Sentinel Node Tumor Research Articles

Cutaneous Melanoma and Sentinel Lymph Node Biopsy

To the Editors: As authors of a similar article,1 we read with great interest the report by Koskivuo et al.,2 in the December issue of the Annals of Surgical Oncology. We enthusiastically support the basic rationale for this paper and the two researched patient groups, which have been correctly balanced for most of the important prognostic factors, such as Breslow thickness, ulceration status, and tumor site. However, some other methodological and other points may not have been entirely correctly addressed. In the previous study from our center,1 we compared two patient groups that consisted of node-positive patients. One group underwent wide local excision (WLE) and developed a regional lymph node metastasis for which we performed a therapeutic lymph node dissection (TLND). The other group had a positive sentinel node (SN) and underwent a completion lymph node dissection (CLND). Recently we have updated our follow-up information; the median follow-up time is now 5 8 months for the TLND group and 5 1 months for the SN+CLND group. When survival rates were calculated from the diagnosis date of the primary tumor, there seemed to be a trend towards a 14% survival benefit for the CLND group (P = 0.065). However, when patients with minimal SN tumor burden (according to the Rotterdam criteria <0.1 mm in maximum diameter3,4) were excluded, because their prognosis is identical to SN-negative patients, this survival benefit disappeared (P = 0.333). Treatment (WLE followed by TLND versus SN followed by CLND) was not an independent prognostic factor for survival.1 The initial paper from our institute1 was already scrutinized for its lack of follow-up balance between the two groups (the WLE-only group versus the SN-staged group), which is now 58 (+2) versus 51 (+14) months. The present study2 has an even greater misbalance in follow-up: a median of 7 4 months for the WLE versus 16 for SN group. It stands to reason to expect that the SN group will develop more recurrences and deaths. Even though the WLE group has a significantly longer follow-up, there seems to be a critical misbalance in nodal disease between the two groups. There were 72 nodal recurrences in the WLE group (11.7%) versus 50 positive SNs (16.4%). This is even without the nodal relapses (n = 5; 1.6%) in the SN group.2 This suggests that not all positive sentinel nodes will develop into palpable nodal disease. The authors state that improved regional disease control is an obvious therapeutic advantage of SN staging and immediate CLND. This statement can only be made in the context of a comparison of nodal recurrence rates after SN+CLND versus those after TLND. This comparison has not been made in the present study. Instead the authors compare the 1.6% nodal recurrences after SN+CLND with the 11.7% of patients that undergo a TLND after WLE only. This is obviously an incorrect comparison since the lymph node dissection in one group has already been performed and therefore this comparison does not make sense. Another important observation in light of another recent publication from Sheri et al.5 in the October edition of this same journal, but also in light of a study from our institute, is the rate and survival of patients in the Starz I tumor burden (<0.3 mm) category.6 The rate of Starz I patients was 9/49 (18%), which is virtually identical to the results from our institute.3, 4 More importantly was the observation of a 100% overall survival rate from this group, which is again a confirmation of the excellent survival of patients with minimal SN tumor burden from other series and recently from a multicenter experience presented at ECCO 14 in Barcelona in September 2007.3 Finally, we agree with the authors with regard to the fact that SN staging is necessary to provide the optimal treatment to melanoma patients. In the absence of effective chemo- or immunotherapy, such treatments need to be identified by the conduct of randomized controlled trials for which SN status is a crucial stratification. SN staging will have increasing competition however from ultrasound-guided fine-needle aspiration cytology (FNAC), which may be able to replace the current SN staging in most patients based on a trial in 400 patients as reported in the Presidential Session of the last ECCO meeting.7

