Prognostic Significance and Management of Sentinel Nodes in the Triangular Intermuscular Space of Patients with Melanoma.

BACKGROUND: The clinical significance of sentinel nodes (SNs) in the triangular intermuscular space (TIS) of patients with melanoma is poorly understood. This study aimed to determine their incidence and positivity rate, and to report their management and patient outcomes. METHODS: This was a single-institution retrospective cohort study of patients with unilateral or bilateral TIS SNs on lymphoscintigraphy treated between 1992 and 2017. Recurrence-free survival was analyzed. RESULTS: Lymphoscintigraphy identified TIS SNs in 266 patients. They were bilateral in 17 patients. Of the 2296 patients with a melanoma on the upper back, 259 (11%) had TIS SNs. Procurement of SNs was not attempted in 122 (43%) of the 283 cases and failed in 11 cases (7%). An SN was successfully retrieved from the TIS in 145 patients (53%) and contained metastasis in 18 of 150 TIS SNs. This was the only positive SN in 12 patients (8%), upstaging all of them. Of the 18 patients with a positive SN in the TIS, 9 (50%) underwent completion axillary lymph node dissection, but no additional involved nodes were found in any of these patients. Recurrence in the TIS was observed in six patients (5%), none of whom had their TIS SN surgically pursued previously. CONCLUSIONS: Lymphoscintigraphy showed TIS SNs in 11% of patients with melanomas on their upper back. In such cases, retrieval of TIS SNs is required for accurate staging and to minimize the risk of TIS recurrence.

Preoperative Ultrasound Assessment of Regional Lymph Nodes in Melanoma Patients Does not Provide Reliable Nodal Staging: Results From a Large Multicenter Trial.

OBJECTIVE: To assess whether preoperative ultrasound (US) assessment of regional lymph nodes in patients who present with primary cutaneous melanoma provides accurate staging. BACKGROUND: It has been suggested that preoperative US could avoid the need for sentinel node (SN) biopsy, but in most single-institution reports, the sensitivity of preoperative US has been low. METHODS: Preoperative US data and SNB results were analyzed for patients enrolled at 20 centers participating in the screening phase of the second Multicenter Selective Lymphadenectomy Trial. Excised SNs were histopathologically assessed and considered positive if any melanoma was seen. RESULTS: SNs were identified and removed from 2859 patients who had preoperative US evaluation. Among those patients, 548 had SN metastases. US was positive (abnormal) in 87 patients (3.0%). Among SN-positive patients, 39 (7.1%) had an abnormal US. When analyzed by lymph node basin, 3302 basins were evaluated, and 38 were true positive (1.2%). By basin, the sensitivity of US was 6.6% (95% confidence interval: 4.6-8.7) and the specificity 98.0% (95% CI: 97.5-98.5). Median cross-sectional area of all SN metastases was 0.13 mm2; in US true-positive nodes, it was 6.8 mm2. US sensitivity increased with increasing Breslow thickness of the primary melanoma (0% for ≤1 mm thickness, 11.9% for >4 mm thickness). US sensitivity was not significantly greater with higher trial center volume or with pre-US lymphoscintigraphy. CONCLUSION: In the MSLT-II screening phase population, SN tumor volume was usually too small to be reliably detected by US. For accurate nodal staging to guide the management of melanoma patients, US is not an effective substitute for SN biopsy.

Ultrasound Examination of the Lymphatic Drainage Area and Regional Lymph Nodes in Melanoma Patients with In-Transit Metastases.

BACKGROUND: In-transit metastases (ITMs) are cutaneous or subcutaneous regional metastases that may occur in patients with melanoma. ITMs are often multiple and new lesions tend to appear over time. Ultrasonography can detect impalpable subcutaneous tumors. OBJECTIVE: The aim of this study was to assess the value of ultrasound examination in detecting additional, non-palpable ITMs and to determine their relevance. METHODS: Melanoma patients with ITMs who underwent regional ultrasound examination of the skin and subcutaneous tissue between the wide excision scar of the primary melanoma and the regional lymph node field were identified. In most, ultrasound assessment also included the regional lymph node field. Relevant data were collected and analyzed. RESULTS: Twenty-eight patients presenting with a total of 40 ITMs were included. Ultrasound examination identified additional ITMs in 15 patients (54%). No nodal recurrences were detected. Most additional lesions were found closer to the regional lymph nodes than the original ITMs. Management was influenced by the ultrasound findings in nine patients (32%), five of whom had more extensive surgery, three received systemic drug therapy instead of surgery, and in one patient surgery was delayed and follow-up intensified. In one patient, only subcutaneous fat was found in the excised specimen and the ultrasound was classified as false-positive. CONCLUSION: In melanoma patients with ITMs, ultrasonography of the lymphatic drainage area provided valuable information, as additional ITMs were identified in more than half of these patients and management was influenced in one-third.

