Minimum number values of excised lymph node for single lymphatic basin.
\r\n\tBasic science studies have provided new insights into the pathophysiology of β-thalassemia. Studies of genotypic and phenotypic heterogeneity among patients and a better understanding of the control of erythropoiesis have provided new targets for designing novel agents that can be tailored to individual patient needs. JAK-2 kinase inhibitors and agents targeting the GDF-11/SMAD pathway are in clinical trials.
\r\n\r\n\tThis book will attempt to discuss the historical background of the disease and present the most up-to-date material regarding disease management in today's world for the reader to be updated on the best practice management of the disease.
",isbn:"978-1-83969-158-4",printIsbn:"978-1-83969-157-7",pdfIsbn:"978-1-83969-159-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"23abb2fecebc48a2df8a954eb8378930",bookSignature:"Dr. Akshat Jain",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10727.jpg",keywords:"History of Gene Mutation, Genetic Counselling, Anemia, Genotyping, Hemoglobin Electrophoresis, HLA typing, Hemolysis, Aplastic Anemia, Blood Transfusion, Laboratory Testing, Fetal Hemoglobin Modifiers, Gene Therapy",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 4th 2021",dateEndSecondStepPublish:"March 4th 2021",dateEndThirdStepPublish:"May 3rd 2021",dateEndFourthStepPublish:"July 22nd 2021",dateEndFifthStepPublish:"September 20th 2021",remainingDaysToSecondStep:"3 days",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"A board-certified pediatrician with a specialization in pediatric hematology-oncology and stem cell transplantation. In collaboration with Harvard Medical School, he studied and reported the outcomes of a global hemophilia collaboration. He is a member of the American Board of Pediatrics, Hematology, and American Board of Pediatrics, also he is a Committee member for the American Society of Pediatric Hematology-Oncology Special Interest Group in Global Pediatric Hematology oncology.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"344600",title:"Dr.",name:"Akshat",middleName:null,surname:"Jain",slug:"akshat-jain",fullName:"Akshat Jain",profilePictureURL:"https://mts.intechopen.com/storage/users/344600/images/system/344600.jpg",biography:"Akshat Jain M.D. M.P.H.\n11175 Campus Street \nLoma Linda, California 92354\nPhone: (917) 331-3216\nakshatjainusa@gmail.com \n\nMEDICAL EDUCATION \n●\tS.S.R. Medical College, Belle Rive, Mauritius - MBBS, Bachelor of Medicine Bachelor of Surgery, 2007\n●\tPediatrics Residency Training ,The New York Medical College, Metropolitan Hospital , Dec2008-Dec 2011\n●\tPediatric Hematology Oncology and Stem Cell Transplant Fellowship, Cohen’s Children's Hospital of New York at LIJ-North Shore Health system. July 2012- September 2015\n●\tMaster’s in Public Health ,Hofstra University School of Public Health ,New York , August 2015\n\n\nHONORS/ AWARDS \n●\tThe New York Academy of Medicine Honorary Associate Award , December 2009\n●\tProgram Leadership Award - Committee of Interns and Residents (C.I.R./SIEU), April 2010\n●\tAmerican Academy of Pediatrics Program Delegate Award, New York Medical College, December 2010.\n●\tCitation of Honor from New York County for Excellence in Medicine and Service to Long Island, New York,Nassau county executive chambers , August 15,2015 \n●\tTimes of India N.R.I. ( Non Resident Achiever ) award , August 2015 \n●\tCertificate for academic excellence –Hofstra University School of Health Science & Human Services, New York August 26, 2015\n●\tAmerican Society of Hematology Leadership Institute Award , April 2016\n●\tGlobal Health Speaker Award , convener of Global Health Symposium, Hofstra NorthWell School of Medicine and School of Public health , May 2016\n●\tInternational Pediatric Lymphoma Meeting ,Session Chairperson of Pediatric Lymphoma , Indian Society of Hematology and Oncology , November 2016\n●\tContent Leader Award for Hematology perspective’s in the Global CoronaVirus Pandemic Preparedness Response for Medical Association of physicians of Indian Origin, April 2020.\n●\tConvener and Chairperson International Webinar for COVID 19 Coagulopathy, May 2020. \n●\tFeatured in the Top Doctors magazine 2020, ranked top pediatric Hematologist Oncologist for Southern California.\n\nNATIONAL/INTERNATIONAL POSITIONS \n●\tHofstra University Dean Advisory Board for the School of Health Professions, December 2017\n●\tEditorial Board – American Society of Pediatric Hematology Oncology Communications Committee, International Journal of Hematology Research (ISSN 2409-3548)\n●\tReviewer - JAMA Pediatrics (ISSN: 2168-6203), British Medical Journal (ISSN, 1468-5833), JAMA Oncology (ISSN: 2374-2437), International Journal of Hematology Research (ISSN 2394—806X), Journal of Pediatric Hematology and Oncology (ISSN: 1536-3678), New England Journal of Medicine (Resident 360). \n●\tMember – Core committee: American Cancer Society (A.C.S.) and American Academy of Pediatrics (A.A.P.) - Joint global pediatric Oncology taskforce.