Isolated Tumor Cells and Long-Term Prognosis of Patients with Melanoma

To the Editor: Sheri et al. reported in the Annals of Surgical Oncology on the significance of isolated tumor cells (ITC).1 At the moment the subject of ITC or SUB-micrometastases, minimal sentinel node (SN) tumor burden is a hot issue. Therefore, it is very interesting that the experience from the John Wayne Cancer Institute (JWCI) has been reported. This recent publication does raise a few questions with regard to the different results acquired by the authors compared with recent publications by others.2,3 The first point of note is that the experience from the JWCI goes back to 1991; this is an advantage, because this leads to a longer median follow-up compared with other single-center studies.2,3 However, at the same time, it means that patients from the early days of SN staging have been included. This is a drawback because the pathology protocol, which nowadays includes bivalving through the hilum, more step-sections, more immunostains, and smaller intervals,4,5 was less extensive in the early days of SN staging. This may be reflected in the very low SN positivity identification rate of only 15%, compared with many other studies, which report rates between 20% and 30%.5,6 This is supported by the fact that the authors have found additional positive nodes in the completion lymph node dissection (CLND) in 6 of 52 patients (12%) with ITC. An extensive “modern” pathology protocol should probably have picked up larger tumor lesions in the original SN. We wonder if the authors have extended the workup of the SNs of these six patients to meet the standard extensive workup used nowadays? The second point of note is the extremely good survival of SN negative patients reported by the authors of 94% at 5y ears. This is somewhat higher than in most other series, including the MSLT-I trial, which report rates of around 90%.6,7 The reason for this is that the SN negative patients had a much smaller median Breslow thickness (1.2mm!) compared with the MSLT-I trial (1.8mm) or other series.5,7 The authors report that even if ITC would have implications, its occurrence is very low at only 4%. However, shouldn’t this rate be calculated as proportion of all SN positive patients? This is 57/214 = 27%, who could possibly not benefit from CLND in our experience. We believe that isolated tumor cells are not always important, as has recently been demonstrated in a multicenter trial for the detection of isolated tumor cells using polymerase chain reaction (PCR) techniques. Scoggins et al. did not demonstrate additional prognostic information beyond standard hematoxylin-eosin (HE) staining of SNs.8 Although Scheri et al. demonstrate a decreased survival in their group of patients with ITC defined as <0.2mm,1 we believe that the prognosis of patients with SUB-micrometastatic disease as defined as <0.1mm has no impact on overall survival. A multicenter study conducted within the EORTC Melanoma Group and recently presented at ECCO 14 in Barcelona, showed that patients with <0.1mm SUB-micrometastases had an excellent 5-year overall survival rate of 91%. The rate of additional non-SN positivity in CLND was 3% (which is identical to the false negative rate in the MSLT-1 trial).9 We have also addressed the limit of 0.2mm as definition for SUB-microscopic disease. The overall survival decreased slightly to 89% at 5y ears; however the occurrence of CLND positivity increases significantly to 10%, which leads us to believe that melanoma and breast cancer have a different biology and thus require different cut-off values for SUB-micrometastases. Whether the excellent survival of patients with <0.1mm SUB-micrometastatic disease is achieved because of or in spite of CLND remains to be seen and is the subject of an EORTC Melanoma Group registration study, the MINITUB, which shall be activated within the next year. Perhaps the MSLT-II trial will also answer the question of which group(s) of SN patients may or may not benefit from CLND. Until more data are available, clinicians should realize that advising removal of all regional nodes to all of their patients might change with respect to further insights in long-term behavior of SUB-micrometastatic involvement of the SN.

Prediction of Nonsentinel Lymph Node Involvement in Patients with a Positive Sentinel Lymph Node in Malignant Melanoma

Completion lymph node dissection (CLND) is routinely performed after metastatic melanoma is detected at sentinel lymph node (SLN) biopsy. Nonsentinel lymph node (NSLN) involvement is found in less than one-third of the cases. Possible predictors of NSLN involvement are examined. A retrospective review of 70 patients with a positive SLN biopsy for melanoma and drainage to one lymphatic basin was performed. The size of metastatic deposits was defined as macrometastases (>2 mm), micrometastases (< or =2 mm), a cluster of cells (10-30 grouped cells) in the subcapsular space or interfollicular zone, or isolated melanoma cells (1-20 or more individual cells) in subcapsular sinuses. Tumor stage, ulceration, SLN tumor burden, mitoses, number of positive SLNs, and total number of lymph nodes removed were examined as predictors of NSLN involvement after CLND. Two additional models based on SLN tumor burden and the number of nodes biopsied were designed. Nineteen patients (24.3%) were found to have NSLN metastases after CLND. Tumor stage, ulceration, SLN tumor burden, mitoses, number of positive SLN, and number of lymph nodes removed were not statistically significant. Residual disease at CLND stratified by SLN tumor burden was: isolated melanoma cells, 0; cluster of cells, 8 (38.1%); < or =2 mm, 5 (20.8%); and >2 mm, 6 (27.3%). A comparison of the means for the models was not predictive of NSLN involvement. None of the risk factors or models examined could predict nonsentinel lymph node involvement with melanoma. The SLN sample and minimal SLN metastatic disease when defined as isolated clusters of cells warrant further study as a potential indicator against CLND after positive SLN.

