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Sentinel Node Biopsy for Melanoma: Where Have We Been and Where Are We Going?

From the Sydney Melanoma Unit and the Melanoma and Skin Cancer Research Institute (JFT, JRS, RFU, VSK, RAS) and Department of Anatomical Pathology (RAS), Royal Prince Alfred Hospital; and Departments of Surgery (JFT, JRS) and Medicine (RFU), The University of Sydney, Sydney, New South Wales, Australia.

Correspondence: Address correspondence and reprint requests to: J. F. Thompson, MD, Sydney Melanoma Unit, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia; Fax: 61-2-9550-6316; E-mail: thompson{at}smu.org.au

ABSTRACT

The sentinel node (SN) concept is not new, but its potential surgical application was not fully appreciated until the landmark report by Morton and Cochran et al. in 1992. It has since been confirmed that SN status in melanoma patients accurately reflects the status of the entire regional node field, and is a critically important prognostic indicator. However, randomized trials have yet to determine whether the SN biopsy technique is of any therapeutic value. With extended follow-up times, false-negative SN rates of up to 15% are being reported and presumably represent failures of nuclear medicine and/or surgery and/or histopathology. Innovative methods of increasing the accuracy of SN identification and of checking this retrospectively are being assessed. The next great challenge is to develop methods of SN assessment that are noninvasive yet are even more accurate than present methods. Techniques such as in vivo proton magnetic resonance spectroscopy hold great promise and suggest that this goal might be achievable.

Key Words: History • Lymphatic mapping • Melanoma • Sentinel node

WHERE HAVE WE BEEN?

Although the sentinel node (SN) biopsy procedure has taken the surgical world by storm over the past decade, the SN concept is not new. As the wise man Solomon remarked 3000 years ago, "There is no new thing under the sun"! In the mid-nineteenth century, the great European pathologist Virchow described very clearly the concept of lymphatic drainage from a given body site to a specific lymph node, before onward passage to other lymph nodes. Virchow’s writings were in German, however, and the first use of the English word "sentinel" to describe a specific lymph node draining a particular area appears to have been by Braithwaite, who in 1923 reported studies of lymphatic drainage using vital dye injections in both a feline model and in man. Braithwaite¹ described the nodes receiving direct lymphatic drainage (identified by vital dye staining) as the "glands sentinel." In 1960, Gould et al.² described a "sentinel node" at the confluence of the anterior and posterior facial veins, to which direct lymphatic drainage of the parotid gland occurred in patients with carcinoma of the parotid. If micrometastatic disease was found in that node on frozen section examination at the time of parotidectomy, a radical neck dissection was performed. In 1966 Sayegh et al.³ used the term "sentinel node" to describe the "primary" node receiving discrete lymphatic drainage from the testis. Subsequently, Cabanas⁴ reported studies of lymphatic drainage in 250 patients with tumors of the penis, testis, breast, anus, rectum, and skin. He described a "sentinel node" draining the penis but did not perform lymphatic mapping to identify the SN in each patient. Although numerous investigators had thus recognized the SN concept, the potential surgical application of lymphatic mapping and SN biopsy was not fully appreciated until the landmark report in 1992 by Morton and Cochran et al.,⁵ from the John Wayne Cancer Institute.

Within 3 years of that 1992 publication, the hypothesis that SN status in melanoma patients very accurately reflects the status of the entire regional node field had been confirmed in studies undertaken by Reintgen et al.⁶ in the United States and by Thompson et al.⁷ in Australia. The results of each of these studies were remarkably similar to those originally reported from the John Wayne Cancer Institute. Both confirmatory studies involved sentinel node biopsy, with immediate complete regional lymph node dissection so that all remaining lymph nodes in the node field could be examined histologically, and the accuracy of the sentinel node as an indicator of regional node field status could be assessed. The study by Reintgen et al.⁶ assessed 42 patients; micrometastatic disease in an SN was found in 8 of them, and in 7 the SN was the exclusive site of disease. None of the other 34 patients had metastases in either sentinel or nonsentinel nodes. In the study by Thompson et al.,⁷ results in 118 patients were analyzed. In 18 of the 22 node fields found to contain metastatic disease, the SN was the only site of dissemination identified. The failure rate in this study (two patients, i.e., 1.9%) was very similar to that noted in the original series by Morton et al. Similar validation studies were subsequently reported from a number of other centers, all with remarkably similar results.⁸