\n●\tAdvisor -World Health Organization, South East Asia for maternal and child health initiatives.( 2013-Ongoing) , Ministry of Health and Family Welfare ,Government of India ( 2014- Ongoing ) , American Academy of Pediatrics &American Cancer Society Global Taskforce on Pediatric Cancers.( 2014-Ongoing )\n●\tEditor – AAPI journal (American Association of Physicians of Indian Origin. Circulation -40,000)\n●\tVisiting Professorship in Hematology Oncology and Stem Cell Transplantation, Rajasthan University of Medical Sciences, India. ( 2009-Ongoing )\n●\tIndustry Advisor – Bayer, UniQure, Sanofi-Genzyme, Takeda, CSL Behring\n●\tDirector of International Bone Marrow Failure Consortium- India, part of the Global Hematology Initiative of Cohen Children’s Medical Center, New York, August 2015-2017. \n●\tCommittee member for the American Society of Pediatric Hematology Oncology Special Interest Group in Global Pediatric Hematology oncology. ( 2016- Ongoing)\n\n\n WORK EXPERIENCE \nNov 2017- Current Loma Linda University Children’s Hospital \n Director Division of Pediatric Hematology \n Director, Comprehensive Hemophilia Program\n Director, Comprehensive Sickle Cell Program \n Division of Pediatric Hematology Oncology and Stem Cell Transplantation\n Professor of Public Health, Loma Linda University School of Public Health \n\nMar 2017– Oct 2017 Pediatrics and Pediatric Hematology Oncology Practice \n Adventist Health Ukiah Valley, California \n\nSept 2015 –Aug 2016 Assistant Professor Pediatrics, Hofstra North Shore LIJ School of Medicine \n Section Head –Global Pediatric Hematology Oncology and Stem Cell Transplantation\n North Shore LIJ Health system.\n Associate Adjunct Faculty, Hofstra University School of Public Health.\n\nJuly 2012 – Sep 2015 The Steven and Alexandra Cohen’s Children's’ Hospital of New York at LIJ-North Shore \n Hofstra University - Pediatrics Hematology Oncology and Stem Cell Transplant Fellowship \n Chief - Jeffrey Lipton MD\n\nDec 2011- April 2012 Global Health : SMS Medical College and Group of Hospitals, Government of India \n Project Director for Project A.G.N.I. - Set up a regional Lead Poisoning prevention and \n anemia nodal center \n \n Course Director - Pediatric Subspecialty training module for Pediatricians at J.K. Lone \n Children’s Hospital for Government of India. \n\nDec 08- Dec 2011 The New York Medical College, Residency in Pediatrics \n Metropolitan Hospital, NY\n Maria Fareri Children's Hospital at Westchester.\n The Memorial Sloan Kettering Hospital. NY\n House staff on Stem Cell Transplantation service.\n \nApril – August 2008 Oklahoma State Medical Association (O.S.M.A.) Externship Program\n The Integris Baptist Teaching Hospital and Nazih Zuhdi Transplant Center\n\nRESEARCH EXPERIENCE \nNov 2017 – Ongoing: Current and ongoing – Director, Inherited Bleeding Disorder Experimental Therapeutics Program, Loma Linda University School of Medicine\nJan 2014 –July 2015 - Hofstra University School of Public Health \n Needs Assessment to barriers in cancer care for newly diagnosed patients in a resource \n Limited setting. \n Principal Investigator - Akshat Jain, Co-PI -Corrine Kyriacou \n\nJune 2012- July 2015 - Steven and Alexandra Cohen Children’s Medical Center \n Study – Non Invasive assessment of endothelial dysfunction in children with Sickle cell \n Disease. \n Co-Principal Investigator – Banu Aygun MD\n Study – Multicenter study assessing outcome of Reduced Intensity Conditioning for \n patients undergoing hematopoetic stem cell transplantation for Sickle cell disease . \n Co-Principal Investigator – Indira Sahdev MD\n \nJan 2012- Mar12 A.G.N.I. (Anterograde Growth Normalization Initiative) \n Project Director, Project of Government of India for establishment of Universal Lead \n Independent Pilot project to study effects of Elevated Blood Lead levels in children \n suffering from Developmental disorders- Adapted by W.H.O. 2014 for a National Level \n Lead Screening program, India \n \nJan 2009- Dec11 The New York Medical College, Metropolitan Hospital Center. NY\n Resident Physician – Hypothalamic volumes in patients with Growth Hormone deficiency.\n Maria Fareri Children's hospital / Dr.Richard Noto - Pediatric Endocrinology\n \nApril 2008-Dec 08 Nazih Zuhdi Transplant Institute, Integris Baptist Hospital, Oklahoma City\n Project – Single institution outcome study for Solid organ transplants\n Research Assistant Department of Hepatology\n \nOct 2007 – Dec07 Mount Sinai School of Medicine, New York, NY\n Project- Arterio-venous fistula post liver transplantation.\n Research mentor-Dr. Charissa Chang, Assistant Professor in Department of Liver Diseases. \n\nCERTIFICATION\n\n1.