Size of Sentinel Node Tumor Deposits and Extent of Axillary Lymph Node Involvement: Which Breast Cancer Patients May Benefit From Less Aggressive Axillary Dissections?

In most breast cancer series, nearly 30% to 40% of all patients are sentinel node positive; however, in a large proportion of these, the disease is limited to three or fewer positive nodes. On the basis of these observations, the object of this study is to identify a subset of patients who might benefit from a less aggressive axillary dissection, without compromising staging or local disease control. We reviewed known clinicopathologic variables associated with a higher risk for axillary metastasis in 467 patients who underwent sentinel node mapping at our institution. We then compared the incidence of these variables in patients with N1a versus N2-3 stage disease. Although the presence of lymphvascular invasion in the primary tumor and extracapsular extension of tumor in the sentinel node were statistically significantly different between N1a and N2-3 patients (P < .025 and P < .01, respectively), the variable that most reliably separated N1a from N2-3 patients was the size of the tumor deposits in the sentinel node (P < .001). All patients with sentinel node tumor deposits <or=5 mm had three or fewer positive nodes; 95% were sentinel node-positive only, and 91% had single-node involvement. Patients at low risk for extensive axillary nonsentinel node involvement may benefit from a more conservative surgical approach to their axillae, perhaps limited to sentinel node biopsy only or to axillary procedures restricted to the group of axillary nodes in close proximity to those designated as sentinel nodes.

Prediction of non-sentinel node status and outcome in sentinel node-positive melanoma patients

Sentinel lymph node (SLN) -positive melanoma patients are usually recommended completion lymph node dissection (CLND) with the aim to provide regional disease control and improve survival. Nevertheless, only 20% these patients have additional metastases in non-sentinel lymph nodes (NSLN), indicating that CLND may be unnecessary in the majority of patients. In this retrospective study, we (i) sought to identify clinico-pathological features predicting NSLN status, as well as disease-free (DFS) and -specific (DSS) survival and (ii) evaluated the applicability of previously published algorithms, which were able to define a group of patients at zero-risk for NSLN-metastasis. This analysis included 504 consecutive melanoma patients stage I and II who underwent successful SLN-biopsy (SLNB) at our institute between 1998 and 2005. Metastatic SLN were re-evaluated for tumor burden and categorized according to two different micro-anatomic classifications and the S/U-score (Size of the sentinel node metastasis > 2 mm/Ulceration of the primary melanoma) was assessed. DFS and DSS were calculated for all analyses. Out of 504 melanoma patients stage I or II, 85 (17%) were SLN-positive and 18 of 85 (21%) were found with positive NSLN in the CLND specimen. Median follow-up was 31 months. Neither primary tumor characteristics (age, gender, Clark level, Breslow thickness, ulceration of the primary melanoma, site and histological subtype of the primary melanoma), nor features of the sentinel node tumor (number and site of draining lymph node basins, number of positive sentinel nodes and size of sentinel node tumor (< 2 mm vs. > or = 2 mm) were able to predict additional positive lymph nodes in the CLND specimen. Likewise the implementation of published algorithms was not able to identify patients at negligible risk for harboring NSLN metastases. Upon univariate analysis, disease-free survival in SLN-positive patients was correlated with Breslow thickness, sentinel node tumor size > 2 mm and S/U score. In respect to disease-specific survival the significant prognostic parameters were Breslow thickness, ulceration, sentinel node tumor size > 2 mm and the S/U score. After a median follow-up of 31 months recurrence rates (37% vs. 78%, p=0.02) and death from disease (24% vs. 50%, p<0.01) were significantly different in patients with SLN-metastasis only as compared to patients with NSLN-metastasis. NSLN status cannot be predicted in this data analysis by using clinico-pathological characteristics. Therefore, CLND is recommended for all patients after positive SLNB pending the results of the second Multicenter Selective Lymphadenectomy Trial.