Elective lymph node dissection procedures for melanoma have now been abandoned in all major melanoma treatment centers around the world, not only because of the morbidity associated with these procedures but, more importantly, because of the failure of clinical trials to demonstrate any associated improvement in overall survival. It is therefore most unlikely that further validation studies such as those described above will ever be undertaken, since staging information that is at least as accurate as that provided by elective lymph node dissection can be obtained by SN examination.

In the earliest studies of lymphatic mapping and SN biopsy, blue dye was injected intradermally at the primary melanoma site and each SN was identified by tracing blue-stained afferent lymphatic channels to a blue-stained lymph node in the regional node field. It soon became clear that preoperative mapping using a nuclear medicine technique (lymphoscintigraphy) was very helpful in making the procedure less tedious and more accurate, and the development of hand-held gamma probes allowed even quicker and more precise intraoperative SN identification.⁹ Use of a gamma probe also provided greater certainty that the correct node was being removed, with the added benefit that residual hot spots of radioactivity in a node field could be checked. The principle was soon established, based on results from several major centers around the world, that in order to achieve the greatest accuracy of SN node identification a preoperative lymphoscintigram, injection of blue dye at the primary melanoma site immediately preoperatively, and the use of a hand-held gamma probe intraoperatively were all required.

In a recent study at the Sydney Melanoma Unit (SMU; Sydney, Australia), we sought to reexamine the question of which method or methods most reliably identified SNs, using the presence of micrometastatic melanoma within them as an indicator of true SN status. Of 1072 patients who underwent SN biopsy procedures, 168 (15.7%) were found to have one or more positive SNs. There was blue staining of 187 of 190 positive SNs (98.4%), and 80 of 83 (96.4%) were considered "hot," registering more than three times the residual radioactivity count in the regional node field (unpublished data). The study thus confirmed that the most reliable technique for SN identification at present involves the use of preoperative lymphoscintigraphy to detect all draining node fields and to identify the SNs, blue dye staining as the standard for intraoperative recognition of an SN, and a gamma probe to assist in locating each SN. However, visual detection of blue staining appeared to be the most reliable criterion for identification of an SN intraoperatively.

From information obtained by performing lymphoscintigraphy on large numbers of melanoma patients prior to SN biopsy procedures, important new insights into cutaneous lymphatic drainage pathways have been obtained.^10,11 It has been shown that many long-held concepts are not correct and that cutaneous lymphatic drainage from some sites on the body is much more unpredictable than had previously been appreciated. For primary melanomas on the head and neck, for example, up to one-third of patients exhibit lymphatic drainage to a site that would not have been predicted clinically.¹² In addition, several previously unsuspected lymphatic drainage pathways have been discovered. These have included drainage to triangular intermuscular-space SNs (from upper-back melanoma sites), to para-aortic and retroperitoneal SNs (from upper- and lower-back sites), and to costal margin SNs, with onward drainage to internal mammary nodes (from periumbilical sites). Sometimes there is drainage to node fields on the opposite side of the body (particularly from head, neck, and trunk sites), and not infrequently there is drainage to "interval" SNs outside recognized node fields. All this new information has highlighted the importance of preoperative lymphoscintigraphy for every patient undergoing an SN biopsy procedure. Knowledge of the possibility of these unusual lymphatic drainage patterns should help to improve the accuracy and completeness of SN identification.

WHERE ARE WE GOING?

