The case for lymphatic mapping and sentinel lymphadenectomy in the management of primary melanoma

We appreciate the opportunity to respond to Dr Medalie's and Dr Ackerman's curious and premature attempt to discredit sentinel node biopsy. For 30 years we have struggled with the problem of managing clinically normal regional lymph nodes in patients with primary cutaneous melanoma. Our efforts have produced a minimally invasive procedure that has been universally adopted by most academic and community‐based surgical oncologists and pathologists—and enthusiastically welcomed by the patients they treat. Our extensive published studies on the evolution and application of the sentinel node concept1–16 have been validated not only by the peer‐review process required for publication in respected scientific journals but also by multiple peer‐reviewed studies subsequently published by other investigators.17–22 Although Drs Medalie and Ackerman are certainly entitled to their opinion and are skilled at its forceful expression, they have made no attempt to refute the scientifically‐based data that underpin the development and conduct of preoperative and intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL), and their repetitious conclusions are ex cathedra and presented without factual basis. Repeatedly saying that something is true or false does not make it so, no matter how vehemently it is stated. The nature of their argument suggests that Drs Medalie and Ackerman are either unaware of the extensive literature on LM/SL or unwilling to accept its consensus. The claim that sentinel node biopsy is the same as elective lymph node dissection (ELND) reflects a limited understanding of this area of surgical oncology. ELND is the surgical removal of an entire regional group of clinically tumour‐free lymph nodes; the premise is that the primary cutaneous melanoma has risk factors (e.g. intermediate thickness, ulceration) which increase the likelihood that it will have spread to the regional nodes. For reasons discussed below, ELND is not accurate for nodal staging but was previously justified by its possible therapeutic value. However, unless preoperative lymphoscintigraphy is performed, ELND is a blind procedure that may not remove the correct nodal basin. Moreover, its potential morbidity is substantial especially considering that 80–90% of patients (depending upon the thickness of the primary melanoma) cannot benefit because they have no nodal metastases. This is in stark contrast to the sentinel node procedure, which is associated with almost no morbidity—a fact that seems to have escaped Drs Medalie and Ackerman. As we previously reported,1 and as Drs Medalie and Ackerman point out, prospective controlled studies of ELND have not demonstrated a survival advantage for all primary melanoma patients treated this way. Nonetheless, a subset of individuals with limited tumour burden may benefit.23, 24 We remind Drs Medalie and Ackerman of the results of the Intergroup Melanoma Surgical Trial, a randomized study that demonstrated a survival benefit of ELND for prospectively defined subgroups of melanoma patients.24 Therapeutic lymph node dissection removes the regional nodes from patients who have detectable nodal metastases. This confers some therapeutic advantage and can lead to prolonged survival, to a degree that is inversely related to the number of tumour‐involved nodes.2, 25 Sentinel node biopsy, which we prefer to describe as preoperative and intraoperative lymphatic mapping and sentinel lymphadenectomy, is a staging and diagnostic procedure that samples the sentinel node (SN). The SN is the first regional lymph node on the direct lymphatic drainage pathway from the primary melanoma—the node which is most likely to contain any tumour cells that have metastasized from the primary.3 LM/SL is designed to identify clinically occult metastases. As noted above, this procedure has little or no morbidity when performed by experienced surgical oncologists,1 and its diagnostic accuracy far exceeds that of blind ELND because the SN specimen is small enough for a highly focused examination by histopathology, immunohistology and molecular biology methods.1, 4 LM/SL is NOT the same as selective complete lymph node dissection (CLND), the purpose of which is the therapeutic excision of all nodes within the regional basin of a patient whose nodal metastases have already been identified by LM/SL staging. Remember that LM/SL was developed and is currently accepted as a staging technique that avoids CLND in approximately 80% of patients without metastases in the SN. It is theoretically possible that this procedure might also be therapeutic if regional metastasis is confined to the SN, and this possibility is currently under study in a Phase III multicentre trial sponsored by a National Institutes of Health Program Project grant. However, if metastasis in the regional nodal basin beyond a tumour‐positive SN is suspected or confirmed, regional nodal surgery beyond the SN procedure is, by definition, a therapeutic lymph node dissection. That