Editorial
False-negative sentinel lymph node biopsy in melanoma patients Gianpiero Mancaa, Domenico Rubelloc, Antonella Romaninib and Giuliano Mariania Nuclear Medicine Communications 2014, 35:989–994 a
b
Regional Center of Nuclear Medicine, University of Pisa, Department of Oncology, University Hospital of Pisa, Pisa and cDepartment of Nuclear Medicine, ‘Santa Maria della Misericordia’ Hospital, Rovigo, Italy
Correspondence to Domenico Rubello, MD, Department of Imaging, Service of Nuclear Medicine & PET/CT Centre, Santa Maria della Misericordia Hospital, Via Tre Martiri 140, 45100 Rovigo, Italy Tel: + 39 0425 39 4548; fax: + 39 0425 39 3436; e-mail: [email protected] Received 15 April 2014 Accepted 23 June 2014
The management of cutaneous melanoma has changed completely with the introduction in clinical practice of lymphatic mapping and sentinel lymph node biopsy (SLNB), universally acknowledged as standard procedure for lymph nodal staging. SLNB allows the identification of approximately one-quarter of melanoma patients with clinically occult lymphatic regional metastasis at diagnosis. Moreover, it is currently recognized that the pathological status of sentinel lymph node (SLN) is the single most important prognostic factor for earlystage cutaneous melanoma patients. Therefore, this factor has been included in the current TNM staging system [1,2]. The introduction of SLNB for the management of cutaneous melanoma patients has also led to better local control of the disease and improved survival [3,4]. Despite a clinically negative lymph node status, this method allows the identification of patients with occult nodal metastasis. Regional complete lymph node dissection (RCLD) of the involved basin, guided by positive SLNB, ameliorates the clinical outcomes of these patients, by preventing clinical (palpable) regional lymph node metastasis [3,4]. Instead, patients with negative SLNB are classified as node negative and hence do not require further treatment – RCLD. Thus, SLNB as a mini-invasive procedure significantly reduces the morbidity associated with elective lymph node dissection systematically carried out on melanoma patients, as it exposes only those patients who actually benefit from lymphadenectomy to the risk of lymphedema or other complications. All these aspects have prompted worldwide diffusion of routine SLNB at an unusually high rate for oncologic surgery, even if the use of this technique has raised several issues: as a matter of fact, great variability exists in the rates of false-negative cases reported in the literature – that is, the histologically negative SLN in the presence of metastatic non-SLN nodes. The significance of falsenegative SLNB on the prognosis of melanoma patients is still debated, as long-term outcomes of ongoing controlled clinical follow-up trials have not yet been made 0143-3636 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
available [3]. Improved diagnostic accuracy of SLNB would, however, be crucial if a drug were produced that could change the survival of melanoma patients in stage III. Morton, who first introduced SLNB for melanoma patients, performed routine RCLD to validate the method, finding a promising low false-negative rate of around 1% [5]. Later, routine RCLD was abandoned, and the false-negative cases were evaluated on the basis of tumour relapse identification in a previously mapped nodal basin, where SLN had been considered negative for metastasis. In this respect, an adequate definition should be used to calculate the SLNB false-negative rate – that is, the ratio of false-negative outcomes (occurrence of lymph node metastasis in a basin formerly classified as negative by SLNB) with respect to the overall number of ‘actual’ positive lymph nodes (namely false negatives plus true positives). The initial studies carried out with this approach showed an incidence of false-negative cases greater than that originally reported by Morton and colleagues [4,6,7]. A number of large-scale studies performed in various institutions and by different collaborative groups confirmed this trend, which resulted in false-negative rates in the 5.6–21% range [8–15]. These values are somewhat alarming, as they are higher than the ones reported by early validation studies on SLNB based on RCLD performed as the gold standard [5]. Possible sources of errors inducing a false-negative SLNB may be attributed to the different basic technical components of the method, used either alone or in combination (nuclear medicine, surgical and pathological components). However, other possible biological sources of failure also exist. First, the fundamental paradigm of SLNB, namely, the ordered and sequential spread of metastasis in a specific lymph node basin, might not always be applicable; indeed, cutaneous melanoma represents a particular tumour associated with a certain degree of variability in metastatic diffusion through the lymphatic system. The metastatic cells may pass through an SLN, colonizing a second-echelon lymph node, without producing metastasis in the SLN. Moreover, at DOI: 10.1097/MNM.0000000000000171
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
990
Nuclear Medicine Communications 2014, Vol 35 No 10
the time of lymphatic mapping the SLN might already contain a cluster of metastatic cells obstructing the lymphatic channel [16], thus determining a bypass of radiocolloid and/or blue dye towards a ‘new’ sentinel node not yet affected by massive metastasis. A false-negative result may also depend on the fact that melanoma cells are still flowing (in transit) at the time of the SLNB procedure. The variabilities in lymphatic drainage pattern and biology of melanoma are intrinsic factors of the disease possibly affecting the accuracy of SLNB in terms of falsenegative findings, but that cannot be properly addressed/ modified. Therefore, in this discussion we focus our attention on those technical variables that can be ameliorated. In particular, we will address the technical issues that the nuclear physician, the surgeon and the pathologist should carefully consider in order to improve the accuracy of SLNB by minimizing the false-negative rate. We also describe the clinicopathologic features of melanoma that are more often associated with a falsenegative SLNB. This issue is extremely important for identifying and monitoring patients at high risk of having a false-negative SLNB, so that local lymph node metastatic disease can be detected as soon as possible. Finally, we will discuss the clinical impact that a false-negative SLNB can have on the prognosis of melanoma patients. With respect to the technical aspects, a possible source of error in identifying the correct SLN is represented by inadequate radiocolloid injection. More precisely, the radiotracer must be administered in closest proximity to the biopsy area or scar (site of the previous cutaneous melanoma), so that radiocolloid drainage can actually reflect the lymphatic drainage from that specific area of the skin. In addition, it is well known that a radiocolloid injection deeper than subdermal may diminish the accuracy of SLNB, similarly as injection at a greater distance from the biopsy site can do [17]. Still from a technical point of view, planar lymphoscintigraphy may in some cases be unable to identify SLNs – in particular if it is carried out without dynamic acquisition. A number of studies [18–27] have demonstrated that single-photon emission computed tomography/computed tomography (SPECT/CT) has a definite incremental value with respect to planar imaging but should be considered complementary and not alternative to dynamic imaging. Improved diagnostic accuracy of SPECT/CT imaging for SLN mapping in melanoma patients includes a higher SLN identification rate (IR), increased ability to detect SLNs in the presence of ambiguous/unclear planar imaging, enhanced SLN visualization close to the radiotracer injection area, better identification of ‘in-transit’ nodes, and ameliorated anatomical SLN localization, in particular in the areas of the trunk, head and neck, for which the false-negative SLNB rate is the highest [14,18–29]. Moreover, three-
dimensional volume rendering imaging obtained by SPECT/CT allows the precise identification of SLN localization with respect to anatomic structures, including muscles, nerves and blood vessels. Therefore, the surgeons supplied with this excellent roadmap are well supported in their SLN search and dissection. Other potential sources of error are related to the surgical technique. The operational definition of an SLN is in itself somewhat arbitrary, with particular regard to the possible visualization of multiple SLNs and to the percentage of radioactivity that a lymph node should have so as to be considered sufficiently ‘hot’ to be removed and examined. In this respect, a number of radioactive nodes are often spotted in the same lymphatic basin by lymphoscintigraphy and/or intraoperative γ-probe counting. It is not always certain whether these multiple radioactive lymph nodes are ‘actual’ SLNs or only second-echelon nodes sequentially visualized by the radiocolloid after crossing the ‘true’ SLN (especially when radiocolloid drainage has not been appropriately evaluated by dynamic lymphoscintigraphic acquisition). Some scholars define SLN according to the absolute number of radioactive counts in the nodes, whereas others use the ratio of in-vivo or ex-vivo radioactive counting in the node with respect to the background [30,31]. All these approaches are rather arbitrary/empiric, and debate is still ongoing on the optimal strategy for harvesting the radioactive lymph nodes to be analysed. A threshold of 10% or more of the count rate in the most radioactive SLN has been extensively reported in the literature [32]. However, this approach may result in an unnecessary removal of a number of non-SLNs [30]. In addition, this empirical modality has not been suitably validated with long-term follow-up for calculating the false-negative rate – that is, the ratio of false-negative results (recurrence in a basin previously classified as negative by SLNB) with respect to the overall number of ‘actual’ positive lymph nodes (false negatives plus true positives). This lack of actual standardization in the technique translates into the absence of a unique operational definition of SLN in the international guidelines [33–35], which in turn results in variable SLNB false-negative rates [4,9–14] The different scientific associations in nuclear medicine should thus reach an agreement to define an optimal intraoperative counting threshold so that the surgeon can be radioguided to detect and remove only those lymph nodes most likely to host metastases, preventing useless harvest of radioactive non-SLNs. Another possible source of error for SLNB may be the pathological examination of SLNs [36]. SLNs are conventionally analysed by hematoxylin and eosin (H&E) staining combined with immunohistochemical analysis, a quite sensitive method that has, nevertheless, some drawbacks. Although SLN is extensively examined with numerous serial tissue slices, the lymph node is seldom
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
False-negative SLNB in melanoma patients Manca et al. 991
analysed in its entirety, and hence the tumour cells may occasionally be undetected, leading to the erroneous classification of SLN as negative for metastasis. In such a case, the patient not submitted to RCLD would be at risk of recurrence in the previously mapped nodal basin where SLN had been considered falsely negative for metastasis. More accurate SLN sampling leads to identification of a larger number of metastatic nodes, thus reducing the number of SLNB false-negative cases [37–42].