Sentinel Node Biopsy for Melanoma Patients with a Local Recurrence or In-Transit Metastasis.

BACKGROUND: Sentinel node (SN) biopsy (SNB) is not routinely performed for melanoma patients with local recurrence (LR) or in-transit metastasis (ITM). This study aimed to describe the technique, findings, and prognostic value of this procedure, and the outcome for such patients at our institution. METHODS: Prospectively collected data were obtained from the Melanoma Institute Australia database. Patients who had SNB for LR or ITM between 1992 and 2015 were included in the study. Patient and primary tumor characteristics, lymphoscintigrams, SNB results, and follow-up data were analyzed. RESULTS: Overall, 7999 patients underwent SNB, 128 (1.6%) of whom met the selection criteria. The SNB procedure was performed for 85 of 1516 patients with LR (6%), 17 of 1671 patients with ITM from a known primary tumor (1%), and 26 of 170 patients who presented with ITM from an unknown primary site (15%). The SN identification rate was 100%. Metastatic melanoma was identified in an SN from 16 of the 128 patients (13%). Follow-up data were available for 114 patients. The false-negative rate was 27%. The SN-positive patients had significantly worse overall survival than the SN-negative patients, with respective 5-year survival rates of 54% and 81% (P = 0.01). CONCLUSION: The SNB procedure was performed infrequently for LR or ITM. The SNs were positive for 13% of the patients with LR or ITM. Positive SNs were associated with worse overall survival. Despite the false-negative rate of 27%, the procedure yielded information that was relevant for staging and prognosis. The SNB procedure should be considered for patients with LR or ITM.

Focused Ultrasound Surveillance of Lymph Nodes Following Lymphoscintigraphy Without Sentinel Node Biopsy: A Useful and Safe Strategy in Elderly or Frail Melanoma Patients.

BACKGROUND: Sentinel node (SN) biopsy (SNB) has become standard of care in clinically localized melanoma patients. Although it is minimally invasive, advanced age and/or comorbidities may render SNB inadvisable in some patients. Focused ultrasound follow-up of SNs identified by preoperative lymphoscintigraphy may be an alternative in these patients. This study examines the outcomes in patients managed in this way at a major melanoma treatment center. METHODS: All patients with clinically localized cutaneous melanoma who underwent lymphoscintigraphy and in whom SNB was intentionally not performed due to advanced age and/or comorbidities were included. RESULTS: Between 2000 and 2009, 160 patients (5.2% of the total) underwent lymphoscintigraphy without SNB because of advanced age and/or comorbidities. Compared with the 2945 patients who had a SNB, the 160 patients were older, had thicker melanomas that were more often located in the head and neck region, and had more SNs in more nodal regions. Of the 160 patients, 150 (94%) were followed with ultrasound examination of their SNs at each follow-up visit; this identified 33% of the nodal recurrences before they became clinically apparent. Compared with SN-positive patients who were treated by completion lymph node dissection, observed patients who developed nodal recurrence had more involved nodes when a delayed lymphadenectomy was performed. Melanoma-specific survival, recurrence-free survival, and distant recurrence-free survival rates were similar, while regional lymph node-free survival was worse. CONCLUSIONS: Lymphoscintigraphy with focused ultrasound follow-up of SNs is a reasonable management alternative to SNB in patients who are elderly and/or have substantial comorbidities.

Outcome of Melanoma Patients Who Did Not Proceed to Sentinel Node Biopsy After Preoperative Lymphoscintigraphy.

