Next day sentinel node biopsy for melanoma after lymphoscintigraphy using 99mTc-labelled nanocolloid does not adversely affect long-term outcomes.

OBJECTIVE: Sentinel Lymph Node Biopsy (SLNB) is an important management tool for early-stage melanoma. Different radiopharmaceuticals are used internationally to localise the sentinel node using lymphoscintigraphy (LSG) before surgery. Recent reports have suggested that a delayed interval between LSG and SLNB using 99mTc-labelled nanocolloid tracer has an adverse survival impact, but not with 99mTc-labelled antimony sulphide colloid. This study aims to analyse survival outcome in a prospective cohort of melanoma patients undergoing same day or next day SLNB after LSG using 99mTc-labelled nanocolloid. METHODS: Outcome data were reviewed for patients undergoing SLNB, stratified by time interval between LSG and SLNB at a single UK academic centre. Kaplan-Meier survival analysis was used to assess overall survival (OS), melanoma-specific survival (MSS) and progression-free survival (PFS). Cox multivariable regression analysis identified independent risk factors. RESULTS: 925 patients had LSG using the 99mTc-nanocolloid tracer between 2009 and 2019, with a median follow-up of 6.36 years. No difference was seen on univariate analysis in OS, MSS, PFS, or nodal recurrence between patients undergoing same day or next day SLNB (Log-rank P = 0.437, 0.293, 0.587, 0.342 respectively). In addition, nodal recurrence as first site or anytime site of recurrence in SLNB negative patients was similar between the groups (Log-rank P = 0.093 and 0.457 respectively). Stratified analysis of time did not demonstrate an outcome difference (MSS Log-rank P = 0.938). Cox multivariable regression did not show time interval to independently influence OS, MSS or PFS. CONCLUSIONS: We do not find a significant effect on long-term outcomes when SLNB is performed the day after LSG with 99mTc-labelled nanocolloid tracer. We infer that tracer migration is not clinically significant within 24 h of injection based on long term clinical outcome data.

Incidental Breast Cancer Diagnosis From Lymphoscintography Using 99mTc-Labeled Nanocolloid for Cutaneous Melanoma of the Upper Arm.

ABSTRACT: A 51-year-old woman with a 2-mm-Breslow-thickness melanoma on her arm had 99mTc-nanocolloid lymphoscintigraphy to localize the associated sentinel lymph node. A single axillary node was identified, and histology confirmed a micrometastasis of breast tissue origin. Imaging of the patient's breasts and subsequent biopsy confirmed ipsilateral stage III breast cancer, which was treated with lumpectomy and axillary node clearance. This is the first reported case of an incidental solid cancer diagnosis from a sentinel lymph node biopsy undertaken for a different tumor origin. This illustrates the importance of recognizing overlapping lymphatic distribution of sentinel lymph nodes, which can drain multiple organs.

Robot-Assisted Pelvic Dissection for Enlarged Lymph Nodes in Melanoma Improves Recovery with Equivalent Oncological Outcomes to Open Pelvic Dissection.

BACKGROUND: Robot-assisted pelvic lymph node dissection (rPLND) has been reported in heterogenous groups of patients with melanoma, including macroscopic or at-high-risk-for microscopic metastasis. With changing indications for surgery in melanoma, and availability of effective systemic therapies, pelvic dissection is now performed for clinically detected bulky lymph node metastasis followed by adjuvant drug therapy. rPLND has not been compared with open pelvic lymph node dissection (oPLND) for modern practice. METHODS: All patients undergoing pelvic node dissection for macroscopic melanoma at a single institution were reviewed as a cohort, observational study. RESULTS: Twenty-two pelvic lymph node dissections were identified (8 oPLND; 14 rPLND). The number of pelvic lymph nodes removed was similar (median oPLND 6.5 (interquartile range [IQR] 6.0-12.5] versus rPLND 6.0 [3.75-9.0]), with frequent matted nodes (11/22, 50.0%). Operative time (median oPLND 130 min [IQR 95.5-182] versus rPLND 126 min [IQR 97.8-160]) and complications (Clavien-Dindo scale) were similar. Length of hospital stay (median 5.34 days (IQR 3.77-6.94) versus 1.98 days (IQR 1.39-3.50) and time to postoperative adjuvant therapy (median 11.6 weeks [IQR 10.6-18.5] versus 7.71 weeks [IQR 6.29-10.4]) were shorter in the rPLND group. No differences in pelvic lymph node recurrence (p = 0.984), distant metastatic recurrence (p = 0.678), or melanoma-specific survival (p = 0.655) were seen (median follow-up 21.1 months [rPLND] and 25.7 months [oPLND]). CONCLUSIONS: rPLND is an effective way to remove bulky pelvic lymph nodes in melanoma, with a shorter recovery and reduced interval to initiating adjuvant therapy compared with oPLND. This group of patients may especially benefit from neoadjuvant systemic approaches to management.

Association of Complex Lymphatic Drainage in Head and Neck Cutaneous Melanoma With Sentinel Lymph Node Biopsy Outcomes: A Cohort Study and Literature Review.