held γ-probe. Some portable small-field-of-view gamma cameras offer the possibility of indicating the SLN location on the skin by laser or external radioactive pointers. These features are particularly important when the melanoma is located in complex areas such as the head and neck, and when SLNs are difficult to locate by conventional γ-probe counting alone because they are close to the radiocolloid injection site [45]. These devices can also help retrieve in-transit SLNs, which, in some cases, appear in rare locations [46].
It has also been demonstrated that a more sensitive method for SLN analysis like RT-PCR molecular analysis [41,42] reduces the false-negative rate of SLNB in melanoma patients, even if this ultrasensitive method may produce some false-positive cases [43].
Although performed in breast cancer patients, in a pilot study Mathelin and colleagues showed the feasibility of an intraoperative small-field-of-view gamma camera SLN detection. The intraoperative gamma camera aided in detecting an additional (metastatic) SLN that had not been visualized by preoperative imaging or by a γ-probe, thus suggesting that intraoperative gamma camera imaging may reduce the false-negative detection rate [47].
In a previous study from our group, a novel operational definition of intrasurgical detection of SLNs (based on a 20% threshold relative to the ‘hottest’ node) combined with SLN molecular analysis (in addition to conventional H&E and immunohistochemistry) considerably reduced the number of false-negative cases. After a median follow-up of 55 months, the false-negative rate was as low as 3.6%, with a negative predictive value of 99% [42]. A recent meta-analysis [44] identified another factor affecting SLNB accuracy – the IR of the technique – namely, the ratio between the number of patients with at least one removed SLN and the total number of patients submitted to SLNB. In particular, IR tended to increase over time in most of the published series, reflecting a learning curve during which the surgeon’s skills improved. As the SLNB false-negative rate decreases as IR improves, enhanced performance in the surgical technique corresponds to a better performance in the SLNB technique. On the basis of the above considerations, one can speculate that the introduction of novel imaging agents and intrasurgical imaging equipment in the clinical routine practice improves the SLN IR, resulting in better global accuracy of the technique. In this regard, portable gamma cameras have recently been employed for intraoperative use. These handy and practical tools offer the advantage of providing realtime high-resolution images during surgery, enabling the comparison of preoperative imaging results (lymphoscintigraphy, SPECT/CT) with findings at intraoperative radioactivity counting obtained by traditional systems. In fact, these portable devices can be oriented to the surgical targets in the operating room, based on the anatomical landmarks previously established by the SPECT/CT fused images. The portable gamma camera is especially helpful for excluding a remaining ‘hotspot’ after the hottest lymph node had been harvested [29]. In both open surgery and laparoscopy, these small devices can be used in combination with a conventional hand-
The new imaging agents introduced for SLN mapping have the potential to further improve the SLN IR. In particular, the novel use of hybrid tracers, which combine fluorescent dyes and radiotracers –for example, indocyanine green-99mTc-nanocolloid – allows intraoperative radio guidance and fluorescence guidance to the SLN by a single tracer injection and at the same time preoperative SLN mapping by lymphoscintigraphy and SPECT/CT imaging [48]. Moreover, the potential of hybrid tracers is especially high when they are combined with new surgical imaging equipment (portable gamma cameras, laparoscopic γ-probes, etc.) and intraoperative navigation tools (such as Freehand SPECT device) [49]. The tumour-related factors most frequently associated with SLNB false-negative cases in patients with cutaneous melanoma are as follows: older age at diagnosis, thicker lesions and ulceration at pathologic examination [14]. The association between advanced age and higher recurrence risk seems to depend on the lymphatic dysfunction associated with age, which possibly causes delayed migration of melanoma cells to the regional lymph nodes at the time of surgery [50]. Elderly patients may thus be at greater risk of false-negative outcomes. Location of the primary lesion in the head and neck region has been reported to be the most common anatomical site associated with local lymph node recurrence after a negative SLNB [14,51]. In this anatomical area, SLNB reliability can in fact be jeopardized by ambiguous and variable lymphatic drainage, and by the ‘shine through effect’ due to proximity with the radiocolloid injection site. Thicker Breslow melanomas are also associated with greater risk for a false-negative SLNB [6,13,14,43,44,52]. Another tumour-related biologic factor increasing the risk of recurrence after negative SLNB is the presence of ulceration at pathologic examination, in keeping with the well-established notion that ulceration is associated with increased biologic aggressiveness of
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
992 Nuclear Medicine Communications 2014, Vol 35 No 10
melanomas. Lymphovascular invasion [9,53], local/intransit recurrence [13], and increased mitotic activity [14, 54,55] are further histopathologic features of biologic aggressiveness associated with SLNB false-negative results. From a clinical point of view, false negativity of SLNB involves only a small subset of the melanoma patients undergoing the procedure; nevertheless, this occurrence leads one to consider the highly debated issue as to whether early detection and treatment of regional lymph nodal metastatic disease can improve patient survival. The rationale of performing RCLD after detecting a metastatic SLN depends on the hypothesis that tumour cells of primary cutaneous melanomas preferably spread through the lymphatic system to the locoregional lymphatic basin first, and then to more distant sites (the socalled ‘incubator hypothesis’). This model of sequential melanoma progression is widely accepted, even if it cannot always be applied, as in the case of thicker Breslow melanomas, in which hematogenous metastases are often concomitant with lymph node metastases (in such instance, neither SNB nor RCLD has a therapeutic significance) [3]. However, the ‘incubator hypothesis’ is supported by clinical trials showing that early detection and treatment of local lymph nodal metastatic disease by RCLD avoids the spread of melanoma cells beyond the SLN, with ensuing improved survival [14,4,56]. The long-term outcomes of these trials also suggest that patients with a false-negative SLNB, defined as clinically recurrent disease in a lymphatic basin originally classified as negative at SLNB, may have a worse prognosis than true-positive SLN patients (generally diagnosed with micrometastatic disease), owing to the more advanced stage of the disease at the time of diagnosis. However, this is still a strongly debated issue as most of the studies have been unable to prove statistically significant differences between false-negative SLNB patients and true-positive SLNB patients in terms of melanoma-specific survival [13]. This topic is being addressed by the Second Multicenter Selective Lymphadenectomy Trial II [3], which has been designed to assess the effects of regional lymphadenectomy on disease-free and overall survival in patients with SLN metastases identified by conventional pathology and/or molecular analysis. In conclusion, over the years it has become increasingly accepted that cutaneous melanoma must be correctly staged, so that patients with metastatic disease are treated surgically and with new molecules in an adjuvant setting for improved survival. The survival rate of melanoma patients in stage III is in the 70–39% range [1]. Interferon is currently the only drug that has been demonstrated to improve progression-free survival (17%) and, although to a lower extent (9%), overall survival [57–59]. At present, analysis is ongoing for the long-term results of a