BACKGROUND: At our institution, a planned sentinel node biopsy (SNB) procedure is occasionally canceled after preoperative lymphoscintigraphy. This study reports the frequency of this, the reasons, and the management and outcomes of these patients. METHODS: All patients with clinically localized cutaneous melanoma treated at Melanoma Institute Australia between 2000 and 2009 whose planned SNB procedure was not undertaken after lymphoscintigraphy were included in this retrospective study. RESULTS: Of the 3148 patients in whom the procedure had been planned, 203 patients (6.4 %) did not have a SNB. The main reason for not proceeding with SNB (in 84 % of cases) was the lymphoscintigraphic demonstration of multiple drainage fields and/or multiple sentinel nodes (SNs). Patients who did not proceed to SNB were significantly older than those who did, more often had melanomas of the head or neck, and had more SNs and more nodal drainage fields. Of the 203 patients, 181 (89 %) were followed with high-resolution ultrasound of their SNs, which identified 33 % of the nodal recurrences before they were clinically apparent. Patients whose SNB was canceled had significantly worse recurrence-free survival and regional node disease-free survival, but melanoma-specific survival was similar. Compared to SN-positive patients, node-positive patients without SNB had significantly more involved nodes when a delayed lymphadenectomy was performed, but melanoma-specific survival was not significantly different after a median follow-up of 42 months. CONCLUSIONS: Lymphoscintigraphy with ultrasound follow-up of previously identified SNs is an acceptable management strategy for patients in whom a SNB procedure is likely to be challenging.

EANM practice guidelines for lymphoscintigraphy and sentinel lymph node biopsy in melanoma.

PURPOSE: Sentinel lymph node biopsy is an essential staging tool in patients with clinically localized melanoma. The harvesting of a sentinel lymph node entails a sequence of procedures with participation of specialists in nuclear medicine, radiology, surgery and pathology. The aim of this document is to provide guidelines for nuclear medicine physicians performing lymphoscintigraphy for sentinel lymph node detection in patients with melanoma. METHODS: These practice guidelines were written and have been approved by the European Association of Nuclear Medicine (EANM) to promote high-quality lymphoscintigraphy. The final result has been discussed by distinguished experts from the EANM Oncology Committee, national nuclear medicine societies, the European Society of Surgical Oncology (ESSO) and the European Association for Research and Treatment of Cancer (EORTC) melanoma group. The document has been endorsed by the Society of Nuclear Medicine and Molecular Imaging (SNMMI). CONCLUSION: The present practice guidelines will help nuclear medicine practitioners play their essential role in providing high-quality lymphatic mapping for the care of melanoma patients.

Outcome following sentinel node biopsy plus wide local excision versus wide local excision only for primary cutaneous melanoma: analysis of 5840 patients treated at a single institution.

OBJECTIVE: Worldwide, sentinel node biopsy (SNB) is now a standard staging procedure for most patients with melanomas 1 mm or more in thickness, but its therapeutic benefit is not clear, pending randomized trial results. This study sought to assess the therapeutic benefit of SNB in a large, nonrandomized patient cohort. METHODS: Patients with primary melanomas 1.00 mm or more thick or with adverse prognostic features treated with wide local excision (WLE) at a single institution between 1992 and 2008 were identified. The outcomes for those who underwent WLE plus SNB (n = 2909) were compared with the outcomes for patients in an observation (OBS) group who had WLE only (n = 2931). Median follow-up was 42 months. RESULTS: Melanoma-specific survival (MSS) was not significantly different for patients in the SNB and OBS groups. However, a stratified univariate analysis of MSS for different thickness subgroups indicated a significantly better MSS for SNB patients with T2 and T3 melanomas (>1.0 to 4.0 mm thick) (P = 0.011), but this was not independently significant in multivariate analysis. Compared with OBS patients, SNB patients demonstrated improved disease-free survival (DFS) (P < 0.001) and regional recurrence-free survival (P < 0.001). There was also an improvement in distant metastasis-free survival (DMFS) for SNB patients with T2 and T3 melanomas (P = 0.041). CONCLUSIONS: In this study, the outcome for the overall cohort after WLE alone did not differ significantly from the outcome after additional SNB. However, the outcome for the subgroup of patients with melanomas more than 1.0 to 4.0 mm in thickness was improved if they had a SNB, with significantly improved disease-free and DMFS.

The unpredictability of lymphatic drainage from the ear in melanoma patients, and its implications for management.