Although remarkable progress in SN technology has been made over the past decade and identification accuracy rates have improved greatly, it is disturbing to note that false-negative rates of up to 15% are now being reported from major centers. Available evidence suggests that these late failures do not occur because the SN concept is flawed, but rather because of shortcomings in nuclear medicine technology, surgical techniques, and histopathological methods. It is important when considering false-negative rates to be clear what is meant by the terminology that is used. Many centers report "success rates" for SN identification of 97% to 100%. However, these figures are often misleading because they indicate the percentage of patients in whom at least one SN was found and removed but do not represent the percentage in whom all SNs (identified by careful preoperative lymphoscintigraphy with dynamic imaging) were found. Even the definition of an SN is not always correct,¹³ and it is not sufficient to claim successful SN identification if a node that contains some radioactivity and/or which is slightly blue-stained is found and removed, because this could actually be a second tier node. In a recent review of patients with head and neck melanomas treated at the SMU, for example, the success rate for identification of at least one node considered to be an SN was 99.3%, but in only 70% of patients were all SNs (identified as such by preoperative lymphoscintigraphy) found and removed.¹² This discrepancy could explain, at least in part, why false-negative SN biopsy procedures occur, with metastatic disease occurring subsequently in a regional node field when the initial SN biopsy report was negative.

Even the calculations used to determine false-negative rates are sometimes incorrect. This is the formula that should be used: false-negative rate = number of false-negative cases/total number of SN-positive cases. Some have inappropriately used as the denominator the total number of patients undergoing SN biopsy, rather than the total number of SN-positive patients (i.e., false-negative patients plus patients initially reported as SN-positive). In a recent review of the SN biopsy experience at the SMU up to June 2001, for example, 176 patients were initially reported to be SN-positive and 957 were reported to be SN-negative. In the course of follow-up, metastatic disease became apparent in a node field from which a "negative" SN had been removed in 27 of the 957 patients (2.8%). Although this percentage is low, it translates into a false-negative rate of 13.3% (27 of 27, plus 176). In other words, 27 of the 203 patients ultimately considered to be SN-positive were originally categorized incorrectly. Similarly high false-negative rates have been reported recently from other centers and are of concern. They make it clear that the accuracy and reliability of the SN biopsy technique are still far from perfect and that methods of checking and improving accuracy and reliability must be sought.

In an attempt to assess how many of these false-negative cases might have been due to surgical failure, i.e., because of removal of a node that was not the SN identified by the preoperative lymphoscintigram, we have developed a technique for assaying antimony in tissue sections. This work was based on the concept that antimony sulfide colloid particles used for the preoperative lymphoscintigram would be retained in the true sentinel node but would be absent or present in only very low concentrations in nonsentinel nodes. A conceptually similar method for confirming SN identity has been reported by Haigh et al.¹⁴ at the John Wayne Cancer Institute, who injected carbon particles at the primary melanoma site and then used the presence of carbon in nodes to confirm or refute their identity as SNs. In our own studies using antimony, we have found that it is possible to detect and quantitate antimony concentrations in tissue sections of sentinel nodes using inductively coupled plasma mass spectrometry.¹⁵ In a preliminary series of 20 patients with false-negative SNs, i.e., who developed metastatic disease in a regional node field despite having had an SN or SNs in that field reported as negative, we noted five patients with very low levels of antimony, a finding suggesting that the nodes recovered from these patients had not been true SNs.¹⁶ It is interesting to note that four of these patients were treated prior to 1994, when use of an intraoperative gamma-probe became routine at the SMU, i.e., in all four patients SN identification had been dependent on the blue dye method alone.