randomized trial, whose accrual has been completed, testing the efficacy of a new drug (ipilimumab) in the adjuvant setting for stage III melanoma patients [60]. If the efficacy of this drug were confirmed, an accurate staging procedure for lymph node status would be even more important both for the patients and for oncologists. In this regard, all members of the multidisciplinary team involved in SLNB (surgeons, nuclear medicine physicians, pathologists, each one in their own fields of competence) should improve the performance of the technique, and thus contribute to diminishing the falsenegative rate of SLNB.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1
2
3
4
5
6
7
8
9
10
11
12
13
14
Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001; 19:3635–3648. Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001; 19:3622–3634. Morton DL. Overview and update of the phase III Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II) in melanoma. Clin Exp Metastasis 2012; 29:699–706. Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 2006; 355:1307–1317. Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992; 127:392–399. Gershenwald JE, Tseng CH, Thompson W, Mansfield PF, Lee JE, Bouvet M, et al. Improved sentinel lymph node localization in patients with primary melanoma with the use of radiolabeled colloid. Surgery 1998; 124:203–210. Gershenwald JE, Colome MI, Lee JE, Mansfield PF, Tseng C, Lee JJ, et al. Patterns of recurrence following a negative sentinel lymph node biopsy in 243 patients with stage I or II melanoma. J Clin Oncol 1998; 16:2253–2260. Jacobs IA, Chevinsky AH, Swayne LC, Magidson JG, Britto EJ, Smith TJ. Gamma probe-directed lymphatic mapping and sentinel lymphadenectomy in primary melanoma: reliability of the procedure and analysis of failures after long-term follow-up. J Surg Oncol 2001; 77:157–164. Chao C, Wong SL, Ross MI, Reintgen DS, Noyes RD, Cerrito PB, et al. Patterns of early recurrence after sentinel lymph node biopsy for melanoma. Am J Surg 2002; 184:520–524, discussion 525. Testori A, De Salvo GL, Montesco MC, Trifirò G, Mocellin S, Landi G, et al. Clinical considerations on sentinel node biopsy in melanoma from an Italian multicentric study on 1,313 patients (SOLISM-IMI). Ann Surg Oncol 2009; 16:2018–2027. Nowecki ZI, Rutkowski P, Nasierowska-Guttmejer A, Ruka W. Survival analysis and clinicopathological factors associated with false-negative sentinel lymph node biopsy findings in patients with cutaneous melanoma. Ann Surg Oncol 2006; 13:1655–1663. Cascinelli N, Bombardieri E, Bufalino R, Camerini T, Carbone A, Clemente C, et al. Sentinel and nonsentinel node status in stage IB and II melanoma patients: two-step prognostic indicators of survival. J Clin Oncol 2006; 24:4464–4471. Scoggins CR, Martin RC, Ross MI, Edwards MJ, Reintgen DS, Urist MM, et al. Factors associated with false-negative sentinel lymph node biopsy in melanoma patients. Ann Surg Oncol 2010; 17:709–717. Jones EL, Jones TS, Pearlman NW, Gao D, Stovall R, Gajdos C, et al. Long-term follow-up and survival of patients following a recurrence of melanoma after a negative sentinel lymph node biopsy result. JAMA Surg 2013; 148:456–461.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
False-negative SLNB in melanoma patients Manca et al. 993
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30 31 32
33
34
Thompson JF, Stretch JR, Uren RF, Ka VS, Scolyer RA. Sentinel node biopsy for melanoma: where have we been and where are we going? Ann Surg Oncol 2004; 11:147S–151S. Leijte JA, van der Ploeg IM, Valdés Olmos RA, Nieweg OE, Horenblas S. Visualization of tumor blockage and rerouting of lymphatic drainage in penile cancer patients by use of SPECT/CT. J Nucl Med 2009; 50:364–367. Uren RF, Howman-Giles R, Chung DK, Morton RL, Thompson JF. The reproducibility in routine clinical practice of sentinel lymph node identification by pre-operative lymphoscintigraphy in patients with cutaneous melanoma. Ann Surg Oncol 2007; 14:899–905. Even-Sapir E, Lerman H, Lievshitz G, Khafif A, Fliss DM, Schwart A, et al. Lymphoscintigraphy for sentinel node mapping using a hybrid SPECT/CT system. J Nucl Med 2003; 44:1413–1420. Ishihara T, Kaguchi A, Matsushita S, Shiraishi S, Tomiguchi S, Yamashita Y, et al. Management of sentinel lymphnodes in malignant skin tumors using dynamic lymphoscintigraphy and the single-photon-emission computed tomography/computed tomography combined system. Int J Clin Oncol 2006; 11:214–220. Van Der Ploeg IM, Valdés Olmos RA, Kroon BB, Wouters MW, van den Brekel MW, Vogel WV, et al. The yield of SPECT/CT for anatomical lymphatic mapping in patients with melanoma. Ann Surg Oncol 2009; 16:1537–1542. Covarelli P, Tomassini GM, Simonetti S, Messina S, Cini C, Petrina A, Noya G. The single-photon emission computed tomography/computed tomography: a new procedure to perform the sentinel node biopsy in patients with head and neck melanoma. Melanoma Res 2007; 17:323–328. Kretschmer L, Altenvoerde G, Meller J, Zutt M, Funke M, Neumann C, Becker W. Dynamic lymphoscintigraphy and image fusion of SPECT and pelvic CT-scans allow mapping of aberrant pelvic sentinel lymphnodes in malignant melanoma. Eur J Cancer 2003; 39:175–183. Mucientes Rasilla J, Cardona Arbonies J, Delgado Bolton R, Izarduy Pereyra L, Salazar Andia G, Prieto Soriano A, et al. SPECT-CT in sentinel node detection in patients with melanoma. Rev Esp Med Nucl 2009; 28:229–234. Vermeeren L, van der Ploeg IM, Olmos RA, Meinhardt W, Klop WM, Kroon BB, Nieweg OE. SPECT/CT for preoperative sentinel node localization. J Surg Oncol 2010; 101:184–190. Nielsen KR, Chakera AH, Hesse B, Scolyer RA, Stretch JF, Thompson JF, et al. The diagnostic value of adding dynamic scintigraphy to standard delayed planar imaging for sentinel node identification in melanoma patients. Eur J Nucl Med Mol Imaging 2011; 38:1999–2004. Veenstra HJ, Vermeeren L, Olmos RA, Nieweg OE. The additional value of lymphatic mapping with routine SPECT/CT in unselected patients with clinically localized melanoma. Ann Surg Oncol 2012; 19: 1018–1023. Klode J, Poeppel T, Boy C, Mueller S, Schadendorf D, Korber A, et al. Advantages of preoperative hybrid SPECT/CT in detection of sentinel lymph nodes in cutaneous head and neck malignancies. J Eur Acad Dermatol Venereol 2011; 25:1213–1221. Carlson GW, Page AJ, Cohen C, Parker D, Yaar R, Li A, et al. Regional recurrence after negative sentinel lymph node biopsy for melanoma. Ann Surg 2008; 248:78–386. Vidal-Sicart S, Valdés Olmos RA. Preoperative and intraoperative lymphatic mapping for radioguided sentinel node biopsy in cutaneous melanoma. In: Mariani G, Manca G, Orsini F, Vidal-Sicart S, Valdés Olmos RA, editors. Atlas of lymphoscintigraphy and sentinel node mapping. Milan, Italy: SpringerVerlag; 2013. pp. 169–180. Coit DG. The ‘true’ sentinel lymph node: in search of an operational definition of a biological phenomenon. Ann Surg Oncol 2001; 8:187–189. Morton DL, Bostick PJ. Will the true sentinel node please stand? Ann Surg Oncol 1999; 6:12–14. McMasters KM, Reintgen DS, Ross MI, Wong SL, Gershenwald JE, Krag DN, et al. Sentinel lymph node biopsy for melanoma: how many radioactive nodes should be removed? Ann Surg Oncol 2001; 8:192–197. Alazraki N, Glass EC, Castronovo F, Olmos RA, Podoloff D, Society of Nuclear Medicine. Procedure guideline for lymphoscintigraphy and the use of intraoperative gamma probe for sentinel lymphnode localization in melanoma of intermediate thickness 1.0. J Nucl Med 2002; 43:1414–1418. Wong SL, Balch CM, Hurley P, Agarwala SS, Akhurst TJ, Cochran A, et al. American Society of Clinical Oncology; Society of Surgical Oncology. Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J Clin Oncol 2002; 30:2912–2918.