Importance: Although sentinel lymph node biopsy (SLNB) is a vital staging tool, its application in head and neck melanoma (HNM) is complicated by a higher false-negative rate (FNR) compared with other regions. This may be due to the complex lymphatic drainage in the head and neck. Objective: To compare the accuracy, prognostic value, and long-term outcomes of SLNB in HNM with melanoma from the trunk and limb, focusing on the lymphatic drainage pattern. Design, Setting, and Participants: This cohort observational study at a single UK University cancer center included all patients with primary cutaneous melanoma undergoing SLNB between 2010 to 2020. Data analysis was conducted during December 2022. Exposures: Primary cutaneous melanoma undergoing SLNB between 2010 to 2020. Main Outcomes and Measures: This cohort study compared the FNR (defined as the ratio between false-negative results and the sum of false-negative and true-positive results) and false omission rate (defined as the ratio between false-negative results and the sum of false-negative and true-negative results) for SLNB stratified by 3 body regions (HNM, limb, and trunk). Kaplan-Meier survival analysis was used to compare recurrence-free survival (RFS) and melanoma-specific survival (MSS). Comparative analysis of detected lymph nodes on lymphoscintigraphy (LSG) and SLNB was performed by quantifying lymphatic drainage patterns by number of nodes and lymph node basins. Multivariable Cox proportional hazards regression identified independent risk factors. Results: Overall, 1080 patients were included (552 [51.1%] men, 528 [48.9%] women; median age at diagnosis 59.8 years), with a median (IQR) follow-up 4.8 (IQR, 2.7-7.2) years. Head and neck melanoma had a higher median age at diagnosis (66.2 years) and higher Breslow thickness (2.2 mm). The FNR was highest in HNM (34.5% vs 14.8% trunk or 10.4% limb, respectively). Similarly, the false omission rate was 7.8% in HNM compared with 5.7% trunk or 3.0% limbs. The MSS was no different (HR, 0.81; 95% CI, 0.43-1.53), but RFS was lower in HNM (HR, 0.55; 95% CI, 0.36-0.85). On LSG, patients with HNM had the highest proportion of multiple hotspots (28.6% with ≥3 hotspots vs 23.2% trunk and 7.2% limbs). The RFS was lower for patients with HNM with 3 or more affected lymph nodes found on LSG than those with fewer than 3 affected lymph nodes (HR, 0.37; 95% CI, 0.18-0.77). Cox regression analysis showed head and neck location to be an independent risk factor for RFS (HR, 1.60; 95% CI, 1.01-2.50), but not for MSS (HR, 0.80; 95% CI, 0.35-1.71). Conclusions and Relevance: This cohort study found higher rates of complex lymphatic drainage, FNR, and regional recurrence in HNM compared with other body sites on long-term follow-up. We advocate considering surveillance imaging for HNM for high-risk melanomas irrespective of sentinel lymph node status.

Lymph node dissections in cutaneous malignancy: Where are we now? A review of 10 years' experience at a tertiary centre.

The surgical management of cutaneous malignancies has evolved over recent years with the introduction of novel medical therapies and an increasing emphasis upon early adjuvant systemic therapy. As such, completion lymph node dissection (cLND) is now no longer recommended following a positive sentinel lymph node biopsy (SLNB) in melanoma. We evaluated our ten-year practice at a regional tertiary centre, assessing the change in lymph node dissection (LND) caseload volume, anatomical distribution, and indication for the procedure. A retrospective search was carried out of all LNDs performed by the Plastic Surgery department at Cambridge University Hospitals NHS Trust, UK from 1 January 2010 to 31 December 2019. Case notes were retrospectively analysed for each procedure, with the site and pathology recorded. A total of 491 LNDs were performed over the 10-year period. Surgical volume peaked in 2015 with 67 cases, followed by a decline to 41 cases in 2019. The number of neck dissections increased over the decade, as well as the proportion of cases due to macroscopic nodal disease. We sub-analysed the number of LNDs in three contiguous 18-month intervals, corresponding to changes in practice due to evidence from the DeCOG and MSLT-II Trials. We found a 41.67% reduction in LNDs caseload between July 2018-Dec 2019, compared to a similar period prior to trial evidence (July 2015-Dec 2016) (p=0.0.14). In summary, the surgical volume of LNDs has decreased significantly since 2018, reflecting emerging evidence and changes to national guidelines. This will require ongoing monitoring for workforce planning and surgical training.

Selection of Oncogenic Mutant Clones in Normal Human Skin Varies with Body Site.