\tCalifornia State Medical License 8/2016- Present , New York State Licensure 8/2013-12/16\n2.\tAmerican Board of Pediatrics - Board certified, 11/14- Present\n3.\tAmerican Board of Pediatric Hematology Oncology – Board Certified , 06/2018- Present\n4.\tNeonatal Advanced Life Support 06/2009-Present \n5.\tPediatric Advanced Life Support 06/2009-Present \n6.\tECFMG Certification 12/2007-Present \n\nORAL PRESENTATIONS \n\n\n1.\tLeukemia and Lymphoma Society of America C.M.E. Symposium presentation – Leukemia and Beyond: Advances in Cancer Care and Blood Disorders in the 21st Century, October 2019\n2.\tLoma Linda University School of Medicine – Grand Rounds, Advances in the Management of Sickle Cell Disease, March 2019.\n3.\tLoma Linda University School of Medicine – Experimental Therapeutics in Sickle Cell Disease – New Horizons at Loma Linda , November 2018 .\n4.\tAdventist Health Ukiah , California - Neurological Defects of Iron Deficiency and Lead Poisoning in Humans , October 2017\n5.\tHofstra NorthWell School of Medicine - National Public Health Symposium on Global Public Health , Convener and Moderator ,April 2016 \n6.\tCleveland Clinic Children’s Medical Center, Ohio – Non BCR-ABL Myeloproliferative syndromes of childhood, January 19, 2016.\n7.\tChildren’s Hospital at SMS Medical College ,India – Pediatric Hematology Oncology Emergencies for the Tropics, November 13, 2015 \n8.\tHarvard Medical School, Boston Children’s Hospital Division of Pediatric Hematology – Advances in Global Hematology, Annual Hemophilia Twining symposium, August 2, 2015.\n9.\tNew York Medical College as Grand Rounds, Division of Pediatrics – Emergencies in Pediatric Hematology and Oncology, April 2015.\n10.\tMaurice A. Deane School of Law, Hofstra University, New York - Healthcare Access to Undocumented immigrants: Immigration reform and its impact, March 2015.\n11.\tPediatric Academic Society/Society of Pediatric Research (PAS/SPR) as platform presentation, Vancouver, BC - Global Child Health in Rich & Poor Countries Lessons Learned from Indigenous Health, May 3 2014.\n12.\tDepartment of Medicine and Medical Oncology, as Guest International faculty , SMS Medical College, India - Advances in Stem Cell Transplantation – January 2014.\n13.\tInternational health conference, Global Association of physicians of Indian Origin , New Jersey – Impact of Lead Intoxication in Low to middle income countries , August 2012.\n14.\t139st APHA Annual Meeting and Exposition 2011, Boston - Use of decision support in a Harlem pediatric emergency department to increase prescription of controller medicines to patients with poorly controlled asthma - Wilson Wang, Carolina Valez, Nicole Falanga, Vikas Bhambhani , Akshat Jain , Farhad Gazi, David Spiller, Paper no-227188 , November 2011 \n15.\tThe New York Academy of Medicine, Resident award night - False negative result in newborn screening for Congenital Adrenal hyperplasia - July 2009.",institutionString:"Loma Linda University Children's Hospital",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Loma Linda University Children's Hospital",institutionURL:null,country:{name:"United States of America"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"280415",firstName:"Josip",lastName:"Knapic",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/280415/images/8050_n.jpg",email:"josip@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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Currently, lymph node involvement is mostly diagnosed after sentinel lymph node biopsy (SLNB). However, although SLNB in melanoma patients at risk for lymph node metastasis is routinely performed almost everywhere, the role of completion lymphadenectomy (CLND) after positive SLNB remains controversial, as only 15-20% of the patients operated show additional lymph node metastases in the dissected basin. The MSLT-1 trial, which evaluated the impact of SLNB and immediate LND versus simple observation and LND after clinical evidence of metastases only, did not show any survival benefit between the two randomized groups of patients [1]. Moreover, other studies have shown that some of the patients with positive sentinel nodes seem at lower risk for additional lymph node metastasis, and will probably never develop additional non sentinel lymph node metastases. On the other hand, the final analysis of the MSLT-1 trial confirmed a longer disease free survival and a gain in survival only in the patients with positive nodes in the CLND group.
Until the results of the two ongoing prospective studies (MSLT-2 and MINITUB) investigating the role of CLND after SLNB positivity are available, radical lymphadenectomy should be considered the standard of care in patients with lymph node metastases, as suggested by the NCCN guidelines, which recommend lymphadenectomy in presence of positivity of SLNB or histological/cytological confirmed clinical lymph node metastases [2].