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
Buscombe J, Paganelli G, Burak ZE, Waddington W, Maublant J, Prats E, et al. Sentinel node in breast cancer procedural guidelines. Eur J Nucl Med Mol Imaging 2007; 34:2154–2159. Karim RZ, Scolyer RA, Li W, Yee VS, McKinnon JG, Li LX, et al. False negative sentinel lymph node biopsies in melanoma may result from deficiencies in nuclear medicine, surgery, or pathology. Ann Surg 2008; 247:1003–1010. Shivers SC, Wang X, Li W, Joseph E, Messina J, Glass LF, et al. Molecular staging of malignant melanoma: correlation with clinical outcome. JAMA 1998; 280:1410–1415. Bostick PJ, Morton DL, Turner RR, Huynh KT, Wang HJ, Elashoff R, et al. Prognostic significance of occult metastases detected by sentinel lymphadenectomy and reverse transcriptase-polymerase chain reaction in early-stage melanoma patients. J Clin Oncol 1999; 17:3238–3244. Blaheta HJ, Ellwanger U, Schittek B, Sotlar K, MacZey E, Breuninger H, et al. Examination of regional lymph nodes by sentinel node biopsy and molecular analysis provides new staging facilities in primary cutaneous melanoma. J Invest Dermatol 2000; 114:637–642. Romanini A, Manca G, Pellegrino D, Murr R, Sarti S, Bianchi F, et al. Molecular staging of the sentinel lymph node in melanoma patients: correlation with clinical outcome. Ann Oncol 2005; 16:1832–1840. Mocellin S, Hoon DS, Pilati P, Rossi CR, Nitti D. Sentinel lymph node molecular ultrastaging in patients with melanoma: a systematic review and meta-analysis of prognosis. J Clin Oncol 2007; 25:1588–1595. Manca G, Romanini A, Pellegrino D, Borsò E, Rondini M, Orlandini C, et al. Optimal detection of sentinel lymph node metastases by intraoperative radioactive threshold and molecular analysis in patients with melanoma. J Nucl Med 2008; 49:1769–1775. Scoggins CR, Ross MI, Reintgen DS, Noyes RD, Goydos JS, Beitsch PD, et al. Prospective multi-institutional study of reverse transcriptase polymerase chain reaction for molecular staging of melanoma. J Clin Oncol 2006; 24:2849–2857. Valsecchi ME, Silbermins D, de Rosa N, Wong SL, Lyman GH. Lymphatic mapping and sentinel lymph node biopsy in patients with melanoma: a metaanalysis. J Clin Oncol 2011; 29:1479–1487. Vermeeren L, Valdés Olmos RA, Klop WM, Balm AJ, van den Brekel MW. A portable gamma-camera for intraoperative detection of sentinel nodes in the head and neck region. J Nucl Med 2010; 51:700–703. Vidal-Sicart S, Paredes P, Zanón G, Pahisa J, Martinez-Román S, Caparrón X, et al. Added value of intraoperative real-time imaging in searches for difficult-to-locate sentinel nodes. J Nucl Med 2010; 51:1219–1225. Mathelin C, Salvador S, Huss D, Guyonnet L. Precise localization of sentinel lymph nodes and estimation of their depth using a prototype intraoperative mini gamma-camera in patients with breast cancer. J Nucl Med 2007; 48:623–629. Van Den Berg NS, Buckle T, Kleinjan GI, Klop WMC, Horenblas S, Van Der Poel H, et al. Hybrid tracers for sentinel node biopsy. Q J Nucl Med Mol Imaging 2014; 58:193–206. KleinJan GH, Bunschoten A, Brouwer OR, Van Den Berg NS, Valdés Olmos RA, van Leeuwen FWB. Multimodal imaging in radioguided surgery. Clin Transl Imaging 2013; 1:433–444. Conway WC, Faries MB, Nicholl MB, Terando AM, Glass EC, Sim M, Morton DL. Age-related lymphatic dysfunction in melanoma patients. Ann Surg Oncol 2009; 16:1548–1552. Saltman BE, Ganly I, Patel SG, Coit DG, Brady MS, Wong RJ, et al. Prognostic implication of sentinel lymph node biopsy in cutaneous head and neck melanoma. Head Neck 2010; 32:1686–1692. Balch CM, Soong SJ, Murad TM, Ingalls AL, Maddox WA. A multifactorial analysis of melanoma. II. Prognostic factors in patients with stage I (localized) melanoma. Surgery 1979; 86:343–351. Clary BM, Brady MS, Lewis JJ, Coit DG. Sentinel lymph node biopsy in the management of patients with primary cutaneous melanoma: review of a large single-institutional experience with an emphasis on recurrence. Ann Surg 2001; 233:250–258. Balch CM, Gershenwald JE, Soong SJ, Thompson JF. Update on the melanoma staging system: the importance of sentinel node staging and primary tumor mitotic rate. J Surg Oncol 2011; 104:379–385. Roach BA, Burton AL, Mays MP, Ginter BA, Martin RC, Stromberg AJ, et al. Does mitotic rate predict sentinel lymph node metastasis or survival in patients with intermediate and thick melanoma? Am J Surg 2010; 200:759–763, discussion 763764.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
994
Nuclear Medicine Communications 2014, Vol 35 No 10
56 Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Nieweg OE, Roses DF, et al. MSLT Group. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 2014; 370:599–609. 57 Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996; 14:7–17.