Skin cancer risk varies substantially across the body, yet how this relates to the mutations found in normal skin is unknown. Here we mapped mutant clones in skin from high- and low-risk sites. The density of mutations varied by location. The prevalence of NOTCH1 and FAT1 mutations in forearm, trunk, and leg skin was similar to that in keratinocyte cancers. Most mutations were caused by ultraviolet light, but mutational signature analysis suggested differences in DNA-repair processes between sites. Eleven mutant genes were under positive selection, with TP53 preferentially selected in the head and FAT1 in the leg. Fine-scale mapping revealed 10% of clones had copy-number alterations. Analysis of hair follicles showed mutations in the upper follicle resembled adjacent skin, but the lower follicle was sparsely mutated. Normal skin is a dense patchwork of mutant clones arising from competitive selection that varies by location. SIGNIFICANCE: Mapping mutant clones across the body reveals normal skin is a dense patchwork of mutant cells. The variation in cancer risk between sites substantially exceeds that in mutant clone density. More generally, mutant genes cannot be assigned as cancer drivers until their prevalence in normal tissue is known.See related commentary by De Dominici and DeGregori, p. 227.This article is highlighted in the In This Issue feature, p. 211.

Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin.

How somatic mutations accumulate in normal cells is central to understanding cancer development but is poorly understood. We performed ultradeep sequencing of 74 cancer genes in small (0.8 to 4.7 square millimeters) biopsies of normal skin. Across 234 biopsies of sun-exposed eyelid epidermis from four individuals, the burden of somatic mutations averaged two to six mutations per megabase per cell, similar to that seen in many cancers, and exhibited characteristic signatures of exposure to ultraviolet light. Remarkably, multiple cancer genes are under strong positive selection even in physiologically normal skin, including most of the key drivers of cutaneous squamous cell carcinomas. Positively selected mutations were found in 18 to 32% of normal skin cells at a density of ~140 driver mutations per square centimeter. We observed variability in the driver landscape among individuals and variability in the sizes of clonal expansions across genes. Thus, aged sun-exposed skin is a patchwork of thousands of evolving clones with over a quarter of cells carrying cancer-causing mutations while maintaining the physiological functions of epidermis.

A single progenitor population switches behavior to maintain and repair esophageal epithelium.

Diseases of the esophageal epithelium (EE), such as reflux esophagitis and cancer, are rising in incidence. Despite this, the cellular behaviors underlying EE homeostasis and repair remain controversial. Here, we show that in mice, EE is maintained by a single population of cells that divide stochastically to generate proliferating and differentiating daughters with equal probability. In response to challenge with all-trans retinoic acid (atRA), the balance of daughter cell fate is unaltered, but the rate of cell division increases. However, after wounding, cells reversibly switch to producing an excess of proliferating daughters until the wound has closed. Such fate-switching enables a single progenitor population to both maintain and repair tissue without the need for a "reserve" slow-cycling stem cell pool.

Chronic low dose UV exposure and p53 mutation: tilting the odds in early epidermal preneoplasia?

PURPOSE: This review addresses how mutation of the TP53 gene (p53) and ultraviolet light alter the behavior of normal progenitor cells in early epidermal preneoplasia. CONCLUSIONS: Cancer is thought to evolve from single mutant cells, which expand into clones and ultimately into tumors. While the mutations in malignant lesions have been studied intensively, less is known about the earliest stages of preneoplasia, and how environmental factors may contribute to drive expansion of mutant cell clones. Here we review the evidence that ultraviolet radiation not only creates new mutations but drives the exponential growth of the numerous p53 mutant clones found in chronically exposed epidermis. Published data is reconciled with a new paradigm of epidermal homeostasis which gives insights into the behavior of mutant cells. We also consider the reasons why so few mutant cells progress into tumors and discuss the implications of these findings for cancer prevention.

Lessons for adult fingertip regeneration: glimpses from basic research.

Understanding the mechanisms involved in limb and finger regeneration holds promise for improving current treatment therapies. Recent animal studies have improved our understanding of the limb regeneration process markedly. Improved sophistication in experimentation has allowed results that partly reveal the cells of origin in fingertip regeneration in mouse models, which implicates a tissue-resident progenitor cell population. The impressive regeneration of amputated salamander limbs has been shown to work through an evolutionarily divergent mechanism and may not be open to direct translational approaches in mammals. In addition, researchers are beginning to understand the complexity of the interrelated mechanisms of axis determinants in chick embryo limb development. In this article, we review lessons to be learned from these divergent experiments, to understand fingertip regeneration in humans.

Early return to function in young adults with neglected femoral neck fractures.

Neglected femoral fractures in young adults are a challenge to the orthopaedic surgeon, requiring prolonged treatment and with attendant risks of nonunion. We postulated treatment in this group by accurate reduction, two cannulated screws, and whole free fibular autograft would allow early mobilization and provide good bony union. Thirty-two patients aged 18 to 50 years were treated at our center in this manner. They presented to our center 3 to 6 months after injury, and had Garden's Grade III/IV fractures with varying degrees of neck resorption, but no avascular necrosis. No plaster was applied, and early return to function was encouraged. Bony union was achieved in 29 (90.6%) patients at a mean of 19.2 weeks (range, 16-24 weeks). All patients with union had good function at long-term followup at an average of 6.1 years postoperatively (range, 2-12 years), and the average Harris hip score was 87.1 points (range, 74.5-94 points). Our procedure allows early return of function in young, active patients disabled by old femoral neck fractures compounded by lack of early treatment.