Despite this recommendation, adherence to clinical practice guidelines remains low among melanoma surgeons. In the USA, 50% of patients with positive SLNB do not undergo completion lymphadenectomy [3]. The still evident degree of confusion on the optimal surgical treatment of AJCC stage III melanoma has been confirmed by a recent international survey on lymphadenectomy in melanoma patients with positive sentinel nodes (SN), which showed an extremely heterogeneous approach to the extent of the completion lymph node dissection (CLND), especially for SN located in the neck or groin [4]. Aside from the indication and the levels of dissection, no agreement has yet been reached on the criteria to define lymphadenectomy as adequate and, even if the minimum number of lymph nodes that should be excised achieves a reasonable consensus, other quality assurance (QA) parameters for lymphadenectomy are far from being accepted.
In this context, a consensus process on indications, technical aspects and QA parameters for SLNB and, in particular, for lymphadenectomy is desirable among melanoma surgeons and pathologists. Providing new evidence-based results in these controversial fields might help to achieve better standards of treatment. The purpose of this chapter is to critically review the most recent literature on the lymph node surgical treatment in melanoma patients providing, wherever available, new evidence and contributing to standardize the current management of this tumor.
Cutaneous melanoma presents an increasing annual incidence worldwide and despite several advances in understanding the molecular mechanism of tumour progression and the development of more selective therapeutic strategies, a significant proportion of patients remain incurable. Lymph nodes represent the most frequent site of metastases from melanoma and the main purposes of lymphadenectomy are to provide loco-regional control of disease, accurate staging as well as to eventually cure patients with AJCC stage III melanoma. A significant number of patients with localized melanoma harbor clinical occult metastases in the regional node basin, which, if left untreated, will lead to palpable metastatic nodes (macroscopic disease). In the past, the common approach to lymph node in melanoma patients ranged between two different strategies; observation followed by therapeutic lymph node dissection (TLND) when clinical disease became evident and elective lymph node dissection (ELND) at the time of treatment of the primary in absence of macroscopic disease. However, removing lymph node metastases before they become evident is potentially a better strategy to prevent local failure and could potentially prevent systemic failure in a significant portion of patients. The drawback of ELND is that 15 to 20% of patients only have microscopic disease in the regional lymph nodes; therefore, the majority of patients will have no benefit from elective surgery and will receive surgical overtreatment. Four randomized controlled trials (RCT) [5] and one meta-analysis [6] have compared these two treatment strategies with, none demonstrating a survival advantage. The negative result in survival of ELND can be explained by the fact that more than 80% of patients in these trials will never develop lymph nodes metastases, making the studies underpowered to discover a statistical difference between the two groups. However, subgroup analysis from the WHO Melanoma Group Trial [7] showed a significant survival advantage in patients with clinically occult disease who underwent ELND compared to patients who underwent TLND for positive nodal recurrence (5-years survival 48.2 versus 26.6, P=0.04 respectively). These data suggest that there may be an improved survival in patients with occult disease, highlighting the importance of identification of early nodal disease. The difficulty in showing a survival advantage after ELND, unnecessary in 80% of patients and frequently associated with a high morbidity rate (including wound complications, lymphedema and pain), has made it, over the years, unappealing.
The controversy on performing ELND disappeared with the advent of SLNB, which determined a consistent paradigm shift in melanoma patients at risk of lymph node metastasis. After the pioneering studies of Donald Morton, who first hypothesized the role of sentinel lymph node as the first lymph node receiving lymphatic drainage from the primary tumour, SLNB emerged as a minimal invasive staging procedure for determining the nodal status in patients with melanoma [8]. The intra-operative use of a combined technique based on blue dye and radiotracer has been demonstrated to be feasible and accurate for nodal staging of patients with melanoma [9]. A recent meta-analysis of 71 studies, which includes 25240 melanoma patients who underwent SLNB in the period 1998-2009, showed that SLNB is highly accurate in melanoma with a proportion of patients successfully mapped (a least one sentinel lymph node removed) of 98.1%, a rate which tends to increase with the year of publication and quality score of the studies, female sex, ulceration and age [10]. The same study reported a false negative rate of SLNB of 12.5% (i.e. the proportion of patients with nodal recurrence in un-dissected nodal basins after a negative SLNB over the total positive patients and the false negative patients), which is inversely associated with the proportion of patients successfully mapped. The ability of SLNB to predict the negative status of the lymph node basin is expressed by the post-test probability negative (PTPN, the ratio of patients with negative SNB who recurred to all patients with negative SLNB). The PTNB in this study is 3.4%, which represents the proportion of patients with negative SLNB who recur. This risk seems inversely related to the proportion of patients successfully mapped and positively associated with the length of follow-up, younger patient age, the proportion of females, the mean Breslow thickness and the proportion of ulcerated tumours. The overall data analysis showed that, after a negative SLNB, the chances of nodal recurrence can be estimated to be equal to or lower than 5% providing reassurance that SLNB is a feasible and reliable method for accurately predicting the lymph node status of melanoma patients and is now considered a reliable staging procedure for melanoma.