58 Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 2010; 102:493–501. 59 Mocellin S, Lens MB, Pasquali S, Pilati P, Chiarion Sileni V. Interferon alpha for the adjuvant treatment of cutaneous melanoma. Cochrane Database Syst Rev 2013; 6:CD008955. 60 Eggermont AM, Testori A, Maio M, Robert C. AntiYCTLA-4 antibody adjuvant therapy in melanoma. Semin Oncol 2010; 37:455Y459.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
False-negative sentinel lymph node biopsy in melanoma patients Gianpiero Mancaa, Domenico Rubelloc, Antonella Romaninib and Giuliano Mariania Nuclear Medicine Communications 2014, 35:989–994 a
b
Regional Center of Nuclear Medicine, University of Pisa, Department of Oncology, University Hospital of Pisa, Pisa and cDepartment of Nuclear Medicine, ‘Santa Maria della Misericordia’ Hospital, Rovigo, Italy
Correspondence to Domenico Rubello, MD, Department of Imaging, Service of Nuclear Medicine & PET/CT Centre, Santa Maria della Misericordia Hospital, Via Tre Martiri 140, 45100 Rovigo, Italy Tel: + 39 0425 39 4548; fax: + 39 0425 39 3436; e-mail: [email protected] Received 15 April 2014 Accepted 23 June 2014
The management of cutaneous melanoma has changed completely with the introduction in clinical practice of lymphatic mapping and sentinel lymph node biopsy (SLNB), universally acknowledged as standard procedure for lymph nodal staging. SLNB allows the identification of approximately one-quarter of melanoma patients with clinically occult lymphatic regional metastasis at diagnosis. Moreover, it is currently recognized that the pathological status of sentinel lymph node (SLN) is the single most important prognostic factor for earlystage cutaneous melanoma patients. Therefore, this factor has been included in the current TNM staging system [1,2]. The introduction of SLNB for the management of cutaneous melanoma patients has also led to better local control of the disease and improved survival [3,4]. Despite a clinically negative lymph node status, this method allows the identification of patients with occult nodal metastasis. Regional complete lymph node dissection (RCLD) of the involved basin, guided by positive SLNB, ameliorates the clinical outcomes of these patients, by preventing clinical (palpable) regional lymph node metastasis [3,4]. Instead, patients with negative SLNB are classified as node negative and hence do not require further treatment – RCLD. Thus, SLNB as a mini-invasive procedure significantly reduces the morbidity associated with elective lymph node dissection systematically carried out on melanoma patients, as it exposes only those patients who actually benefit from lymphadenectomy to the risk of lymphedema or other complications. All these aspects have prompted worldwide diffusion of routine SLNB at an unusually high rate for oncologic surgery, even if the use of this technique has raised several issues: as a matter of fact, great variability exists in the rates of false-negative cases reported in the literature – that is, the histologically negative SLN in the presence of metastatic non-SLN nodes. The significance of falsenegative SLNB on the prognosis of melanoma patients is still debated, as long-term outcomes of ongoing controlled clinical follow-up trials have not yet been made 0143-3636 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
available [3]. Improved diagnostic accuracy of SLNB would, however, be crucial if a drug were produced that could change the survival of melanoma patients in stage III. Morton, who first introduced SLNB for melanoma patients, performed routine RCLD to validate the method, finding a promising low false-negative rate of around 1% [5]. Later, routine RCLD was abandoned, and the false-negative cases were evaluated on the basis of tumour relapse identification in a previously mapped nodal basin, where SLN had been considered negative for metastasis. In this respect, an adequate definition should be used to calculate the SLNB false-negative rate – that is, the ratio of false-negative outcomes (occurrence of lymph node metastasis in a basin formerly classified as negative by SLNB) with respect to the overall number of ‘actual’ positive lymph nodes (namely false negatives plus true positives). The initial studies carried out with this approach showed an incidence of false-negative cases greater than that originally reported by Morton and colleagues [4,6,7]. A number of large-scale studies performed in various institutions and by different collaborative groups confirmed this trend, which resulted in false-negative rates in the 5.6–21% range [8–15]. These values are somewhat alarming, as they are higher than the ones reported by early validation studies on SLNB based on RCLD performed as the gold standard [5]. Possible sources of errors inducing a false-negative SLNB may be attributed to the different basic technical components of the method, used either alone or in combination (nuclear medicine, surgical and pathological components). However, other possible biological sources of failure also exist. First, the fundamental paradigm of SLNB, namely, the ordered and sequential spread of metastasis in a specific lymph node basin, might not always be applicable; indeed, cutaneous melanoma represents a particular tumour associated with a certain degree of variability in metastatic diffusion through the lymphatic system. The metastatic cells may pass through an SLN, colonizing a second-echelon lymph node, without producing metastasis in the SLN. Moreover, at DOI: 10.1097/MNM.0000000000000171
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
990
Nuclear Medicine Communications 2014, Vol 35 No 10
the time of lymphatic mapping the SLN might already contain a cluster of metastatic cells obstructing the lymphatic channel [16], thus determining a bypass of radiocolloid and/or blue dye towards a ‘new’ sentinel node not yet affected by massive metastasis. A false-negative result may also depend on the fact that melanoma cells are still flowing (in transit) at the time of the SLNB procedure. The variabilities in lymphatic drainage pattern and biology of melanoma are intrinsic factors of the disease possibly affecting the accuracy of SLNB in terms of falsenegative findings, but that cannot be properly addressed/ modified. Therefore, in this discussion we focus our attention on those technical variables that can be ameliorated. In particular, we will address the technical issues that the nuclear physician, the surgeon and the pathologist should carefully consider in order to improve the accuracy of SLNB by minimizing the false-negative rate. We also describe the clinicopathologic features of melanoma that are more often associated with a falsenegative SLNB. This issue is extremely important for identifying and monitoring patients at high risk of having a false-negative SLNB, so that local lymph node metastatic disease can be detected as soon as possible. Finally, we will discuss the clinical impact that a false-negative SLNB can have on the prognosis of melanoma patients. With respect to the technical aspects, a possible source of error in identifying the correct SLN is represented by inadequate radiocolloid injection. More precisely, the radiotracer must be administered in closest proximity to the biopsy area or scar (site of the previous cutaneous melanoma), so that radiocolloid drainage can actually reflect the lymphatic drainage from that specific area of the skin. In addition, it is well known that a radiocolloid injection deeper than subdermal may diminish the accuracy of SLNB, similarly as injection at a greater distance from the biopsy site can do [17]. Still from a technical point of view, planar lymphoscintigraphy may in some cases be unable to identify SLNs – in particular if it is carried out without dynamic acquisition. A number of studies [18–27] have demonstrated that single-photon emission computed tomography/computed tomography (SPECT/CT) has a definite incremental value with respect to planar imaging but should be considered complementary and not alternative to dynamic imaging. Improved diagnostic accuracy of SPECT/CT imaging for SLN mapping in melanoma patients includes a higher SLN identification rate (IR), increased ability to detect SLNs in the presence of ambiguous/unclear planar imaging, enhanced SLN visualization close to the radiotracer injection area, better identification of ‘in-transit’ nodes, and ameliorated anatomical SLN localization, in particular in the areas of the trunk, head and neck, for which the false-negative SLNB rate is the highest [14,18–29]. Moreover, three-
dimensional volume rendering imaging obtained by SPECT/CT allows the precise identification of SLN localization with respect to anatomic structures, including muscles, nerves and blood vessels. Therefore, the surgeons supplied with this excellent roadmap are well supported in their SLN search and dissection. Other potential sources of error are related to the surgical technique. The operational definition of an SLN is in itself somewhat arbitrary, with particular regard to the possible visualization of multiple SLNs and to the percentage of radioactivity that a lymph node should have so as to be considered sufficiently ‘hot’ to be removed and examined. In this respect, a number of radioactive nodes are often spotted in the same lymphatic basin by lymphoscintigraphy and/or intraoperative γ-probe counting. It is not always certain whether these multiple radioactive lymph nodes are ‘actual’ SLNs or only second-echelon nodes sequentially visualized by the radiocolloid after crossing the ‘true’ SLN (especially when radiocolloid drainage has not been appropriately evaluated by dynamic lymphoscintigraphic acquisition). Some scholars define SLN according to the absolute number of radioactive counts in the nodes, whereas others use the ratio of in-vivo or ex-vivo radioactive counting in the node with respect to the background [30,31]. All these approaches are rather arbitrary/empiric, and debate is still ongoing on the optimal strategy for harvesting the radioactive lymph nodes to be analysed. A threshold of 10% or more of the count rate in the most radioactive SLN has been extensively reported in the literature [32]. However, this approach may result in an unnecessary removal of a number of non-SLNs [30]. In addition, this empirical modality has not been suitably validated with long-term follow-up for calculating the false-negative rate – that is, the ratio of false-negative results (recurrence in a basin previously classified as negative by SLNB) with respect to the overall number of ‘actual’ positive lymph nodes (false negatives plus true positives). This lack of actual standardization in the technique translates into the absence of a unique operational definition of SLN in the international guidelines [33–35], which in turn results in variable SLNB false-negative rates [4,9–14] The different scientific associations in nuclear medicine should thus reach an agreement to define an optimal intraoperative counting threshold so that the surgeon can be radioguided to detect and remove only those lymph nodes most likely to host metastases, preventing useless harvest of radioactive non-SLNs. Another possible source of error for SLNB may be the pathological examination of SLNs [36]. SLNs are conventionally analysed by hematoxylin and eosin (H&E) staining combined with immunohistochemical analysis, a quite sensitive method that has, nevertheless, some drawbacks. Although SLN is extensively examined with numerous serial tissue slices, the lymph node is seldom
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
False-negative SLNB in melanoma patients Manca et al. 991
analysed in its entirety, and hence the tumour cells may occasionally be undetected, leading to the erroneous classification of SLN as negative for metastasis. In such a case, the patient not submitted to RCLD would be at risk of recurrence in the previously mapped nodal basin where SLN had been considered falsely negative for metastasis. More accurate SLN sampling leads to identification of a larger number of metastatic nodes, thus reducing the number of SLNB false-negative cases [37–42].