Drs Medalie and Ackerman fail to grasp this distinction is surprising. It is claimed that ‘if END is bereft of benefit, so, too, it must be for SNB followed by RND’. This bald and unsupported statement ignores the diagnostic utility of LM/SL and discloses the absence of any real understanding of the scientific method of clinical investigation. The statement may be true but is clearly susceptible to scientific proof. Ongoing trials will answer this question with a degree of certainty that cannot come from flamboyant dialectics. Any attempt to discredit LM/SL for a lack of possible impact on survival/cure ignores the undisputed potential clinical benefit of early cancer diagnosis. Are Drs Medalie and Ackerman suggesting that we withhold assessment of the regional tumour‐draining lymph nodes until they become clinically suspicious? Do they truly countenance this type of passive therapeutic nihilism? Such an approach would allow disease to advance from a relatively early clinical stage that can be readily diagnosed by LM/SL and is amenable to therapy, to more advanced and potentially untreatable stages. Are we being asked to discount or ignore the peer‐reviewed literature?26, 27 Even though the chance of long‐term survival is inversely related to the tumour burden within regional nodes, Drs Medalie and Ackerman apparently would have us wait until a patient develops multiple palpable (and thus relatively burdensome) metastases with a concomitant decrease in the chance of long‐term survival. Since virtually all patients who have SN micrometastases detectable by LM/SL will eventually develop clinically detectable nodal metastases if managed only by wide excision and observation, what do they propose? Surely they would not leave a patient with grossly involved, melanoma‐filled lymph nodes untreated by surgery. If the patient is going to require therapeutic CLND within 12–31 months after wide excision (the period of latency before clinical evidence of nodal metastases, as indicated by our own published findings as well as the inappropriately maligned assertions of Drs Pack and Balch) (Table 1), why leave that patient untreated and at risk of dissemination from the nodal metastases for such a long period of time? Their premise is that all patients with nodal metastases also have distant metastases and eventually will die of melanoma; therefore, all attempts at surgical therapy of the regional nodes are futile. If we are to believe this (and ignore the available peer‐reviewed studies2, 25, 28), even microscopic metastasis to regional lymph nodes must inevitably be accompanied by fatal haematogenous metastasis. As shown below, this is not the case. In fact, from clinical, epidemiological and autopsy studies it is probable that many tumour cells that spread systemically either fail to survive or form latent or dormant microcolonies that may never grow sufficiently to become clinically detectable or cause death. It is in their treatment of the subject of mechanisms and significance of metastases that the authors seem least informed and their arguments weakest. Incidence of positive nodes found at LM/SL compared with the incidence of clinically evident nodal metastases after wide excision (WE) alone4 a Proportion of patients with nodal metastases found by histopathological assessment of SN vs. proportion of patients developing clinical nodal recurrence after WE. b Student's t‐test for total number of tumour‐involved nodes in patients undergoing immediate CLND after LM/SL vs. those undergoing delayed CLND for clinical nodal recurrence after WE. LM/SL, Lymphatic mapping and sentinel lymphadenectomy; CLND, complete lymph node dissection. Incidence of positive nodes found at LM/SL compared with the incidence of clinically evident nodal metastases after wide excision (WE) alone4 a Proportion of patients with nodal metastases found by histopathological assessment of SN vs. proportion of patients developing clinical nodal recurrence after WE. b Student's t‐test for total number of tumour‐involved nodes in patients undergoing immediate CLND after LM/SL vs. those undergoing delayed CLND for clinical nodal recurrence after WE. LM/SL, Lymphatic mapping and sentinel lymphadenectomy; CLND, complete lymph node dissection. The single most important prognostic factor for most primary solid neoplasms melanoma is the tumour of regional lymph nodes the primary (Table the only method to identify regional node metastasis in patients without palpable lymph nodes was ELND and examination of all nodes, to examination of of node by and This technique only a small of the total nodal area and the true of nodal but was no it would be to node in the lymphadenectomy specimen by an approach that would be and beyond the of of tumour of lymph nodes in melanoma with from of tumour of lymph nodes in melanoma with from In to its as a staging procedure, ELND patients to most without the possibility of therapeutic of patients who have primary and regional lymph nodes have nodal metastasis by The 80% of patients with intermediate have tumour‐free regional nodes and