic protocols, then regional node dissection may be necessary. Unless there are effective adjuvant therapy programs available that use such metastatic nodal information, however, regional node dissection may be avoided.

Increasing research into the metastatic process suggests the great inefficiency, singularity, and specificity of metastatic cells.¹⁸ The development of a metastasis requires multiple steps, from dislodgement from the primary cancer and dissemination to adherence on endothelial surfaces, local penetration through the vessel wall, acquisition of neovasculature, and progressive growth. These processes are so cell- and organ-specific that it is entirely likely that a lymph node metastasis may contain cells that have no capacity to lodge or grow in other organs.¹⁹ For example, lymph node metastatic cells from human melanoma were found to adhere only to lymph node stroma cells in an animal model.¹⁹ Animal models of organ-specific metastases are well known.²⁰ Clinical experience with the curative outcome after surgical removal of regional lymph node metastases,⁵ hepatic metastases in colorectal cancer,²¹ and pulmonary metastases in sarcomas²² all dramatically confirm this specificity. In these situations, the greater the number of metastases, the less likely the survival, which implies a statistical correlation between the greater likelihood of multiclonal, multicapacity metastatic cells and, therefore, the likelihood of multiple organ metastatic spread. Only the lymph nodes are easily accessible, are not a vital organ for survival, and, therefore, are more able to be removed and observed for relationships to patient survival; however, similar statistics apply to all three metastatic sites. Cure rates are high if only one, two, or three lymph node metastases, hepatic metastases, or pulmonary metastases are discovered and resected. Cures are uncommon or absent if more than five or 10 lymph node metastases, hepatic metastases, or pulmonary metastases occur, all of which are likely indications of a wider array of multiple clones of metastatic cells that lodge and grow in more organ sites. If the organ sites are essential, death will occur with progressive growth, but nonvital sites may harbor metastases with prolonged survival. If these speculations are true, then we may have a greater understanding of the metastatic process and a greater appreciation of the nonvital role of lymph node metastases, because they alone affect nonvital organs. This supports the development of sentinel node biopsy as a technique that provides prognostic information but without direct therapeutic implications.²³

The report by de Hullu et al¹ will help speed the process of adaptation of sentinel node biopsy as a standard approach, with avoidance of regional nodal dissections that are unnecessary and morbid, not only in vulvar carcinoma but in other sites as well. The data presented are carefully analyzable and generalizable to the role of lymphatic metastases and sentinel node biopsy.

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