held γ-probe. Some portable small-field-of-view gamma cameras offer the possibility of indicating the SLN location on the skin by laser or external radioactive pointers. These features are particularly important when the melanoma is located in complex areas such as the head and neck, and when SLNs are difficult to locate by conventional γ-probe counting alone because they are close to the radiocolloid injection site [45]. These devices can also help retrieve in-transit SLNs, which, in some cases, appear in rare locations [46].
It has also been demonstrated that a more sensitive method for SLN analysis like RT-PCR molecular analysis [41,42] reduces the false-negative rate of SLNB in melanoma patients, even if this ultrasensitive method may produce some false-positive cases [43].
Although performed in breast cancer patients, in a pilot study Mathelin and colleagues showed the feasibility of an intraoperative small-field-of-view gamma camera SLN detection. The intraoperative gamma camera aided in detecting an additional (metastatic) SLN that had not been visualized by preoperative imaging or by a γ-probe, thus suggesting that intraoperative gamma camera imaging may reduce the false-negative detection rate [47].
In a previous study from our group, a novel operational definition of intrasurgical detection of SLNs (based on a 20% threshold relative to the ‘hottest’ node) combined with SLN molecular analysis (in addition to conventional H&E and immunohistochemistry) considerably reduced the number of false-negative cases. After a median follow-up of 55 months, the false-negative rate was as low as 3.6%, with a negative predictive value of 99% [42]. A recent meta-analysis [44] identified another factor affecting SLNB accuracy – the IR of the technique – namely, the ratio between the number of patients with at least one removed SLN and the total number of patients submitted to SLNB. In particular, IR tended to increase over time in most of the published series, reflecting a learning curve during which the surgeon’s skills improved. As the SLNB false-negative rate decreases as IR improves, enhanced performance in the surgical technique corresponds to a better performance in the SLNB technique. On the basis of the above considerations, one can speculate that the introduction of novel imaging agents and intrasurgical imaging equipment in the clinical routine practice improves the SLN IR, resulting in better global accuracy of the technique. In this regard, portable gamma cameras have recently been employed for intraoperative use. These handy and practical tools offer the advantage of providing realtime high-resolution images during surgery, enabling the comparison of preoperative imaging results (lymphoscintigraphy, SPECT/CT) with findings at intraoperative radioactivity counting obtained by traditional systems. In fact, these portable devices can be oriented to the surgical targets in the operating room, based on the anatomical landmarks previously established by the SPECT/CT fused images. The portable gamma camera is especially helpful for excluding a remaining ‘hotspot’ after the hottest lymph node had been harvested [29]. In both open surgery and laparoscopy, these small devices can be used in combination with a conventional hand-
The new imaging agents introduced for SLN mapping have the potential to further improve the SLN IR. In particular, the novel use of hybrid tracers, which combine fluorescent dyes and radiotracers –for example, indocyanine green-99mTc-nanocolloid – allows intraoperative radio guidance and fluorescence guidance to the SLN by a single tracer injection and at the same time preoperative SLN mapping by lymphoscintigraphy and SPECT/CT imaging [48]. Moreover, the potential of hybrid tracers is especially high when they are combined with new surgical imaging equipment (portable gamma cameras, laparoscopic γ-probes, etc.) and intraoperative navigation tools (such as Freehand SPECT device) [49]. The tumour-related factors most frequently associated with SLNB false-negative cases in patients with cutaneous melanoma are as follows: older age at diagnosis, thicker lesions and ulceration at pathologic examination [14]. The association between advanced age and higher recurrence risk seems to depend on the lymphatic dysfunction associated with age, which possibly causes delayed migration of melanoma cells to the regional lymph nodes at the time of surgery [50]. Elderly patients may thus be at greater risk of false-negative outcomes. Location of the primary lesion in the head and neck region has been reported to be the most common anatomical site associated with local lymph node recurrence after a negative SLNB [14,51]. In this anatomical area, SLNB reliability can in fact be jeopardized by ambiguous and variable lymphatic drainage, and by the ‘shine through effect’ due to proximity with the radiocolloid injection site. Thicker Breslow melanomas are also associated with greater risk for a false-negative SLNB [6,13,14,43,44,52]. Another tumour-related biologic factor increasing the risk of recurrence after negative SLNB is the presence of ulceration at pathologic examination, in keeping with the well-established notion that ulceration is associated with increased biologic aggressiveness of
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
992 Nuclear Medicine Communications 2014, Vol 35 No 10
melanomas. Lymphovascular invasion [9,53], local/intransit recurrence [13], and increased mitotic activity [14, 54,55] are further histopathologic features of biologic aggressiveness associated with SLNB false-negative results. From a clinical point of view, false negativity of SLNB involves only a small subset of the melanoma patients undergoing the procedure; nevertheless, this occurrence leads one to consider the highly debated issue as to whether early detection and treatment of regional lymph nodal metastatic disease can improve patient survival. The rationale of performing RCLD after detecting a metastatic SLN depends on the hypothesis that tumour cells of primary cutaneous melanomas preferably spread through the lymphatic system to the locoregional lymphatic basin first, and then to more distant sites (the socalled ‘incubator hypothesis’). This model of sequential melanoma progression is widely accepted, even if it cannot always be applied, as in the case of thicker Breslow melanomas, in which hematogenous metastases are often concomitant with lymph node metastases (in such instance, neither SNB nor RCLD has a therapeutic significance) [3]. However, the ‘incubator hypothesis’ is supported by clinical trials showing that early detection and treatment of local lymph nodal metastatic disease by RCLD avoids the spread of melanoma cells beyond the SLN, with ensuing improved survival [14,4,56]. The long-term outcomes of these trials also suggest that patients with a false-negative SLNB, defined as clinically recurrent disease in a lymphatic basin originally classified as negative at SLNB, may have a worse prognosis than true-positive SLN patients (generally diagnosed with micrometastatic disease), owing to the more advanced stage of the disease at the time of diagnosis. However, this is still a strongly debated issue as most of the studies have been unable to prove statistically significant differences between false-negative SLNB patients and true-positive SLNB patients in terms of melanoma-specific survival [13]. This topic is being addressed by the Second Multicenter Selective Lymphadenectomy Trial II [3], which has been designed to assess the effects of regional lymphadenectomy on disease-free and overall survival in patients with SLN metastases identified by conventional pathology and/or molecular analysis. In conclusion, over the years it has become increasingly accepted that cutaneous melanoma must be correctly staged, so that patients with metastatic disease are treated surgically and with new molecules in an adjuvant setting for improved survival. The survival rate of melanoma patients in stage III is in the 70–39% range [1]. Interferon is currently the only drug that has been demonstrated to improve progression-free survival (17%) and, although to a lower extent (9%), overall survival [57–59]. At present, analysis is ongoing for the long-term results of a