SLNB status has been identified as the most important prognostic factor for overall survival in melanoma patients with no clinical evidence of metastatic disease [11] and has been included in the AJCC TNM staging system since the 6th edition in 2001 [12]. For this reason, a general consensus on performing SLNB in patients with intermediate thickness melanomas (Breslow 1-4mm)) [13] has been reached, as SLNB gives important prognostic information that can be used for planning follow-up protocols and adjuvant treatments [14]. Although the use of SLNB in thick melanomas remains uncertain, the procedure is recommended in this sub-group of patients mainly for staging purposes and local control of disease [14]. For thin melanoma (≤1mm), the role of SLNB is more controversial. It is known that the risk of node positivity in thin melanoma patients is less than 5%, but we should consider that this group accounts for the majority of patients with melanoma (about 65%) and therefore a large number of patients with microscopic disease might be left under staged and possibly undertreated. A sufficient level of evidence exists to also consider SLNB in patients with thin melanoma, particularly in presence of ulceration and/or mitotic rate ≥1 (AJCC T1b melanomas) [15]. Several studies have investigated the optimal cut-off value to consider SLNB cost-effective in thin melanomas. In patients with Breslow ≤0.50 mm, SLNB positivity is very unlikely, with a reported incidence of positive nodes of 0% [16]. Between 0.51 and 0.99 mm, the risk tends to increase and in a subgroup of patients with thin melanoma of at least 0.76 mm in depth and 1 or more mitosis, a 12.5% incidence of SN metastases has been reported [17].
It has been calculated that only 50-60% of patients with positive SLNB underwent CLND in USA [3] and Europe [18]. This proportion is probably higher among surgeons normally dealing with melanoma, as reported by a recent survey [4]. In this study, mainly involving surgeons working in melanoma or surgical oncology units, 91.8% of responders recommend CLND in patients with positive SLNB. However, the role of CLND in the presence of positive SLNB, remains uncertain. The Multicenter Selective Lymphadenectomy (MSTL-1) trial was started in 1994 and evaluated over 8 years the outcome of 2001 patients with primary cutaneous melanoma randomly assigned to undergo wide excision and nodal observation (observation group) or wide excision and SLNB, with immediate lymphadenectomy in presence of nodal metastases detected on biopsy (biopsy group). The prognostic value of SLNB was overall confirmed in patients with intermediate-thickness (1.2 to 3.5 mm) melanoma; 10-years Melanoma-Specific survival was 85.1±1.5 in negative SLNB and 62.1± 4.8 in positive SLNB [1]. Moreover, the MSLT-1 confirms that, among other established prognostic factors (Breslow thickness and ulceration), SLNB status is the most powerful indicator for disease recurrence (HR=2.64) and death from melanoma (HR=2.40). Considering survival analysis of patients with intermediate-thickness melanomas, a better 10-year disease free survival was detected in the biopsy group (71.3±1.8% versus 64.7±2.3%, HR for recurrence and metastasis=0.76, P=0.01), even though no difference was detected in the 10-year melanoma-specific survival among the two arms (81.4±1.5 and 78.3±2.0%, P=0.18). Even if no impact on overall survival has been observed in the biopsy group, at this level of evidence the present data suggest performing CLND for all patients with positive SLNB, mainly for achieving better regional control [2, 14]. Furthermore, a complete LND with therapeutical intent is recommended in presence of clinically evident, cyto/histologically proven lymph node metastasis.
SLNB involves preoperative lymphoscintigraphy, obtained through the injection of human albumin nanocolloid labelled with technetium 99mTc. The injection is in the intradermal layer, close to the scar of the removed melanoma or to the tumor if still present, and followed by scintigraphic scans (early and late) in the likely locations of lymphatic drainage [9]. Once the basin and location of the sentinel node has been identified, cutaneous projection area of each single node is marked on the skin. Immediately prior to surgery, the primary site is further injected intradermally with 0.5 to 1 mL of a vital dye (patent Blu), to increase the sensitivity of the method and to facilitate the finding of the lymph node (figure 1). SLNB is performed through a small skin incision, which should take into consideration the incision necessary for a subsequent radical lymphadenectomy [14]. Under the guidance of a radioisotope probe and following the blue lymphatic channels, the sentinel lymph node(s) is identified and removed (figure 1). Care should be taken not to disrupt or cauterize the lymph node capsule. Each SLN removed is checked ex vivo for radioactivity and the nodal basin is rescanned. Drains are seldom required and most patients are operated in one day-surgery regimen. The incidence of post-operative complications is relatively low, mainly related to wound (dehiscence/infection or lymphatic collection), although limb lymphedema occurs not so un-frequently as generally supposed [19].
