Alexander C.J. van Akkooi

The prognostic significance of sentinel node tumour burden in melanoma patients: An international, multicenter study of 1539 sentinel node-positive melanoma patients

INTRODUCTIONnSentinel node (SN) biopsy (SNB) and completion lymph node dissection (CLND) when SN-positive have become standard of care in most cancer centres for melanoma. Various SN tumour burden parameters are assessed to determine the heterogeneity of SN-positivity. The aim of the present study was to validate the prognostic significance of various SN tumour burden micromorphometric features and classification schemes in a large cohort of SN-positive melanoma patients.nnnMETHODSnIn 1539 SN-positive patients treated between 1993 and 2008 at 11 melanoma treatment centres in Europe and Australia, indices of SN tumour burden (intranodal location, tumour penetrative depth (TPD) and maximum size of SN tumour deposits) were evaluated.nnnRESULTSnNon-subcapsular location, increasing TPD and increasing maximum size were all predictive factors for non-SN (NSN) status and were independently associated with poorer melanoma-specific survival (MSS). Patients with subcapsular micrometastases <0.1mm in maximum dimension had the lowest frequency of NSN metastasis (5.5%). Despite differences in SN biopsy protocols and clinicopathologic features of the patient cohorts (between centres), most SN parameters remained predictive in individual centre populations. Maximum SN tumour size>1mm was the most reliable and consistent parameter independently associated with higher non-SN-positivity, poorer disease-free survival (DFS) and poorer MSS.nnnCONCLUSIONSnIn this large retrospective, multicenter cohort study, several parameters of SN tumour burden including intranodal location, TPD and maximum size provided prognostic information, but their prognostic significance varied considerably between the different centres. This could be due to sample size limitations or to differences in SN detection, removal and examination techniques.

EORTC Melanoma Group sentinel node protocol identifies high rate of submicrometastases according to Rotterdam Criteria

Sentinel node (SN) status is the most important prognostic factor for disease-free survival (DFS) and overall survival (OS) in stages I-II melanoma. We evaluated the positive sentinel node identification rate of the EORTC Melanoma Group (MG) protocol as well as its capacity to identify minimal tumour burden, according to the Rotterdam Criteria in 421 consecutive patients. Correlations between primary tumour characteristics and SN tumour burden were investigated. The same 2 pathologists worked up all SNs according to the EORTC MG protocol and tumour burden was scored according to the Rotterdam Criteria (<0.1 mm, 0.1-1.0 mm and >1.0 mm for the largest diameter of the largest metastasis in the SN). The positive SN detection rate was 28.7% with a false negative rate of 10.4% at a median Breslow thickness of 2.1 mm. The high positive identification rate of about 30% of the EORTC MG protocol has been confirmed in this study. The protocol is sensitive and identifies submicrometastases (<0.1 mm) in a high percentage (18%). The variables SN tumour load, non-SN (NSN) status and ulceration of the primary were independent prognostic factors for DFS and OS in the multivariate analysis. At a median follow-up time of 4.3 years patients with minimal tumour burden (<0.1 mm) had a 5 year OS rate of 91%, virtually identical to 90% for SN-negative patients. The NSN positivity rate of 0% in these patients indicates that they may be spared a completion lymph node dissection (CLND) and its morbidity.

Outcome After Therapeutic Lymph Node Dissection in Patients with Unknown Primary Melanoma Site

PurposeThe aim of this study was to evaluate the incidence and outcome of melanoma of unknown primary site (MUP) after therapeutic lymph node dissection (TLND) of palpable nodal melanoma metastases. Disease-free (DFS) and overall survival (OS) time of MUP patients were analyzed and compared to patients undergoing a TLND for known primary melanomas (MKP).MethodsThis single institution retrospective study analyzed 342 consecutive patients who were treated with 415 TLNDs for palpable nodal disease from 1982 to 2009. Univariate and multivariate analyses included: MUP versus MKP, gender, Breslow thickness, ulceration of primary tumor, site of primary tumor, site of dissection, extracapsular extension, number of collected nodes, number of positive nodes and the node positive ratio.ResultsA total of 47 MUP were identified in 342 patients (13.7%). In univariate analysis, a trend was seen toward better survival for MUP patients compared to MKP patients having 5-year OS rates of 40% and 27%, respectively (Pxa0=xa00.06). Multivariate analysis for OS showed two highly significant factors associated with worse prognosis: extracapsular extension and N3 status (both Pxa0<xa00.001). Two factors were associated with a significant better prognosis: MUP (Pxa0=xa00.03) and a neck dissection (Pxa0=xa00.04).ConclusionsPatients with MUP showed a statistically significant better OS compared to patients with melanoma metastases from known primary tumors. Presence of extracapsular extension and an increased number of positive nodes are statistically significantly negative prognostic factors for OS. The absence of a primary melanoma in stage III melanoma patients does not preclude surgery.