will be at risk for and the of Our lymphatic studies to the SN and the selective approach to CLND 30 years that ELND was for in such as the of the or to the or because can to or more lymphatic In we the of cutaneous lymphoscintigraphy to identify the lymph at risk for metastasis from primary and the of the tumour of the node of as the node to patients for We found that lymphatic drainage not the for a melanoma on the might to the or a melanoma of the might to an lymph node in the to the nodes. Our studies of mapping of the that lymphatic from the primary tumour to the regional lymphatic basin to or lymph nodes. In we found that of or the lymphatic and or regional lymph nodes. nodes in a and and thus we identified the SN as the first lymph node within the lymphatic basin by a lymphatic the primary Although and the sentinel to identify nodes in a in our the SN by its its SN is because its with the cutaneous of the primary melanoma and with the lymphatic drainage of of the SN a mapping In the early we developed as the first for cells of for demonstrated the of occult melanoma cells in regional nodes at a previously on the of We also noted that when the of melanoma in the node group was tumour was in only or the nodes to the primary nodes also as indicated by selective of the area of the nodal and in the and of we LM/SL in as a to the of Surgical this technique was designed to a minimally but highly accurate to the the of ELND as a staging procedure in melanoma. LM/SL from our that a primary melanoma the will in the first lymph nodes on the direct lymphatic drainage pathway from the primary cutaneous before to other nodes the lymphatic the tumour of this the tumour of the entire lymphatic basin. Our first published study of LM/SL in the results of LM/SL in lymphatic of patients with primary cutaneous preoperative lymphoscintigraphy to identify the basin of lymphatic within this and lymph nodes. the of was the primary melanoma. identified a SN in lymphatic of tumour‐positive lymphatic in the of tumour‐positive a of Although this was with as the mapping our group and other have the of and for mapping the SN. from an Phase III trial have and validated that LM/SL with a and and removes the first lymph node in the lymphatic pathway from the primary tumour in of patients with primary on and molecular of multiple of this SN is more likely to nodal metastasis is of limited from the nodes identified in a ELND of LM/SL in and virtually all solid neoplasms that spread to the lymph have the SN of an of cells from the primary the to or in the regional nodal basin. This that a focused histopathological and molecular assessment of the SN can staging far more accurate that by nodal biopsy or assessment of the ELND For this the staging by LM/SL has been the on staging for cutaneous Drs Medalie and Ackerman apparently have little in the staging or in the to this to their that melanoma to the regional lymph nodes is associated with a fatal However, are all in the a diagnosed patient an informed of or and risk of from melanoma. Drs Medalie and who apparently prognostic the patient that the is an and thus cannot be diagnostic or prognostic is The of even the most to a or will be when a patient with a subsequently develops fatal metastases that Drs Medalie and Ackerman we with the that the tumour of the SN has no clinical upon patients by our group before if the lymph node is positive by or the chance of recurrence is if the node is positive only by molecular the chance of recurrence is at least if this node is by histopathological and molecular by years the chance of recurrence is only and the chance of survival is highly in and survival for a patient who is to make an informed the and treatment If the SN a the chance of survival of years or will be upon the number of lymph nodes and their tumour However, if the SN is by and molecular the chance of long‐term survival will be or more and survival to histopathological and and and molecular for and of the sentinel with from SN, Sentinel survival. are no in which is why we have an informed process in which the patient can and the preoperative with our we that the therapeutic utility of LM/SL and selective CLND has not been at this this we certainly do not the SN procedure is This with Drs Medalie and who claim to that it is not they do not to with us the of that and no data to their However, LM/SL can with a degree of accuracy the patient has nodal metastases and the risk of our almost all patients to LM/SL because they this the of their disease and its risk of LM/SL has become a staging procedure in cancer the As more a by ELND in patients without clinical evidence of regional metastasis the studies to a survival advantage when patients without evidence of nodal metastasis However, if melanoma does not spread first to the regional nodes before to distant as ELND may not be In fact, randomized prospective clinical trials have to an survival benefit for all melanoma patients undergoing a subset of individuals with limited tumour burden may benefit.23, 24 We have possible of metastasis from