Another problem with the SN biopsy technique is that SN removal remains an invasive procedure, associated with a small but definite risk of morbidity. Wound problems, particularly seroma development and infection, are well documented as early postoperative complications. Perhaps more significant, persisting lymphedema of the lower limb is a disappointing and troublesome complication of what must at this time still be considered a diagnostic test (since the results of randomized trials designed to assess effects on survival are not yet available).¹⁷ And quite apart from the potential for morbidity, the financial implications of SN biopsy must be considered; the majority of the expenses are generated by the operative component of the assessment. One estimate of the cost of performing an SN biopsy procedure in an operating room on an outpatient basis, for example, was US$7150.⁸ In the Australian setting, a cost of AU$4100 has been calculated for a wide excision and SN biopsy procedure.¹⁸ Such costs represent a significant impost on the resources required to provide melanoma treatment service to the community. Our group has therefore been motivated to explore the possible application of other technologies, both to improve the accuracy of SN evaluation and to minimize or eliminate the morbidity of the procedure. Preliminary studies indicate that proton magnetic resonance spectroscopy (MRS) may have the capacity to achieve both these aims.

Work with other tumor types, including breast, prostate, and colon cancer, has established the capacity of MRS to identify these malignancies by spectrographic analysis of tissue samples. We have sought to investigate the application of MRS to the diagnosis of micrometastatic disease in SNs, initially by examining fine-needle aspirates of operatively harvested sentinel and nonsentinel nodes. Small-volume (droplet) needle aspirates of sentinel and nonsentinel nodes have been analyzed and the resulting spectra evaluated. The spectrographic profiles have been assessed by both direct visual inspection and a mathematical algorithm.¹⁹ Initial studies involved tissue aspirates from 47 lymph nodes subsequently found on histologic examination to contain micrometastatic disease, as well as another 23 benign lymph nodes. Metastatic nodal disease was predicted with a sensitivity of 97.3%, specificity of 90.2%, and accuracy of 94.7%. Related validation MRS has similarly distinguished cultured melanoma cells from benign cells by the presence or relative abundance of particular metabolites, notably choline compounds and taurine (Fig. 1).

View larger version (23K): [in this window] [in a new window]   FIG. 1. Proton magnetic resonance spectra (8.5 Tesla) for a melanoma and a benign skin lesion (a keratosis), showing signature choline and taurine peaks for the melanoma.

The exciting early results of this research have also encouraged us to consider the prospect of achieving completely noninvasive assessment with in vivo MRS. Conventional nuclear magnetic resonance scanners have to date been based on 1.5-Tesla magnets. However, 3-Tesla machines are now becoming available and along with them the prospect of advances in diagnostic imaging for oncology patients. While these more powerful scanners will offer improved conventional imaging, they will also be able to perform in vivo noninvasive spectroscopy of identified areas of pathological abnormality. The current experience being accumulated with in vitro MRS promises to allow the definitive identification of specific malignancies on the basis of signature MRS spectra. It is relevant to consider that current diagnostic imaging in the form of CT and magnetic resonance imaging yields only spatial images and essentially limited information regarding the nature of the disease process. Spectrographic analysis of these tissues will change this, extending the advances of PET scanning, which utilizes the glucose avid metabolism of malignant cells. The prospect of using minimally or indeed noninvasive MRS to assess SNs and to screen for metastatic disease elsewhere would lead to enormous benefits for melanoma patients. Their morbidity and duress might be substantially diminished, the accuracy of SN assessment augmented, and costs dramatically reduced.

Finally, there is an important unanswered question relating to the need for a full regional node dissection if a positive SN is found in that node field, by whatever means. It is already known that in only about 20% of patients will additional positive nodes be found in a completion regional lymphadenectomy. In other words, further surgery with its attendant inconvenience and morbidity may be unnecessary in up to 80% of these patients. To examine this question, an international randomized trial is planned, with patient accrual expected to commence in the latter part of 2004.

ACKNOWLEDGMENTS

The work reported in this article was supported by The Melanoma Foundation of the University of Sydney and by The Melanoma and Skin Cancer Research Institute. Vivian S. Ka was a Sydney Melanoma Unit research student supported by a Fulbright Scholarship.

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

FOOTNOTES

Sentinal node (SN) status in melanoma patients accurately reflects the status of the entire regional node field and is a critically important prognostic indicator. However, randomized trials have yet to determine whether the SN biopsy technique is of any therapeutic value. Methods of increasing the accuracy of SN identification and of checking this retrospectively are being assessed.