New developments in melanoma: utility of ultrasound imaging (initial staging, follow-up and pre-SLNB)

Melanoma incidence is still increasing, but the mortality rate has remained unchanged. Lymph node metastases are the single most important prognostic factor for stage I/II melanoma patients. Currently, the standard of care with regard to the staging of these patients is the surgical sentinel node procedure. Ultrasound is not routine for the diagnostic work-up of primary melanomas. Some may use ultrasound for the preoperative assessment of the tumor thickness and lymphatic drainage, but this has not found wide application. For the follow-up of melanoma patients, ultrasound has been proven to be superior to physical examination for the detection of lymph node metastases. A meta-analysis has shown that ultrasound is superior to computed tomography (CT) and/or positron emission tomography (PET)-CT for the detection of lymph node metastases, whereas PET-CT was superior for the detection of distant visceral metastases. Ultrasound of regional lymph nodes has been incorporated into many national guidelines across Europe and in Australia for the follow-up of melanoma patients. A new avenue for ultrasound (US)-guided fine-needle aspiration cytology (FNAC) is the pre-sentinel node modality. Like the situation in breast and thyroid cancer, US-FNAC, a minimally invasive procedure, may decrease the need for surgical sentinel node staging. New ultrasound morphology criteria have significantly increased the sensitivity of this technique. Peripheral perfusion is an early sign of metastases (77% sensitivity, 52% positive-predictive value), whereas balloon-shaped lymph node was a late sign of metastases (30% sensitivity, 96% positive-predictive value). Together, these new ultrasound morphology criteria were able to accurately demonstrate metastases in 65% of sentinel node-positive patients. Future perspectives of ultrasound in melanoma include the start of a large multicenter, multicountry validation study – USE-FNAC – by the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group. In light of new and promising adjuvant therapies, the need for ultrasound staging might increase rapidly.

Importance of tumor load in the sentinel node in melanoma: clinical dilemmas

There are two hypotheses to explain melanoma dissemination: first, simultaneous lymphatic and hematogeneous spread, with regional lymph nodes as indicators of metastatic disease; and second, orderly progression, with regional lymph nodes as governors of metastatic disease. The sentinel node (SN) has been defined as the first draining lymph node from a tumor and is harvested with the use of the triple technique and is processed by an extensive pathology protocol. The SN status is a strong prognostic factor for survival (83–94% for SN negative, 56–75% SN-positive patients). False-negative rates are considerable (9–21%). Preliminary results of the MSLT-1 trial did not demonstrate a survival benefit for the SN procedure, although a subgroup analysis indicates a possible benefit. A mathematical model has demonstrated 24% prognostic false positivity. SN tumor burden represents a heterogenous patient population and is classified most frequently with the Starz, Dewar or Rotterdam Criteria. A completion lymph-node dissection might not be indicated in all SN-positive patients. Patients classified with metastases <0.1xa0mm by the Rotterdam Criteria have excellent survival rates. Ultrasound-guided fine-needle aspiration cytology is emerging as a staging tool for high-risk patients, but more research is necessary before this can change clinical practice.

Ultrasound-guided fine needle aspiration cytology as an addendum to sentinel lymph node biopsy can perfect the staging strategy in melanoma patients