Sentinel lymph nodes of colorectal carcinoma: reappraisal of 123 cases

Results concerning the usefulness of the sentinel lymph node (SLN) in colorectal carcinoma have been discordant. The SLN technique may be used to guide surgical resection (lymph mapping), restrict the lymph node analysis solely to the SLN (accuracy) and upgrade tumor staging when micrometastases are specifically detected in the SLN. The blue dye injection technique was used. Serial sections of the SLNs were analyzed after hematoxylin-eosin (HES) staining. The SLN technique was tested in 123 patients, successfully in 112/118 (feasibility 95%) (five intraoperative exclusions). On average, twenty lymph nodes (range: 5-74) and two SLNs (range: 1-5) were identified. Lymph mapping was used in 11% of patients to guide surgical resection; the SLN was negative in 14 of 36 N+ patients (39% false-negatives); HES staining enabled detection of micrometastases in 8 of 84 initially N0 patients (10% secondary upgrading to N+). Limiting node analysis to the SLN cannot replace a complete pathology examination of all resected lymph nodes. Careful examination of serial sections of the SLN can however affect therapeutic decision making since staging may be upgraded in up to 10% of initially N0 patients.

Predictive Value of Tumor Load in Breast Cancer Sentinel Lymph Nodes for Second Echelon Lymph Node Metastases

Background: The need for routine axillary lymph node dissection (ALND) in patients with invasive breast cancer and low-volume sentinel node (SN) involvement is questionable. Accurate prediction of second echelon lymph node involvement could identify those patients most likely to benefit from ALND. Methods: A consecutive series of 317 patients with invasive breast cancer and a tumor positive axillary SN followed by ALND was reviewed. Clinicopathologic features of the primary tumor and the SN were assessed as possible predictors of second echelon lymph node involvement. Results: Second echelon metastases were found in 116/317 cases (36.6%). Frequency of second echelon lymph node involvement in patients with isolated tumor cells (ITC, N = 23), micro- (N = 101) and macrometastases (N = 193) was 13%, 20% and 48%, respectively (p < 0.001). Based on the area % of SN occupied by tumor no subgroup of patients could be selected with less than 20% second echelon lymph node involvement. However, none of the patients with SN ITC or micrometastases and a primary tumor size ≤1 cm (N = 12, 3.8%) had second echelon lymph node involvement. Conclusions: Accurately measured SN tumor load predicts second echelon lymph node involvement. However, even in patients with ITC, the second echelon lymph nodes are involved in 13% justifying ALND.

Microscopic tumor burden in sentinel lymph nodes (SLNs) best predicts nonsentinel lymph node (NSLN) involvement in patients with melanoma

8004 Background: Therapeutic lymph node dissection (TLND) has long been the standard of care for melanoma metastatic to the regional LNs and is commonly used for patients (pts) with microscopic disease identified by SLN biopsy. We and others have demonstrated that additional histologically positive (pos) nodes are identified in 8%-33% of completion LN dissection (CLND) specimens. The purpose of this study was to determine predictors of additional LN involvement in pts. with pos SLNs. Methods: Pts with clinically node-negative melanoma who underwent SLN biopsy at our institution between 1991 and 2003 and had pos SLNs were identified. Patient and primary tumor factors, number of pos SLNs, and extent of microscopic disease within the SLN were evaluated as potential predictors of pos NSLNs. Results: Overall, 359 (16%) of 2,203 pts had a pos SLN. Pos NSLNs were identified in 48 (14%) of the 343 pts with pos SLNs who underwent CLND. On univariate analysis, several markers of SLN microscopic tumor burden, tumor thickness &gt;2mm, age &gt;50 years, and Clark level &gt;III were predictive of additional pos nodes in the TLND specimen. Primary tumor ulceration was not predictive. On multivariable logistic regression analysis, markers of microscopic tumor burden (large SLN met focus, large SLN tumor square area, presence of SLN extracapsular extension, and synchronous subcapsular and intramedullary SLN deposits) were the most powerful independent predictors of pos NSLNs; tumor thickness &gt;2mm also predicted additional disease. A model was established using tumor thickness and SLN tumor burden to identify pts with low, intermediate, or high risk for NSLN involvement (Table). Conclusions: In melanoma pts with ≥1 pos SLN, SLN tumor burden and primary tumor thickness may be useful in identifying a group at low risk for pos NSLNs. This information is valuable in designing clinical trials in which pts may be randomly assigned to TLND versus observation alone after removal of a pos SLN. [Table: see text] No significant financial relationships to disclose.