a primary melanoma to the the primary tumour to sentinel nodes in the regional lymph the tumour cells may survive and grow or latent in some to distant melanoma cells may spread from the primary to distant However, to the a primary melanoma lymphatic and haematogenous that the of nodal metastases a a of clinically and and to the metastasis of a primary cutaneous melanoma. to the primary melanoma the to the sentinel node which is by factors from the primary melanoma. in the SN may grow but latent before to distant tumour cells in the SN that the primary melanoma has the to removal of the tumour‐involved SN before is spread distant metastasis. to the a primary melanoma lymphatic and haematogenous tumour cells in the SN is a of a primary melanoma that can removal of the tumour‐involved SN is to the of distant metastases and would have no therapeutic The absence of melanoma cells in the SN a primary melanoma that is to spread to distant this has important prognostic with from factors to patients undergoing immediate CLND with patients undergoing delayed CLND lymph with from on CLND, complete lymph node LM/SL, lymphatic mapping and sentinel lymphadenectomy; SN, sentinel wide factors to patients undergoing immediate CLND with patients undergoing delayed CLND lymph with from on CLND, complete lymph node LM/SL, lymphatic mapping and sentinel lymphadenectomy; SN, sentinel wide survival to the of complete lymph node dissection for nodal metastases. node dissection is performed after of tumour cells in the sentinel node or it is delayed until the regional nodes develop palpable metastases. survival. with from We with Drs Medalie and Ackerman that no prospective randomized trial has demonstrated a benefit for ELND in all patients with melanoma. We believe that this reflects a problem of trial The question is not ELND is to all but a patient is likely to benefit because that patient has regional nodal metastasis without metastasis. Drs Medalie and Ackerman for the the of no and that patients with lymph node metastasis also have spread of disease and will die of melanoma they die of something We their with the data that are from their the of to we have the melanoma This the of all patients by our is complete to within 30 months of or for of patients in the The thus a prospective of the results of therapy by The of survival (the period with of patients on associated with lymph node dissection for palpable nodal metastases is compared with for patients with positive but clinically nodes. data clearly that not all patients with melanoma develop distant metastases and die of and refute Dr Medalie's and Dr Ackerman's therapeutic data are with an from who their of patients with primary cutaneous melanoma to identify patients who developed clinical evidence of metastases. the developed metastases as the first clinical of disease However, only of those with regional nodal metastases subsequently developed distant metastases, which suggests that disease in of patients was not beyond the regional nodes to a degree that at the of therapeutic are with the and that not all patients with regional nodal metastases develop distant metastases. The fact that the before clinical metastasis was for spread distant disease for regional nodal disease months vs. suggests that nodal metastasis distant metastasis in many the of group was on a clinical staging no data on the incidence of occult or SN metastases in patients with direct distant disease or We have found that many patients with metastases have occult nodal metastases detectable by For we do not with the conclusions of we believe that their clinical findings the SN and the of diagnostic LM/SL followed by therapeutic CLND when the SN our LM/SL in we already have The of survival from wide excision of primary LM/SL and immediate CLND for occult metastases in the SN is compared with only after wide excision and delayed CLND for palpable nodal metastases This is on patients by the most accepted important prognostic and primary stage and and number of tumour‐involved lymph nodes (Table If the have been no in survival the we found a survival at years vs. which to a at years vs. if only of the patients lymph node the possible therapeutic benefit of immediate vs. delayed CLND for all patients with primary cutaneous melanoma from at years of to at years of data are with the findings of Melanoma whose randomized trial compared survival after immediate vs. delayed lymphadenectomy for nodal metastases of patients after immediate lymphadenectomy nodal vs. delayed lymphadenectomy nodal with from of the ELND trials thus far have been enough to an survival of only the treatment for the entire study group of melanoma patients without nodal metastases cannot benefit from of would require more patients in Even the which in of has only 80% to a in survival patients who wide excision vs. those who wide excision and LM/SL CLND if the SN was Moreover, as discussed above, the chance of metastasis to the regional nodes with the thickness of the primary (Table patients with primary have a risk of nodal ELND only a