BACKGROUNDnUltrasound guided fine needle aspiration cytology (US-guided FNAC) can identify microscopic involvement of lymph nodes as in breast cancer and avoid surgical sentinel node (SN). Its utility in melanoma patients is controversial and subject of this study.nnnMETHODSnBetween 2001 and 2010 over 1000 stage I/II consecutive melanoma patients prospectively underwent US-FNAC prior to SN biopsy. All patients underwent lymphoscintigraphy prior to US-FNAC. The Berlin US morphology criteria: Peripheral perfusion (PP), loss of central echoes (LCE) and balloon shaped (BS) were registered. FNAC was performed in case of presence of any of these factors. SN tumour burden was measured according to the Rotterdam criteria. All patients underwent SN or lymph node dissection (LND) in case of positive FNAC.nnnFINDINGSnMean/median Breslow thickness was 2.58/1.57 mm. Mean/median follow-up was 56/53 months (1-132). SN positivity rate was 21%. US-FNAC Sensitivity was 71% (US only) and 51% (US-FNAC). Sensitivity of US-FNAC was highest for T4 (76%) and ulcerated melanomas (63%). PP, LCE and BS had sensitivity of 69%, 24% and 24% respectively. Sensitivity of US-FNAC increased with increasing SN tumour burden. PP was an early sign of metastasis (58% in <0.1mm metastases). Threshold size of a metastasis for FNAC was 0.3mm. Five-year survival correlated to US-FNAC status (95% in negative and 59% in positive).nnnINTERPRETATIONnUltrasound guided FNAC (US-FNAC) according to the Berlin morphology criteria could correctly identify at least half of all tumour positive sentinel nodes, prior to the surgical SN procedure. Peripheral perfusion is an early sign of metastasis, which is very sensitive, but with lower positive predictive value (PPV). It is responsible for the sensitivity of the procedure. Balloon shape is a sign of advanced metastases, with lower sensitivity, but high PPV. US-FNAC sensitivity correlated with increasing T-stage, ulceration of the primary and increasing SN tumour burden. US-FNAC status accurately predicts survival.

Potential Cost-Effectiveness of US-Guided FNAC in Melanoma Patients as a Primary Procedure and in Follow-Up

We read with great interest the vivid correspondence between the authors of recent papers in the Annals of Surgical. 1–3 The discussion focuses on a possible survival benefit for patients treated by sentinel lymph node biopsy (SNLB) procedure compared with observation (OBS) and the potential cost-effectiveness of SNLB in the light of such a supposed survival benefit, based on the third interim results of the prospective Multicenter Selective Lymphad-enectomy Trial-1 (MSLT-1). 4 Interestingly, the discussion also focuses on the nodal relapse rates for both arms of the MSLT-1 trail (Table 1). Strikingly, there seems to be an increase in late relapses in both arms, which might either be the result of selection bias, as follow-up has not yet matured to 10 years in the entire MSLT-1 population and thus might lead to an overestimation of the data, or these continuous late relapses in both arms may indicate a failure rate of completion lymph node dissection (CLND) completeness. Interestingly we did not see any late relapses in our submicrometastases (0.1 mm) patients. In light of the lack of survival benefit for the sentinel node (SN) procedure from the point of randomization in the MSLT-1 trial, the cost-effectiveness of the SN procedure as a staging procedure is debatable. Recently a study by Voit et al. demonstrated that presurgical ultrasound (US)-guided fine-needle aspiration cytology (FNAC) has a sensitivity of 65% compared with surgical SN procedure. 8 Moreover, the sensitivity of US-guided FNAC increases significantly with increasing SN tumor burden. 8 Considering that only 15–30% of all stage I/II melanoma patients are SN positive, 70– 85% are negative but still undergo a SN procedure. 4 US-guided FNAC has the potential to save 65–80% of SN-positive patients a SN staging procedure and to save an estimated 61–92% of SN-negative patients a surgical procedure, and the accompanying costs. Here we would like to submit the argument for ultra-sound-guided FNAC as a cost-effective alternative scenario to the surgical SN procedure. For the purpose of these calculations, based on the data by Voit et al., we considered that 40% will undergo an US with FNAC whereas 60% will have a benign US and will not undergo a FNAC. 8 Moreover , 50% will be FNAC positive and 50% will be FNAC negative. Finally, the negative patients will undergo routine US follow-up (four times a year), with an average of one FNAC. At our centers in The Netherlands and …

Detection of melanoma micrometastases in sentinel nodes – The cons

The sentinel node (SN) procedure in melanoma patients is important for prognostic information, but has no impact on survival. Micrometastases are identified in approximately 20% of the SNs. When a Completion Lymph Node Dissection (CLND) is performed for positive SN, additional non-SN lymph node involvement is also approximately 20%. Several classification criteria have been proposed to identify patients with SNs without a risk for additional nodes or a good prognosis. Micro anatomic analyses of metastatic SNs suggest that patients with sub-micrometastases (<0.1mm) in the SN may be judged as SN negative. Patients with this limited tumor burden in their SN have an excellent prognosis and are highly unlikely to benefit from CLND. New techniques such as ultrasound of the lymph nodal basin can be promising as an alternative for SN biopsy.