Utility of Computed Tomography and Magnetic Resonance Imaging Staging Before Completion Lymphadenectomy in Patients With Sentinel Lymph Node–Positive Melanoma

Although melanoma patients with regional nodal metastases are frequently imaged with computed tomography (CT) and magnetic resonance imaging (MRI) scans, the efficacy of routine radiologic staging in asymptomatic patients with microscopic nodal involvement has not been established. To determine the utility of this approach, we analyzed the incidence of synchronous distant metastases (SDM) detected by CT or MRI of the head, chest, and abdomen in a large group of patients with sentinel lymph node (SLN) -positive melanoma. Positive SLNs were identified in 314 (16.2%) of the 1,934 melanoma patients who underwent sentinel lymphadenectomy at our institution from 1996 to 2003. Within 3 months of sentinel lymphadenectomy, 270 (86.0%) of the 314 SLN-positive patients were radiologically staged. To determine which prognostic factors were associated with SDM, associations between final staging outcomes and clinicopathologic variables, including SLN tumor burden, were analyzed. CT and/or MRI scans identified lesions that were suspicious for SDM in 23 (8.6%) of the 270 patients who underwent staging. In eight of these patients, further diagnostic studies determined that these abnormalities were benign. The remaining 15 suspicious lesions were percutaneously biopsied (10 negative and five positive), yielding a radiologically detectable SDM rate of 1.9%. Detection of SDM was associated with primary tumor thickness (P = .011), ulceration (P = .018), and SLN tumor burden (P = .018). These data suggest that the vast majority of asymptomatic patients with a new diagnosis of microscopic SLN-positive melanoma do not harbor radiologically detectable SDM and can proceed to completion lymph node dissection without immediate CT or MRI staging.

Objective assessment of sentinel node tumor burden and its impact on sentinel node localisation in breast cancer

605 Background: Extensive tumor infiltration of the draining lymph nodes may prevent the migration of tracer to the sentinel node(SN), adversely affecting SN identification. Methods: A total of 202 breast cancer patients underwent SN biopsy using 99mTc albumin colloid and Patent Blue V injected peritumorally. This was followed by standard axillary clearance in all patients at the same operation. Tumor burden in the SN was assessed by measuring the size of metastasis, percentage replacement(PR) of the SN by tumor and by documenting extranodal invasion(EI). Digital images of the marked slides were acquired and measurements were made using Image Pro Plus software. Results: The overall SN identification rate was 94.6% (191/202), of which 5 were false negatives. Only 18% (2/11) of patients with failed SNB had evidence of nodal metastases on completion axillary clearance. A total of 83 positive SNs were removed from 64 patients. Radioisotope count in the SNs decreased with increasing PR of the SNs by tumor (p=0.005). 30% (24) of the nodes removed were not hot (counts&lt;10 times the background count). The mean PR by tumor of these nodes was 55% (SD 36) as compared to 33% (SD 33) for hot nodes (p=0.009). 20% (16/81) of the positive SNs showed EI. 69% (11) of nodes with EI were not hot (radioisotope count ratio &lt;10) and would not be localised if the radioisotope was used alone. SNs with EI had a lower radioisotope count compared to SNs without EI (p&lt;0.0001). The mean PR by tumor of nodes with EI was 70% (SD 26) compared to 32% (SD 33) of nodes without EI. This shows that extranodal growth of the tumor would occur once the node is &gt;50% replaced with tumor. There was no correlation between radioisotope uptake and size of metastasis in the SN. There was no correlation between blue dye uptake and tumor burden in the positive SN. Conclusion: In an individual SN, the PR by tumor and EI are markers of lymphatic obstruction and significantly associated with reduced radioisotope uptake. These results suggest that &gt;50% replacement of the node by tumor will compromise the lymphatic flow and may lead to failed localisation of the node if the radioisotope is used alone. However, the SN tumor burden does not affect blue dye uptake. This result provides an argument for using a combination of blue dye and radioisotope for SN biopsy. No significant financial relationships to disclose.