randomized trial, whose accrual has been completed, testing the efficacy of a new drug (ipilimumab) in the adjuvant setting for stage III melanoma patients [60]. If the efficacy of this drug were confirmed, an accurate staging procedure for lymph node status would be even more important both for the patients and for oncologists. In this regard, all members of the multidisciplinary team involved in SLNB (surgeons, nuclear medicine physicians, pathologists, each one in their own fields of competence) should improve the performance of the technique, and thus contribute to diminishing the falsenegative rate of SLNB.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1
2
3
4
5
6
7
8
9
10
11
12
13
14
Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001; 19:3635–3648. Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001; 19:3622–3634. Morton DL. Overview and update of the phase III Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II) in melanoma. Clin Exp Metastasis 2012; 29:699–706. Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 2006; 355:1307–1317. Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992; 127:392–399. Gershenwald JE, Tseng CH, Thompson W, Mansfield PF, Lee JE, Bouvet M, et al. Improved sentinel lymph node localization in patients with primary melanoma with the use of radiolabeled colloid. Surgery 1998; 124:203–210. Gershenwald JE, Colome MI, Lee JE, Mansfield PF, Tseng C, Lee JJ, et al. Patterns of recurrence following a negative sentinel lymph node biopsy in 243 patients with stage I or II melanoma. J Clin Oncol 1998; 16:2253–2260. Jacobs IA, Chevinsky AH, Swayne LC, Magidson JG, Britto EJ, Smith TJ. Gamma probe-directed lymphatic mapping and sentinel lymphadenectomy in primary melanoma: reliability of the procedure and analysis of failures after long-term follow-up. J Surg Oncol 2001; 77:157–164. Chao C, Wong SL, Ross MI, Reintgen DS, Noyes RD, Cerrito PB, et al. Patterns of early recurrence after sentinel lymph node biopsy for melanoma. Am J Surg 2002; 184:520–524, discussion 525. Testori A, De Salvo GL, Montesco MC, Trifirò G, Mocellin S, Landi G, et al. Clinical considerations on sentinel node biopsy in melanoma from an Italian multicentric study on 1,313 patients (SOLISM-IMI). Ann Surg Oncol 2009; 16:2018–2027. Nowecki ZI, Rutkowski P, Nasierowska-Guttmejer A, Ruka W. Survival analysis and clinicopathological factors associated with false-negative sentinel lymph node biopsy findings in patients with cutaneous melanoma. Ann Surg Oncol 2006; 13:1655–1663. Cascinelli N, Bombardieri E, Bufalino R, Camerini T, Carbone A, Clemente C, et al. Sentinel and nonsentinel node status in stage IB and II melanoma patients: two-step prognostic indicators of survival. J Clin Oncol 2006; 24:4464–4471. Scoggins CR, Martin RC, Ross MI, Edwards MJ, Reintgen DS, Urist MM, et al. Factors associated with false-negative sentinel lymph node biopsy in melanoma patients. Ann Surg Oncol 2010; 17:709–717. Jones EL, Jones TS, Pearlman NW, Gao D, Stovall R, Gajdos C, et al. Long-term follow-up and survival of patients following a recurrence of melanoma after a negative sentinel lymph node biopsy result. JAMA Surg 2013; 148:456–461.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
False-negative SLNB in melanoma patients Manca et al. 993
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30 31 32
33
34
Thompson JF, Stretch JR, Uren RF, Ka VS, Scolyer RA. Sentinel node biopsy for melanoma: where have we been and where are we going? Ann Surg Oncol 2004; 11:147S–151S. Leijte JA, van der Ploeg IM, Valdés Olmos RA, Nieweg OE, Horenblas S. Visualization of tumor blockage and rerouting of lymphatic drainage in penile cancer patients by use of SPECT/CT. J Nucl Med 2009; 50:364–367. Uren RF, Howman-Giles R, Chung DK, Morton RL, Thompson JF. The reproducibility in routine clinical practice of sentinel lymph node identification by pre-operative lymphoscintigraphy in patients with cutaneous melanoma. Ann Surg Oncol 2007; 14:899–905. Even-Sapir E, Lerman H, Lievshitz G, Khafif A, Fliss DM, Schwart A, et al. Lymphoscintigraphy for sentinel node mapping using a hybrid SPECT/CT system. J Nucl Med 2003; 44:1413–1420. Ishihara T, Kaguchi A, Matsushita S, Shiraishi S, Tomiguchi S, Yamashita Y, et al. Management of sentinel lymphnodes in malignant skin tumors using dynamic lymphoscintigraphy and the single-photon-emission computed tomography/computed tomography combined system. Int J Clin Oncol 2006; 11:214–220. Van Der Ploeg IM, Valdés Olmos RA, Kroon BB, Wouters MW, van den Brekel MW, Vogel WV, et al. The yield of SPECT/CT for anatomical lymphatic mapping in patients with melanoma. Ann Surg Oncol 2009; 16:1537–1542. Covarelli P, Tomassini GM, Simonetti S, Messina S, Cini C, Petrina A, Noya G. The single-photon emission computed tomography/computed tomography: a new procedure to perform the sentinel node biopsy in patients with head and neck melanoma. Melanoma Res 2007; 17:323–328. Kretschmer L, Altenvoerde G, Meller J, Zutt M, Funke M, Neumann C, Becker W. Dynamic lymphoscintigraphy and image fusion of SPECT and pelvic CT-scans allow mapping of aberrant pelvic sentinel lymphnodes in malignant melanoma. Eur J Cancer 2003; 39:175–183. Mucientes Rasilla J, Cardona Arbonies J, Delgado Bolton R, Izarduy Pereyra L, Salazar Andia G, Prieto Soriano A, et al. SPECT-CT in sentinel node detection in patients with melanoma. Rev Esp Med Nucl 2009; 28:229–234. Vermeeren L, van der Ploeg IM, Olmos RA, Meinhardt W, Klop WM, Kroon BB, Nieweg OE. SPECT/CT for preoperative sentinel node localization. J Surg Oncol 2010; 101:184–190. Nielsen KR, Chakera AH, Hesse B, Scolyer RA, Stretch JF, Thompson JF, et al. The diagnostic value of adding dynamic scintigraphy to standard delayed planar imaging for sentinel node identification in melanoma patients. Eur J Nucl Med Mol Imaging 2011; 38:1999–2004. Veenstra HJ, Vermeeren L, Olmos RA, Nieweg OE. The additional value of lymphatic mapping with routine SPECT/CT in unselected patients with clinically localized melanoma. Ann Surg Oncol 2012; 19: 1018–1023. Klode J, Poeppel T, Boy C, Mueller S, Schadendorf D, Korber A, et al. Advantages of preoperative hybrid SPECT/CT in detection of sentinel lymph nodes in cutaneous head and neck malignancies. J Eur Acad Dermatol Venereol 2011; 25:1213–1221. Carlson GW, Page AJ, Cohen C, Parker D, Yaar R, Li A, et al. Regional recurrence after negative sentinel lymph node biopsy for melanoma. Ann Surg 2008; 248:78–386. Vidal-Sicart S, Valdés Olmos RA. Preoperative and intraoperative lymphatic mapping for radioguided sentinel node biopsy in cutaneous melanoma. In: Mariani G, Manca G, Orsini F, Vidal-Sicart S, Valdés Olmos RA, editors. Atlas of lymphoscintigraphy and sentinel node mapping. Milan, Italy: SpringerVerlag; 2013. pp. 169–180. Coit DG. The ‘true’ sentinel lymph node: in search of an operational definition of a biological phenomenon. Ann Surg Oncol 2001; 8:187–189. Morton DL, Bostick PJ. Will the true sentinel node please stand? Ann Surg Oncol 1999; 6:12–14. McMasters KM, Reintgen DS, Ross MI, Wong SL, Gershenwald JE, Krag DN, et al. Sentinel lymph node biopsy for melanoma: how many radioactive nodes should be removed? Ann Surg Oncol 2001; 8:192–197. Alazraki N, Glass EC, Castronovo F, Olmos RA, Podoloff D, Society of Nuclear Medicine. Procedure guideline for lymphoscintigraphy and the use of intraoperative gamma probe for sentinel lymphnode localization in melanoma of intermediate thickness 1.0. J Nucl Med 2002; 43:1414–1418. Wong SL, Balch CM, Hurley P, Agarwala SS, Akhurst TJ, Cochran A, et al. American Society of Clinical Oncology; Society of Surgical Oncology. Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J Clin Oncol 2002; 30:2912–2918.