Received for publication September 21, 2003. Accepted for publication December 8, 2003.

REFERENCES

1. Braithwaite LR. The flow of lymph from the ileocaecal angle, and its possible bearing on the cause of duodenal and gastric ulcer. Br J Surg 1923; 11: 7–26.[CrossRef]
2. Gould EA, Winship T, Philbin PH, Kerr HH. Observations on a "sentinel node" in cancer of the parotid. Cancer 1960; 13: 77–8.[CrossRef][Medline]
3. Sayegh E, Brooks T, Sacher E, Busch F. Lymphangiography of the retroperitoneal lymph nodes through the inguinal route. J Urol 1966; 95: 102–7.[Medline]
4. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer 1977; 39: 456–66.[CrossRef][Medline]
5. Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992; 127: 392–9.[Abstract]
6. Reintgen D, Cruse CW, Wells K, et al. The orderly progression of melanoma nodal metastases. Ann Surg 1994; 220: 759–67.[Medline]
7. Thompson JF, McCarthy WH, Bosch CM, et al. Sentinel lymph node status as an indicator of the presence of metastatic melanoma in regional lymph nodes. Melanoma Res 1995; 5: 255–60.[Medline]
8. Essner R, Stern S, Bostick P, Morton DL. Results of lymphatic mapping in melanoma. In: Nieweg OE, Essner R, Reintgen D, Thompson JF, eds. Lymphatic Mapping and Probe Applications in Oncology. New York: Marcel Dekker, 2000: 101–24.
9. Thompson JF, Niewind P, Uren RF, et al. Single-dose isotope injection for both preoperative lymphoscintigraphy and intraoperative sentinel lymph node identification in melanoma patients. Melanoma Res 1997; 7: 500–6.[CrossRef][Medline]
10. Uren RF, Thompson JF, Howman-Giles R. Lymphatic Drainage of the Skin and Breast: Locating the Sentinel Nodes. Amsterdam: Harwood Academic Publishers, 1999.
11. Thompson JF, Uren RF, Shaw HM, et al. Location of sentinel lymph nodes in patients with cutaneous melanoma: new insights into lymphatic anatomy. J Am Coll Surg 1999; 189: 195–204.[CrossRef][Medline]
12. de Wilt JHW, Thompson JF, Uren RF, et al. Correlation between preoperative lymphoscintigraphy and metastatic nodal disease sites in 362 patients with cutaneous melanomas of the head and neck. Ann Surg (in press).
13. Thompson JF, Uren RF. What is a ‘sentinel’ lymph node? Eur J Surg Oncol 2000; 26: 103–4.[CrossRef][Medline]
14. Haigh PI, Lucci A, Turner RR, et al. Carbon dye histologically confirms the identity of sentinel lymph nodes in cutaneous melanoma. Cancer 2001; 92: 535–41.[CrossRef][Medline]
15. Dawson M, Doble P, Beavis A, et al. Antimony by ICP-MS as a marker for sentinel lymph nodes in melanoma patients. Analyst 2003; 128: 217–9.[CrossRef][Medline]
16. Scolyer RA, Thompson JF, Li LX, et al. Failure to remove "true" sentinel nodes can cause failure of the sentinel node biopsy technique. Antimony quantitation in false negative sentinel nodes from melanoma patients. Ann Surg Oncol (in press).
17. Morton DL, Thompson JF, Essner R, et al. Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: a multicenter trial. Ann Surg 1999; 230: 453–63;discussion, 463–5.
18. Bonenkamp JJ, Logan DR, Suemnig AA, Thompson JF. The cost of sentinel node biopsy for melanoma. Melanoma Res 2001; 11 (Suppl 1): S107.
19. Lean CL, Bourne R, Thompson JF, et al. Rapid detection of metastatic melanoma in lymph nodes using proton magnetic resonance spectroscopy of fine needle aspiration biopsy specimens. Melanoma Res 2003; 13: 259–61.[CrossRef][Medline]

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