2–34 The Effect of Sentinel Node Tumor Burden on Non-Sentinel Node Status and Recurrence Rates in Breast Cancer

2–34 The Effect of Sentinel Node Tumor Burden on Non-Sentinel Node Status and Recurrence Rates in Breast Cancer

Clinical relevance of melanoma micrometastases (&lt;0.1 mm) in sentinel nodes: are these nodes to be considered negative?

As only about 20% of sentinel node (SN) positive melanoma patients have additional non-SN lymph node involvement in the Completion Lymph Node Dissection (CLND) specimen, we tried to identify a SN positive patient group, which can be spared CLND. Micro anatomic analyses of metastatic SNs were performed to identify patient/tumor and/or SN factors predicting additional non-SN positivity as well as disease-free and overall survival. SN positivity was found in 77 of 262 stage I/II patients, included into a prospective database (10/97-5/04). Of 74 patients pathology material was available for re-evaluation. Micro anatomic analyses categorized topography of SN-metastases, Starz classification and amount of SN tumor burden. Additional non-SN positivity, DFS, OS and was calculated for all analyses. Mean Breslow thickness was 3.5 mm (0.8-12.0); mean FU was 35 (6-81) months. There was no additional non-SN positivity for SN-micrometastases <0.1 mm. Topography of SN involvement had no impact on OS. Estimated 5-year OS rates for the different groups of <0.1 mm, 0.1-1.0 mm and >1.0 mm SN tumor burden were 100%, 63% and 35% respectively. Distant metastases were exceedingly rare (1/16 = 6.3%) in <0.1 mm SN-positive patients. On multivariate analysis the SN tumor burden was the most important prognostic factor for DFS (P = 0.005) and OS (P = 0.03). Distant metastasis-free survival was identical (91%) to the 5-yr OS of SN negative patients, the estimated 5-yr OS was 100% for these patients and additional non-SN positivity was not observed. Therefore, our data suggest that patients with sub-micrometastases (<0.1 mm) in the SN may be judged as SN negative, as non-stage III, and are highly unlikely to benefit from CLND, which we no longer recommend.

Objective assessment of sentinel node tumor burden and its impact on sentinel node localisation in breast cancer

Objective assessment of sentinel node tumor burden and its impact on sentinel node localisation in breast cancer

The Effect of Sentinel Node Tumor Burden on Non–Sentinel Node Status and Recurrence Rates in Breast Cancer

Routine axillary lymph node dissection (ALND) after selective sentinel lymphadenectomy (SSL) in the treatment of breast cancer remains controversial. We sought to determine the need for routine ALND by exploring the relationship between sentinel lymph node (SLN) and non-SLN (NSLN) status. We also report our experience with disease relapse in the era of SSL and attempt to correlate this with SLN tumor burden. This was a retrospective study of 390 patients with invasive breast cancer treated at a single institution who underwent successful SSL from November 1997 to November 2002. Of the 390 patients, 115 received both SSL and ALND. The percentage of additional positive NSLNs in the SLN-positive group (34.2%) was significantly higher than in the SLN-negative group (5.1%; P = .0004). The SLN macrometastasis group had a significantly higher rate of positive NSLNs (39.7%) compared with the SLN-negative group (5.1%; P = .0001). Sixteen patients developed recurrences during follow-up, including 6.1% of SLN-positive and 3.3% of SLN-negative patients. Among the SLN macrometastasis group, 8.7% had recurrence, compared with 2.2% of SLN micrometastases over a median follow-up period of 31.1 months. One regional failure developed out of 38 SLN-positive patients who did not undergo ALND. ALND is recommended for patients with SLN macrometastasis because of a significantly higher incidence of positive NSLNs. Higher recurrence rates are also seen in these patients. However, the role of routine ALND in patients with a low SLN tumor burden remains to be further determined by prospective randomized trials.

Interim results of the Multicenter Selective Lymphadenectomy Trial (MSLT-I) in clinical stage I melanoma