Surgical technique of SLNB
Radical lymphadenectomy for melanoma involves the “en bloc” excision of lymph nodes with surrounding fat tissue. In the axilla, a radical lymphadenectomy should include dissection of levels I, II and III lymph nodes around the axillary vein [20]. A section of the pectoralis minor muscle is suggested by some for a better access to level II lymph nodes or in presence of bulky level II and III nodes. Long thoracic and thoracodorsal nerves should be preserved and sectioned only if directly involved by the tumor. In case of metastasis to the inguinal lymph nodes, the standard approach involves the removal of the inguinal, external iliac and obturator lymph nodes [21]. In the classic description of inguinal dissection, a longitudinal or lazy-S-shaped skin incision is employed, extending a few centimeters cranially to the superior anterior iliac spine up to the apex of the femoral triangle (figure 2). The incision should include the SLNB scar. The cutaneous flaps are created medially and laterally, up to the pubic tubercle, the anterior margin of the gracilis and abductor muscles and up to the superior anterior iliac spine and Sartorius muscle, respectively. Deep dissection continues through the fascia lata, over the underlining muscles and femoral vessels. The saphena magna vein is generally sectioned at the apex of the femoral triangle and at the level of the saphenofemoral junction. In case of the risk of femoral vessel exposition after wound dehiscence, transposition of the sartorious muscle is warranted. Iliac and obturatory dissection is obtained through an extra-peritoneal approach. After sectioning of the oblique muscles and the inguinal ligament, the pelvic area is reached and the external iliac and obturatory lymph nodes removed, after identification of the urether and the obturator nerve.
Intraoperative view of inguinal LND.
For cervical lymph node metastastis, clear indications on the thoroughness of dissection are lacking and all the recommendations are supported by a low level of evidence and are obtained from opinions of experts in this field [22]. In case of clinically evident cervical lymph node metastasis, surgery is aimed at the removal of all five levels of lymph nodes (submandibular, jugular and supraclavicular), preserving sternocleidomastoid muscle, internal giugular vein and accessory spinal nerve (figure 3). Removal of the superficial part of the parotid is recommended only if clinically involved, because of the high risk of nerve damage observed.
Although general principles and technical details to perform adequate SLNB and LND are diffusely reported, surgeons in the clinical setting find many controversial aspects, regarding, in particular, the extent of given lymphadenectomy [22]. The question on what can be considered an adequate lymphadenectomy for metastatic melanoma is therefore largely un-answered. National guidelines are vague in defining this issue and simply suggest describing the anatomical limits of dissection [2]. This level of indeterminateness affects the attitude of melanoma surgeons in performing lymph node dissection [4]. A general agreement emerges in the presence of clinical evident lymph node metastatic disease, where a full regional lymphadenectomy is considered by most surgeons. More controversial is the thoroughness of lymphadenectomy in SLNB positive patients, in which, due to the significant risk, the approach is heterogeneous and controversial. For neck dissection, considering the risk of nerve damage as well as for the anatomic complexity, a consensus seems to emerge on performing CLND selectively and to remove the levels likely to be involved, depending on the site of the primary tumour, the site of the sentinel node and the lymphatic drainage highlighted at lymphoscintigraphy. Meanwhile, a superficial parotidectomy is associated only in presence of clinically evident metastasis [22]. For axilla, a general agreement exists on performing, in all cases, a three level dissection as the risk of lymphedema seems not affected by a more extensive lymphadenectomy. In fact, despite the risk of metastases of the third level is quite low [23], surgical management of recurrent disease in the apex of axilla appears more difficult. More controversial is the approach to the groin, in particular for CLND after a positive SLNB, where two distinct lymphatic basin (inguinal and pelvic) are involved. Several national guidelines suggest combining pelvic dissection out of the inguinal, only in presence of radiological evidence of pelvic metastases, >3 positive inguinal nodes and metastases to the Cloquet’s lymph node (so called sentinel lymph node of the pelvis). However, the evidence is low to sustain this surgical approach and a randomized controlled trial from the Australian and New Zealand Melanoma Trial Group comparing inguinal and pelvic CLND in SLNB-positive patients with negative PET/CT pelvic scan is about to start (EAGLE FM Study, ClinicalTrials.gov Identifier, NCT02166788) [24].
Referring to the most recent literature on SLNB and LND in melanoma patients, new evidence-based results are now available which can contribute to answer to (and find consensus on) the three main questions still pending: 1) How can we make surgeons more confident with indications to SLNB and Lymphadenectomy (in SN positive patients)? 2) How can we get them convinced that completeness of lymphadenectomy is an important issue?, and 3) are new, more convincing, evidence-based referral values for the minimum number of lymph node to be excised now available?