BACKGROUND: The ear is known to have variable lymphatic drainage. The purpose of this study was to define better the lymphatic drainage patterns of the ear by correlating the location of primary tumors, classified according to the embryologically derived anatomical subunits of the ear, with their mapped sentinel nodes (SNs) identified by lymphoscintigraphy (LS). METHODS: Lymphatic drainage data for patients with a primary melanoma of the ear were reviewed and correlated with the precise primary melanoma site. RESULTS: Between 1993 and 2010, LS was performed in 111 patients with a primary melanoma on the ear, identifying 281 SNs in 195 lymph node (LN) fields. The mean numbers of SNs and LN fields identified by LS per patient were 2.65 and 1.76. SN biopsy was performed in 71 patients (64 %). The mean number of SNs removed was 2.36. The 111 ear melanomas were mostly located on the helical rim (55 %), followed by the lobule (24.3 %). The five different primary ear sites drained mainly to SNs in level CII, level CV and the preauricular region. Drainage was most often to level CII (36.4 %). Drainage to the contralateral neck was not observed. CONCLUSIONS: Lymphatic drainage of the ear has no predictable pattern and can be to SNs anywhere in the ipsilateral neck. Most commonly drainage is to cervical level II and the preauricular and postauricular LN fields. LS defines the lymphatic drainage pattern in individual melanoma patients and is essential for accurate SN identification and reliable SN biopsy.

The EANM and SNMMI practice guideline for lymphoscintigraphy and sentinel node localization in breast cancer.

PURPOSE: The accurate harvesting of a sentinel node in breast cancer includes a sequence of procedures with components from different medical specialities, including nuclear medicine, radiology, surgical oncology and pathology. The aim of this document is to provide general information about sentinel lymph node detection in breast cancer patients. METHODS: The Society of Nuclear Medicine and Molecular Imaging (SNMMI) and the European Association of Nuclear Medicine (EANM) have written and approved these guidelines to promote the use of nuclear medicine procedures with high quality. The final result has been discussed by distinguished experts from the EANM Oncology Committee, the SNMMI and the European Society of Surgical Oncology (ESSO). CONCLUSION: The present guidelines for nuclear medicine practitioners offer assistance in optimizing the diagnostic information from the SLN procedure. These guidelines describe protocols currently used routinely, but do not include all existing procedures. They should therefore not be taken as exclusive of other nuclear medicine modalities that can be used to obtain comparable results. It is important to remember that the resources and facilities available for patient care may vary.

Incomplete sentinel node biopsy is not clearly related to survival or regional recurrence in cutaneous melanoma patients.

BACKGROUND: In melanoma patients, we define incomplete sentinel node biopsy (I-SNB) as when fewer lymph nodes are removed during sentinel node biopsy (SNB) than identified on preoperative lymphoscintigraphy (LS). This study quantifies the frequency of I-SNB and evaluates any correlation with patient outcomes. METHODS: Evaluation of a prospective database of consecutive patients having LS and negative SNB from 1996 to 2006. Additional LS information was obtained from a nuclear medicine database. All statistical analyses were performed using the IBM SPSS Statistic 19.0 software package. RESULTS: I-SNB occurred in 20% of the cohort (n = 2007). For axillary (n = 895), groin (n = 569), and neck/axial patients (n = 334) I-SNB occurred in 12%, 26%, and 28% of cases, respectively (P < .001). On univariate analysis, there was a significant association between I-SNB and worse disease-free survival (DFS), P = .007 and trend toward worse melanoma-specific survival (MSS), P = .056. I-SNB was not associated with worse regional recurrence-free survival (RRFS), P = .144. There was no relationship between I-SNB and worse DFS, RRFS, or MSS on multivariate analysis. Sentinel node region (axilla better than groin and neck/axial) had a significant association with RRFS (P = .039) on univariate analysis and DFS on univariate (P = .009) and multivariate analysis. Significantly worse outcomes for MSS, DFS, and RRFS were seen with male gender, increasing age, high mitotic count, ulceration, and increasing Breslow thickness. CONCLUSION: This study demonstrates no statistically significant relationship between I-SNB and patient outcomes when adjusting for known prognostic factors. These data do not exclude the possibility that I-SNB may have a weak association with worse outcomes.