7500 Background: Regional node management remains controversial because 80% of patients undergoing routine elective complete lymph node dissection (CLND) do not have nodal metastases. We developed lymphatic mapping and sentinel node biopsy (LM/SNB) to detect occult nodal metastases and thereby identify patients who might benefit from CLND. MSLT-I is an international, 17-center randomized trial to evaluate the accuracy and clinical impact of LM/SNB in patients with clinically localized cutaneous melanoma. Methods: Patients with primary melanoma were stratified by Breslow thickness (<1.2, 1.2–3.5, or >3.5 mm) and randomly assigned in a 40:60 ratio to wide excision (WE) followed by nodal observation (WEO), or to WE plus LM/SNB followed immediately by CLND only if the sentinel node (SN) contained tumor (SN+) by hematoxylin/eosin or immunostaining. Results: From 1/1/94 to 3/31/02, 797 patients were assigned to WEO and 1204 patients were assigned to LM/SNB. The third of 5 planned analyses was completed in October 2004 at a median follow-up of 54 months. Five-year disease-free survival was 78% with LM/SNB vs. 73% with WEO (p=0.01; HR 0.74). SN tumor status was the most important factor for 5-year survival of LM/SNB patients: survival was 88% for 944 SN- patients vs. 71% for 215 SN+ (p<0.0001, log rank). Nodal metastases were identified in 215 (19%) LM/SNB patients; nodal recurrence developed in 142 (18%) WEO patients. Five-year survival was significantly higher after immediate CLND for SN+ than delayed CLND for clinical nodal recurrence (71% vs. 55%; P = 0.0033, log rank; P = 0.0077, Cox multivariate). Conclusions: SN status is the most important prognostic factor in early-stage melanoma, and LM/SNB allows early and accurate detection of occult nodal metastases. Disease-free and melanoma-specific survival rates are significantly higher after immediate CLND for occult nodal metastases than delayed CLND for clinical nodal recurrence. LM/SNB should become standard for staging and assessment of prognosis in primary melanoma, and for identifying patients who may benefit from immediate CLND. MSLT-II will examine the therapeutic value of CLND vs. SNB alone for patients who are SN+. Supported by NIH CA29605. No significant financial relationships to disclose.

Sentinel Lymph Node Tumor Load: An Independent Predictor of Additional Lymph Node Involvement and Survival in Melanoma

Even though 60% to 80% of melanoma patients with a positive sentinel lymph node (SLN) have no positive additional lymph nodes (ALNs), all these patients are subjected to an ALN dissection (ALND) with its associated morbidity. The aim of this study was to predict the absence of ALN metastases in patients with a positive SLN by using features of the primary melanoma and SLN tumor load. Of 71 SLN-positive patients, 52 had metastasis limited to the SLN (group 1), and 19 had > or =1 positive ALN after ALND (group 2). The tumor load of the SLN was assessed by measuring the total surface area by computerized morphometry. Breslow thickness, ulceration and lymphatic invasion of the primary tumor, and total SLN metastatic area were tested as covariates predicting the absence of positive ALNs. The mean SLN metastatic area was 1.18 mm(2) (group 1) and 3.39 mm(2) (group 2) (P = .003) and was the only significant and independent factor after multivariate analysis (P = .02). None of the patients with both a Breslow thickness <2.5 mm and an SLN metastatic area <.3 mm(2) had a positive ALN. SLN metastatic area can be used to predict the absence of positive ALNs in melanoma patients. In this study, patients with a Breslow thickness <2.5 mm and an SLN tumor load <.3 mm(2 )seemed to have no positive ALN and had excellent survival. We hypothesize that this subgroup might not benefit from ALND. Prospective larger trials, using this model and randomizing between ALND and no ALND, should confirm this hypothesis.

Breast cancer patients with pN0(i+) and pN1(mi) sentinel nodes have high rate of nonsentinel node metastases

The recent American Joint Committee on Cancer revision of the staging system for breast cancer classifies sentinel node metastases < 0.2 mm (pN0[i+]) as node negative and those > 0.2 mm but < 2 mm are designated pN1(mi). We examined the association between size of sentinel node metastases and rate of nonsentinel node metastases, specifically in the subgroup of patients with micrometastases. We examined the nonsentinel nodes of 124 patients with positive sentinel nodes and correlated the likelihood of nonsentinel node involvement with the size of the metastasis in the sentinel node and primary tumor characteristics. Nonsentinel node metastases were found in 19% (6 of 31) of patients with sentinel node metastases <or= 0.2 mm, 20% (6 of 30) of patients with metastases 0.2 mm to 2 mm, and 46% (29 of 63) of patients with metastases > 2 mm. Multivariate analysis found that involvement of the majority of sentinel nodes (p = 0.01) and sentinel metastases > 2 mm (p = 0.001) were significantly related to presence of metastases in nonsentinel nodes. Age, tumor size, pathology, multifocality, satellites, and lymphovascular invasion were not significantly related to nonsentinel node metastases in multivariate analysis. These findings indicate that frequency of nonsentinel node metastases with sentinel node metastases <or= 0.2 mm is comparable to the frequency when sentinel metastases are > 0.2 to 2 mm. Omitting complete axillary dissection in pN1(mi) and pN0(i+) patients may leave residual disease in up to 20% of these patients.