The role of completion lymphadenectomy (CLND) after positive SLNB remains uncertain as additional non sentinel nodes (i.e. identified within lymph node dissection after SLNB) have been identified in 9 to 25% of patients. This rate is probably underestimated because, unlike the pathologic protocols normally applied for SLNB specimens, those for therapeutic lymphadenectomy are routinely limited to bisecting lymph nodes without any immunohistochemical stains. Aimed at investigating the prognostic and therapeutic impact of CLND in sentinel positive nodes two prospective trials have been undertaken: The Multicenter Selective Lymphadenectomy Trial-2 (MSTL-2) and the MiniTub trial. The MSTL-2 trial randomized patients with at least one positive SLN to observation or CLND. MSTL-2, whose patient accrual was completed in 2014, was designed to verify the incidence of nodal recurrence after removal of positive SLN(s) without CLND, the incidence and predictors of additional lymph nodes in the SLNB basin after CLND and the survival impact of CLND in SLNB positive patients. The MiniTub trial is a prospective registry investigating the outcome of patients with a T2-T3 primary melanoma and minimal SN tumour burden treated with CLND or nodal observation. While waiting for the results of these important studies, other important scientific reports have recently appeared in the literature, supporting the indication for CLND. For instance, the strength of the indication for CLND in these patients has been recently increased by the long-term results of the MSLT-1 trial [1, 25] Despite the lack of survival benefit of performing SLNB in the whole group, in a sub-group analysis, which excluded the SLNB negative patients, the node positive patients with intermediate thickness melanoma showed a 21% higher 10-year survival compared to patients who underwent lymphadenectomy for metastases discovered during follow-up. Of note is that the mean number of tumour involved nodes was significantly lower in the biopsy group with respect to the observation group (1.4 versus 3.3, P>0.001) [25]. The therapeutic effect of immediate CLND over lymphadenectomy at the time of clinically evident disease in patients with microscopic disease is confirmed by an interesting study which shows that immediate CLND is associated with a 10-year survival of 60% compared to delayed lymphadenectomy (around 45%), despite patients with early lymphadenectomy presenting worse adverse prognostic factors [26]. Moreover, a meta-analysis of non randomized studies encompassing 2633 patients, demonstrates, in patients with clinically undetectable lymph node metastasis, a 20% survival benefit after with SLNB followed by CLND [27].
Another argument in favour of the appropriateness of CLND comes from the important observation that patients with <11excised nodes were not adequately staged [28]. Furthermore, in case of sentinel node positivity, non sentinel lymph node status has an independent prognostic value in melanoma patients. The value of this observation is re-inforced by a meta-analysis suggesting the use of this new and easily reproducible prognostic factor as risk stratification criteria for clinical trials investigating adjuvant therapies and its inclusion in the future edition of the AJCC staging system [29]. Thus, not performing CLND in a SL positive patient today means lack of knowledge about his staging work-up, depriving him of important clinical information.
Taken together, all this information strongly supports that an early diagnosis of lymph node metastases (SLNB) and the removal of the affected lymphatic basin (CLND) can more effectively cure melanoma patients. Likely, some immunological events within the SL environment precede melanoma sentinel spread, suggesting that melanoma is preparing the sentinel lymph nodes to receive metastatic melanoma cells [30]. Removing SLNs and non sentinel LNs at an early stage, when probably the loco-regional immunosuppressive changes are not fully active, could explain in part the different prognostic impact of sentinel and non sentinel metastatic lymph node and opens the door to future investigations on the mechanisms of tumor response and on the immunological role of sentinel lymph nodes in melanoma.
Although the extent of each LND is still argued, it has recently been demonstrated in melanoma patients that the so-called lymph node ratio (i.e. the number of positive lymph nodes over the total number of excised lymph nodes) is associated with survival [31-33]. Patients with low ratio present better prognosis independently of the number of the positive nodes, indirectly confirming the prognostic value of the number of lymph node removed during surgery. Moreover, a recent multicentric Italian study showed, in the largest caseload so far available, that patients who had a higher number of excised lymph nodes after lymphadenectomy have a better prognosis, independently of AJCC T stage, ulceration, LN tumor burden and N stage [28] (figure 3). A clear and univocal explanation of this data is not available. The association between the number of lymph nodes and prognosis can find different explanations; 1) more lymph nodes means a better immunological control of melanoma, 2) a more accurate patient staging of patients 3) a therapeutic role of more extensive surgery. The latter lends support to the hypothesis that a thorough lymphadenectomy might have a therapeutic effect in melanoma patients with lymph node metastases, in particular in those who underwent CLND for a positive SLNB with intermediate thickness primary tumour.
Patient survival according to the number of excised lymph nodes categorized as follow: ≤ 10 LNs, 11-20 LNs, 21-30 LNs and > 30 LNs. From IMI (Italian Melanoma Intergroup) caseload.
Once the need of a CLND in melanoma patients with lymph node metastases is accepted and the anatomical extent of a given procedure is established, how can we provide surgeons with parameters and referral values for QA? Unfortunately, shared parameters for QA of lymph node dissections for melanoma are still lacking, with the exception of the minimum number of retrieved lymph nodes, for which a general consensus seems to exist for its simplicity, reproducibility and comparability [4]. However, the benchmark values of this quality parameter (minimum number of lymph nodes for each dissected field) and the method to obtain these benchmark values are still matter of study. The minimum number values proposed in the literature are quite heterogeneous, reflecting the different method adopted for proposing it (table 1).