Multimarker Reverse Transcriptase-Polymerase Chain Reaction Assay in Lymphatic Drainage and Sentinel Node Tumor Burden

PurposeWe assessed molecular (presence of melanoma cells markers in lymph fluid [LY]) and pathological features (sentinel lymph node [SN] tumor burden according to Rotterdam criteria, metastases microanatomic location) and correlated them with survival and melanoma prognostic factors in a group of patients with positive SN biopsy.MethodsWe analyzed 368 consecutive SN-positive patients after completion lymph node dissection (CLND). In 321 patients we obtained data on SLN microanatomic location/tumor burden (only 7 cases had metastases <0.1xa0mm); in 137 we additionally analyzed 24-hour collected LY after CLND (multimarker reverse transcriptase-polymerase chain reaction [MM-RT-PCR] with primers for tyrosinase, MART1 (MelanA), and uMAGE mRNA (27.7% positive samples)]. Median follow-up time was 41xa0months.ResultsAccording to univariate analysis, the following factors had a negative impact on overall survival (OS): higher Breslow thickness (Pxa0=xa0.0001), ulceration (Pxa0<xa0.0001), higher Clark level (Pxa0=xa0.008), male gender (Pxa0=xa0.0001), metastatic lymph nodes >1 (Pxa0<xa0.0001), nodal metastases extracapsular extension (Pxa0<xa0.0001), metastases to additional non-SNs (Pxa0=xa0.0004), micrometastases size ≥0.1xa0mm (Pxa0=xa0.0006), and positive LY MM-RT-PCR (Pxa0=xa0.0007). SN tumor burden showed linear correlation with increasing Breslow thickness (Pxa0=xa0.01). The 5-year OS rates for SLN tumor burden <0.1xa0mm, 1–1.0xa0mm, and >1.0xa0mm were 84%/66%/44%, respectively, and for positive and negative LY MM-RT-PCR 47%/0%, respectively. The independent factors for shorter OS (multivariate analysis): male gender, primary tumor ulceration, number of involved nodes ≥4, micrometastases size >1.0xa0mm, and, in additional model including molecular analysis—positive MM-RT-PCR results (hazard ratio [HR] 3.2), micrometastases size >1.0xa0mm (HR 1.13), and primary tumor ulceration (HR 2.17). Similar results were demonstrated for disease-free survival (DFS) data.ConclusionsSN tumor burden categories according to Rotterdam criteria and the positive result of LY MM-RT-PCR assay demonstrated additional, independent prognostic value in SN-positive melanoma patients, showing significant correlation with shorter DFS and OS.

Increased sampling will lead to an increase in detection, but is it clinically relevant?: Reply letter regarding: "treatment influencing down-staging in EORTC Melanoma Group sentinel node histological protocol compared with complete step-sectioning: A national multicentre study" by Riber-Hansen et al.

However, we would like to expressa great concern regarding the pathology protocols,which were used. The authors claim to have used theEuropean Organisation for Research and Treatment ofCancer (EORTC) Melanoma Group (MG) protocol.However there is an internal contradiction between theabstract and methods in their description of this proto-col and furthermore neither of the methods describedadequately reflects the EORTC protocol. There appearsto be a misunderstanding between the meaning of stepsand levels. A step is the distance between levels, a level isa section or sections stained to represent that level. TheEORTC protocol as it has evolved consists of six pairsof sections, each stained with haematoxylin–eosin andS100. These are separated by steps at 50 lm thickness,so there are five steps and six levels whereas in theabstract there is a description of five sections 50 m apartand in the methods there is a description of six levels50 m apart. It was then stated that the first five levelswere treated differently. Furthermore in Fig. 1 there isagain confusion between the words steps and sectionsor levels.Despite this confusion we would like to acknowledgethat increased sampling will lead to increased detectionrates, as it was also demonstrated by the study by Cooket al. The extensive protocol identified 33.8% versus 25.2for the EORTC MG protocol, this is close to the detec-tion rate achieved by RT-PCR.