Sentinel node status and tumor characteristics: a study of 234 invasive breast carcinomas.

Abstract Context.—Axillary lymph node status is the most important prognostic factor in patients with breast cancer. Tumor size and lymph node status, the most reliable pathologic bases of the tumor staging system, are practical parameters for estimating survival status. With the advent of lymphatic mapping and sentinel node (SN) identification, there is potential for a more efficient and sensitive evaluation of the axillary lymph node status. Objective.—To correlate SN status with tumor size, grade, and lymphovascular invasion. Design.—We examined 234 patients with unifocal breast carcinomas measuring 25 mm or less as detected by preoperative ultrasound during the period May 1998 through December 2002. Sentinel nodes were examined by frozen section and paraffin section as per protocol. Results.—Of the 234 patients, SN was identified in 221 (94.5%). An average of 1.38 SNs were examined per patient. Seventy-seven of 221 patients were SN positive on paraffin section. Sixty-six (85.7%) of these 77 cases coul...

Use and Limitations of a Nomogram Predicting the Likelihood of Non-Sentinel Node Involvement after a Positive Sentinel Node Biopsy in Breast Cancer Patients

After a positive sentinel lymph node (SLN) biopsy, some patients may be considered to have a very low risk of non-SLN involvement and could be candidates for axillary sparing. The aim of this study was to validate the nomogram created at the Memorial Sloan-Kettering Cancer Center (MSKCC) for the prediction of non-SLN involvement in an independent set of 140 patients with both positive SLNs and axillary dissection. The predicted proportions of positive non-SLNs were compared with the observed percentages of non-SLN metastasis. Although the SLN metastasis size and tumor size did influence the risk of non-SLN involvement, the correlation between the predicted and observed proportions was weaker for our patients (R: 0.84) than for the patients assessed at the MSKCC (R: 0.97). Differences were noted in the intraoperative assessment and in the final histology of the SLNs (imprints vs frozen sections and more detailed vs less detailed, respectively), and these could partly explain the lower level of the correlation. The nomogram could not be validated and was found to be of only limited use for the prediction of non-SLN involvement in patients operated on under similar, though not fully identical conditions. We therefore warn against the unvalidated use of this prediction tool.

Update on lymphatic mapping and sentinel node biopsy in the management of patients with melanocytic tumours

To communicate best practices for sentinel lymph node evaluation and assessment of prognosis for patients with melanoma. Description and justification of approaches derive from experience with management of more than 2000 melanoma patients evaluated by lymphatic mapping and sentinel node biopsy (LMSNB). Pathologists, by detecting blue dye or carbon particles or alterations in nodal cell populations should attempt to confirm that a node submitted as sentinel is truly sentinel. Pathologists must adequately sample the node by examining multiple tissue sections and determine the presence or absence of metastatic melanoma using sections stained by H&E and immunocytochemistry. Approximately 20% of patients have melanoma in the sentinel node (SN) and accurate evaluation of SN tumour status is the most precise technique for staging clinically localised cutaneous melanoma. The remaining non-sentinel nodes (NSN) in the basin are tumour-free in 67% of patients with melanoma in the SN. Breslow thickness of the primary, the area of tumour in the SN (relative to total nodal area) and density of dendritic leukocytes in the SN paracortex (factors that are combinable in prognostic algorithms) predict metastases in the NSN and the likelihood of recurrence and melanoma-specific death. Careful pathological analysis is essential to determine the presence or absence of metastatic melanoma in sentinel nodes, findings that indicate whether completion lymphadenectomy is required. Quantitative analysis of the primary melanoma and the amount of tumour in the sentinel node, with evaluation of the dendritic cells in that node, provide invaluable information that predicts non-sentinel node tumour status with increased accuracy and the likelihood of future recurrence and death from melanoma. While these activities require considerable effort from pathologists, their clinical impact justifies the increased workload.