small increase in survival with primary are more likely to have tumour‐involved regional nodes and a risk of distant metastasis. of the regional nodes seems to survival in the of substantial and distant metastases, the on survival of patients with or latent metastases to be we are to a to the will have enough patients to complete removal of the regional lymph nodes is of therapeutic benefit in patients with lymph node metastases identified by The trial will at least patients at cancer in the and It is possible that LM/SL will therapeutic in the of patients with primary in thickness, most of patients will have metastases only in the SN, CLND what patients whose SN is positive but who also may have metastases in of the same regional early removal of metastases be of We will have the answer in years if most of the melanoma This trial has been from the National in of the SN, sentinel and LM/SL, lymphatic mapping and sentinel the we have a the of metastasis from the primary melanoma to the regional and to distant The primary melanoma as we some years the nodes to a primary melanoma are to This is also evident in the defined SN, the node most to the the direct drainage lymphatic pathway from the primary melanoma. is in multiple but especially in the and of cells and cells in the We believe this to a in that to the and of micrometastases in the SN. the of tumour cells in the SN exceeds a the of factors can lead to of lymph nodes the lymphatic and to of lymph nodes, which the risk of and the of spread tumour This the number of tumour‐involved nodes and relatively survival when CLND is delayed and performed to remove palpable metastases (Table 4 of the and area of cells and cells in of sentinel nodes and nodes from patients with on stage melanoma. SN was with a from the same with from the development of substantial and metastases, surgical removal of the regional nodes not the of distant metastases are relatively small and of tumour cells susceptible to by the long‐term survival. the patients who are most likely to benefit from LM/SL are those in nodal metastases are in the SN to the incidence of nodal metastases on the thickness of the primary melanoma (Table 4 lymph node removal have little on survival when the primary tumour is of patients have nodal in the the primary is before the melanoma has an opportunity to spread to the regional nodes. patients with 4 primary cutaneous are to benefit from ELND because the risk of metastasis beyond the regional lymph nodes is However, this a group of patients with primary whose disease is limited to the regional node basin and to the SN within that basin. In early removal of the SN the how can we identify We developed LM/SL as a to this Although primary tumour is the most important factor in the risk of regional and metastases, it is not the 25, in the primary melanoma associated with of are involved, as is the Even palpable nodal metastases may be confined to the regional nodes by that the and of tumour cells or because of the make tumour cells to to the and grow at distant factors why a clinically palpable nodal metastasis more melanoma cells can without nodal or and why therapeutic lymph node dissection can be followed by survival of 25 years or more without Although we with Drs Medalie and Ackerman with to the and of in the of patients with nodal we that randomized trials with such as therapeutic cancer will the clinical The of trials of on accurate staging of patient whose disease is can benefit by immediate in a trial of a potentially therapy that would not be available until after the trial is which in an might be many years The of Drs Medalie and Ackerman in this is thus curious and The of LM/SL to a from a has been found in when the cannot a of melanoma or a We do not the opinion that of by an informed will allow accurate to or If the cannot be of the we the as a possible with a excision and In the by SN can and in the of If the node is or no regional surgery is required and the patient can be If the node true metastases, CLND is and therapy the and of Drs Medalie and Ackerman are The of LM/SL in the of primary cutaneous melanoma is on its to more staging and prognostic on its potential therapeutic benefit in patients whose metastasis is limited to the SN, and for in the and of the We believe that LM/SL has been shown to have an important in the staging of primary cutaneous melanoma and in of likely clinical accuracy for staging and has been validated in multicentre trials and by multiple in the and Our data that of melanoma patients with microscopic nodal metastases by LM/SL will be and well years and may never the with the number of tumour‐involved nodes. LM/SL may also have therapeutic utility in patients whose primary has spread to the regional lymph nodes; the and of a therapeutic benefit cannot be until the results of the randomized and trials are immediate of the sentinel node procedure, a technique that is justified by its in staging the regional nodes and or not it to be Dr Medalie and Dr Ackerman would be well to of the Phase III trials and this in more on the of