Evaluation of incomplete sentinel node biopsy procedures and sentinel node positivity rates as surgical quality-assurance parameters in melanoma patients.

BACKGROUND: There is little literature describing quality assurance (QA) validation of an individual surgeon's ability to perform sentinel node biopsy (SNB) in melanoma patients. This study aims to evaluate incomplete SNB rates and SNB positivity rates as potential QA parameters. METHODS: An institutional database identified 2,874 patients with primary melanoma who had SNB performed when there was lymphoscintigraphy drainage to a single lymphatic field. Lymphoscintigraphy data were obtained from another database. Lymphoscintigraphy utilized small-particle colloid, allowing visualization of channels entering sentinel nodes on early dynamic scanning. Incomplete SNB was defined as retrieval of fewer sentinel nodes than identified on lymphoscintigraphy. RESULTS: The overall rate of incomplete SNB was 17.7 % (including axilla 7.8 %, neck 23.3 %, and groin 28.8 %). Individual surgeons varied significantly in their proportion of SNBs performed in each region (p < 0.001). The surgeons' overall incomplete SNB rate varied significantly (p < 0.001). The surgeons' incomplete SNB rate in the axilla ranged 3-16 % (p < 0.001), median 6 %; groin 21-41 % (p = 0.002), median 26 %; and neck 19-43 % (p = 0.374), median 22 %. The respective axillary, groin, and neck SNB positivity rate for incomplete SNB patients were 10, 23, and 18 % compared to "complete" SNB patients 14, 19, and 14 %. There were no significant differences between surgeons' SNB positivity rates. CONCLUSIONS: Incomplete SNB rates vary between surgeons in each region. SNB positivity rates do not vary commensurate with the incomplete SNB rates. The ranges described could be used as QA parameters, however because none of these experienced surgeons are outliers, the robustness of these parameters remains unproven.

Predicting lymphatic drainage patterns and primary tumour location in patients with breast cancer.

Detailed knowledge of the lymphatic drainage of the breast is limited. Lymphoscintigraphy is a technique used during breast cancer treatment to accurately map patterns of lymphatic drainage from the primary tumour to the draining lymph nodes. This study aimed to create a statistical model to analyse the spread of breast cancer and primary tumour location using a large lymphoscintigraphy database, and visualise the results with a novel computational model. This study was based on lymphoscintigraphy data from 2,304 breast cancer patients treated at the Royal Prince Alfred Hospital Medical Centre in Sydney, Australia. Bayesian inferential techniques were implemented to estimate the probabilities of lymphatic drainage from each region of the breast to each draining node field, to multiple node fields, and to determine probabilities of tumour prevalence in each breast region. A finite element model of the torso and discrete model of the draining node fields were created to visualise these data and a software tool was developed to display the results ( www.abi.auckland.ac.nz/breast-cancer ). Results confirmed that lymphatic drainage is most likely to occur to the axillary node field, and that there is significant likelihood of drainage to the internal mammary node field. The likelihood of lymphatic drainage from the whole breast to the axillary, internal mammary, infraclavicular, supraclavicular and interpectoral node fields were 98.2, 35.3, 1.7, 3.1, and 0.7%, respectively; whilst the probability of lymphatic drainage to multiple node fields was estimated to be 36.4%. Additionally, primary tumours are most likely to develop in the upper regions of the breast. The models developed provide quantitative estimates of lymphatic drainage of the breast, giving important insights into understanding breast cancer metastasis and have the potential to benefit both clinicians and patients during breast cancer diagnosis and treatment.

Treatment and prognostic significance of positive interval sentinel nodes in patients with primary cutaneous melanoma.