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
Buscombe J, Paganelli G, Burak ZE, Waddington W, Maublant J, Prats E, et al. Sentinel node in breast cancer procedural guidelines. Eur J Nucl Med Mol Imaging 2007; 34:2154–2159. Karim RZ, Scolyer RA, Li W, Yee VS, McKinnon JG, Li LX, et al. False negative sentinel lymph node biopsies in melanoma may result from deficiencies in nuclear medicine, surgery, or pathology. Ann Surg 2008; 247:1003–1010. Shivers SC, Wang X, Li W, Joseph E, Messina J, Glass LF, et al. Molecular staging of malignant melanoma: correlation with clinical outcome. JAMA 1998; 280:1410–1415. Bostick PJ, Morton DL, Turner RR, Huynh KT, Wang HJ, Elashoff R, et al. Prognostic significance of occult metastases detected by sentinel lymphadenectomy and reverse transcriptase-polymerase chain reaction in early-stage melanoma patients. J Clin Oncol 1999; 17:3238–3244. Blaheta HJ, Ellwanger U, Schittek B, Sotlar K, MacZey E, Breuninger H, et al. Examination of regional lymph nodes by sentinel node biopsy and molecular analysis provides new staging facilities in primary cutaneous melanoma. J Invest Dermatol 2000; 114:637–642. Romanini A, Manca G, Pellegrino D, Murr R, Sarti S, Bianchi F, et al. Molecular staging of the sentinel lymph node in melanoma patients: correlation with clinical outcome. Ann Oncol 2005; 16:1832–1840. Mocellin S, Hoon DS, Pilati P, Rossi CR, Nitti D. Sentinel lymph node molecular ultrastaging in patients with melanoma: a systematic review and meta-analysis of prognosis. J Clin Oncol 2007; 25:1588–1595. Manca G, Romanini A, Pellegrino D, Borsò E, Rondini M, Orlandini C, et al. Optimal detection of sentinel lymph node metastases by intraoperative radioactive threshold and molecular analysis in patients with melanoma. J Nucl Med 2008; 49:1769–1775. Scoggins CR, Ross MI, Reintgen DS, Noyes RD, Goydos JS, Beitsch PD, et al. Prospective multi-institutional study of reverse transcriptase polymerase chain reaction for molecular staging of melanoma. J Clin Oncol 2006; 24:2849–2857. Valsecchi ME, Silbermins D, de Rosa N, Wong SL, Lyman GH. Lymphatic mapping and sentinel lymph node biopsy in patients with melanoma: a metaanalysis. J Clin Oncol 2011; 29:1479–1487. Vermeeren L, Valdés Olmos RA, Klop WM, Balm AJ, van den Brekel MW. A portable gamma-camera for intraoperative detection of sentinel nodes in the head and neck region. J Nucl Med 2010; 51:700–703. Vidal-Sicart S, Paredes P, Zanón G, Pahisa J, Martinez-Román S, Caparrón X, et al. Added value of intraoperative real-time imaging in searches for difficult-to-locate sentinel nodes. J Nucl Med 2010; 51:1219–1225. Mathelin C, Salvador S, Huss D, Guyonnet L. Precise localization of sentinel lymph nodes and estimation of their depth using a prototype intraoperative mini gamma-camera in patients with breast cancer. J Nucl Med 2007; 48:623–629. Van Den Berg NS, Buckle T, Kleinjan GI, Klop WMC, Horenblas S, Van Der Poel H, et al. Hybrid tracers for sentinel node biopsy. Q J Nucl Med Mol Imaging 2014; 58:193–206. KleinJan GH, Bunschoten A, Brouwer OR, Van Den Berg NS, Valdés Olmos RA, van Leeuwen FWB. Multimodal imaging in radioguided surgery. Clin Transl Imaging 2013; 1:433–444. Conway WC, Faries MB, Nicholl MB, Terando AM, Glass EC, Sim M, Morton DL. Age-related lymphatic dysfunction in melanoma patients. Ann Surg Oncol 2009; 16:1548–1552. Saltman BE, Ganly I, Patel SG, Coit DG, Brady MS, Wong RJ, et al. Prognostic implication of sentinel lymph node biopsy in cutaneous head and neck melanoma. Head Neck 2010; 32:1686–1692. Balch CM, Soong SJ, Murad TM, Ingalls AL, Maddox WA. A multifactorial analysis of melanoma. II. Prognostic factors in patients with stage I (localized) melanoma. Surgery 1979; 86:343–351. Clary BM, Brady MS, Lewis JJ, Coit DG. Sentinel lymph node biopsy in the management of patients with primary cutaneous melanoma: review of a large single-institutional experience with an emphasis on recurrence. Ann Surg 2001; 233:250–258. Balch CM, Gershenwald JE, Soong SJ, Thompson JF. Update on the melanoma staging system: the importance of sentinel node staging and primary tumor mitotic rate. J Surg Oncol 2011; 104:379–385. Roach BA, Burton AL, Mays MP, Ginter BA, Martin RC, Stromberg AJ, et al. Does mitotic rate predict sentinel lymph node metastasis or survival in patients with intermediate and thick melanoma? Am J Surg 2010; 200:759–763, discussion 763764.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
994
Nuclear Medicine Communications 2014, Vol 35 No 10
56 Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Nieweg OE, Roses DF, et al. MSLT Group. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 2014; 370:599–609. 57 Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996; 14:7–17.
58 Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 2010; 102:493–501. 59 Mocellin S, Lens MB, Pasquali S, Pilati P, Chiarion Sileni V. Interferon alpha for the adjuvant treatment of cutaneous melanoma. Cochrane Database Syst Rev 2013; 6:CD008955. 60 Eggermont AM, Testori A, Maio M, Robert C. AntiYCTLA-4 antibody adjuvant therapy in melanoma. Semin Oncol 2010; 37:455Y459.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