BACKGROUND: Interval sentinel nodes (SNs) are lymph nodes receiving direct lymphatic drainage from a primary site and lying between the tumor and a recognized node field. It is not clear what further nodal surgery should be performed when interval nodes are found to contain micrometastatic disease. In this study, the incidence, location, and treatment of interval SNs in melanoma patients were analyzed to develop recommendations regarding the treatment of patients with interval SNs. METHODS: A retrospective review was undertaken of all patients with primary cutaneous melanoma who underwent lymphoscintigraphy at a single institution between 1992 and 2007. Data concerning the primary melanoma, location of SNs, treatment and survival were analyzed. RESULTS: Of 4895 patients who had a lymphoscintigram during the study period, 442 (9.0%) had an interval SN identified on lymphoscintigraphy. Interval SNs occurred significantly more often in patients with melanomas on the posterior trunk than in those with melanomas at other sites (P<0.001). A total of 197 patients (44.6%) with an identified interval SN underwent excision biopsy of the node. Of the 16 patients found to have metastatic melanoma in their interval SN, four also had negative SNs in a recognized lymph node field, and no other positive nodes were found on completion lymphadenectomy. CONCLUSIONS: Interval SNs are present in approximately 1 in 10 melanoma patients but are about half as likely to contain metastases as SNs in recognized node fields. If a positive interval SN is found, completion lymphadenectomy of the recognized lymph node field is only recommended if a SN in this field is also positive.

Lymphatic drainage and tumour prevalence in the breast: a statistical analysis of symmetry, gender and node field independence.

Current understanding of the lymphatics draining the breast is controversial, despite its known importance in the spread of breast cancer. Similarly, knowledge regarding the spatial distribution of primary tumours in the breast is limited. This study sought to test commonly held assumptions in this field, including: (i) that breast lymphatic drainage and tumour prevalence are symmetric between the left and right sides of the body, (ii) that males and females have the same drainage patterns and tumour prevalences, and (iii) that lymphatic drainage in the breast occurs independently to different node fields. This study has used lymphoscintigraphy data from 2304 breast cancer patients treated at the RPAH Medical Centre, Sydney, Australia. Symmetry of lymphatic drainage and tumour distribution as well as gender differences were tested using Fisher's exact test. Drainage independence was assessed using Fisher's exact test, and a multivariate probit model was used to test for drainage correlations. Results showed that the breasts are likely to have symmetric lymphatic drainage and tumour prevalence, and that there is no significant difference between males and females. Furthermore, results showed that direct lymphatic drainage of the breasts is likely to be independent between node fields. Collectively, these results serve to further our understanding of lymphatic anatomy and the distribution of tumours in the breast.

The diagnostic value of adding dynamic scintigraphy to standard delayed planar imaging for sentinel node identification in melanoma patients.

PURPOSE: The aim of this study was to compare early dynamic imaging combined with delayed static imaging and single photon emission computed tomography (SPECT)/CT with delayed, planar, static imaging alone for sentinel node (SN) identification in melanoma patients. METHODS: Three hundred and seven consecutive melanoma patients referred for SN biopsy (SNB) were examined using combined imaging. Secondary interpretation of only the delayed static images was subsequently performed. In 220 patients (72%), complete surgical and pathological information relating to the SNB was available. The number of SNs identified and number of patients with positive SNs were compared between the two interpretations of the imaging studies and, when available, related to pathology data. RESULTS: A slightly higher number of SNs (mean 0.12/patient) was identified when interpreting only delayed static images compared to combined imaging. In a direct patient-to-patient comparison, the number of SN(s) identified on the combined vs static images only showed moderate agreement (kappa value 0.56). In 38 patients (17%), positive SNs were identified by the combined procedure compared to 35 (16%) by static imaging only. Thus by static imaging only, tumour-positive SNs were not identified in 3 of 38 patients (8%). CONCLUSION: For SN identification in melanoma patients, dynamic imaging combined with delayed static imaging and SPECT/CT is superior to delayed static imaging only because the latter is more likely to fail to identify SNs containing metastases.

Ultrasound assessment of lymph nodes in the management of early-stage melanoma.

It has been suggested that ultrasound examination of regional lymph nodes provides staging and prognostic information that is as accurate as sentinel node biopsy in patients who present with cutaneous melanoma. However, in most studies the sensitivity of ultrasound in detecting nodal metastasis has been low (23% in a recent large series). For the present, sentinel node biopsy remains the most accurate method of regional node staging in patients with newly diagnosed melanoma.

Guidelines for lymphoscintigraphy and F18 FDG PET scans in melanoma.

Melanoma has a high potential to develop metastases. Accurate staging is essential for appropriate management. Sentinel node (SN) status is a powerful prognostic factor in early stage melanoma. Staging is assisted by SN biopsy after lymphoscintigraphy to locate all true SNs prior to biopsy. PET using F18-FDG can detect metastases and is used to restage patients with AJCC Stages III and IV disease before planning surgery with curative intent.