\n\t\t\t | \n\t\t\t\tMinimum number of excised lymph nodes\n\t\t\t | \n\t\t|||||
\n\t\t\t\tReference\n\t\t\t | \n\t\t\t\n\t\t\t\tMethod\n\t\t\t | \n\t\t\t\n\t\t\t\tAxilla\n\t\t\t | \n\t\t\t\n\t\t\t\tNeck\n\t\t\t | \n\t\t\t\n\t\t\t\tGroin\n\t\t\t | \n\t\t||
\n\t\t\t\t≤3 levels\n\t\t\t | \n\t\t\t\n\t\t\t\t≥4 levels\n\t\t\t | \n\t\t\t\n\t\t\t\tInguinal\n\t\t\t | \n\t\t\t\n\t\t\t\tInguinal and pelvic\n\t\t\t | \n\t\t|||
Balch et al. [34] | \n\t\t\tExpert opinion | \n\t\t\t10 | \n\t\t\t20 | \n\t\t\t20 | \n\t\t\t5 | \n\t\t\t5 | \n\t\t
MSLT-2 [1] | \n\t\t\tExpert opinion | \n\t\t\t15 | \n\t\t\t30 | \n\t\t\t\n\t\t\t | 6 | \n\t\t\t6 | \n\t\t
Eggermont et al [35] | \n\t\t\tExpert opinion | \n\t\t\t10 | \n\t\t\t15 | \n\t\t\t15 | \n\t\t\t5 | \n\t\t\t5 | \n\t\t
Galliot-Repkat et al. [36] | \n\t\t\tSurvival analysis | \n\t\t\t10 | \n\t\t\t10 | \n\t\t\t10 | \n\t\t\t10 | \n\t\t\t10 | \n\t\t
Xing et al. [33] | \n\t\t\tSurvival analysis | \n\t\t\t8 | \n\t\t\t15 | \n\t\t\t\n\t\t\t | 6 | \n\t\t\t6 | \n\t\t
Billimoira et al. [37] | \n\t\t\tExpert opinion | \n\t\t\t10 | \n\t\t\t15 | \n\t\t\t15 | \n\t\t\t5 | \n\t\t\t5 | \n\t\t
Spillane et al. [38, 39] | \n\t\t\t10th percentile | \n\t\t\t10 | \n\t\t\t6 | \n\t\t\t20 | \n\t\t\t7 | \n\t\t\t14 | \n\t\t
Rossi et al. [40] | \n\t\t\t10th percentile | \n\t\t\t12 | \n\t\t\t7 | \n\t\t\t14 | \n\t\t\t6 | \n\t\t\t13 | \n\t\t
Rossi et al. [28] | \n\t\t\tSurvival analysis | \n\t\t\t11 | \n\t\t\t14 | \n\t\t\t9 | \n\t\t\t12 | \n\t\t
Minimum number values of excised lymph node for single lymphatic basin.
The most recently proposed cut-offs to deem a lymph-node dissection adequate are evidence-based (obtained by the 10th percentile/survival method) and come from two independent caseloads: one from Australia [38, 39] and the other from Italy [28, 40]. As reported in table 1, the results are similar and should prompt surgeons (and pathologists) to adopt them as referral standards to measure their own performance, making a through revision of the procedure necessary when the reported numbers are below these thresholds. Another interesting evidence-based observation in this field comes from an already cited study which, besides a correlation between the absolute number of excised lymph nodes and survival, shows that, an adequate sub-staging of AJCC stage III melanoma patients is not possible below the cut-offs reported in the table [28] (figure 4).
Loss of prognostic significance of AJCC TNM N substages according to the number of lymph nodes (< or > 11). From IMI (Italian Melanoma Intergroup) caseload.
The implementation of QA programs at institutional/multi-institutional levels needs to define other parameters for monitoring quality and the relative benchmark values. Beyond the minimum number of lymph nodes, complication rates and local recurrence rates have been suggested as QA parameters for lymphadenectomy in a recent national consensus [22]. In the near future, standardization and implementation of effective QA programs for major surgical procedures in melanoma should increase patients’ standard of care as well as the likelihood of reliable results from clinical trials testing new treatments in the adjuvant setting.
Almost 80% of patients who undergo SLNB do not harbor node metastases. Having no benefit from the procedure, they are considered to receive a surgical over-treatment. Moreover, SLNB represents a surgical procedure associated with a defined morbidity rate (10%) [41] and significant cost for the health care system [42]. For these reasons, a series of clinical pathological variables associated with SLN status has been widely studied in the literature, but the statistical predictive power of each single factor on SLNB positivity remains poorly defined (table 2).
Breslow thickness | \n\t\t
Ulceration | \n\t\t
Mitotic rate | \n\t\t
Lymphovascular invasion | \n\t\t
Clarke level IV | \n\t\t
Young age | \n\t\t
Factors associated with risk of metastases in sentinel nodes
The development of statistical predictive models which analyse independent variables seems able to spare an unnecessary SLNB in between 18 to 30% of cases with an estimated error rate (i.e. patient with sentinel negative prediction even if they are sentinel positive at pathological examination) of 0.5-2.1% [43]. However, these tools need to be tested and validated in prospective studies and eventually implemented in the clinical setting. On the other hand, new markers of biologic behaviour can overcome and define the metastatic phenotype in primary melanoma and quantify the true risk of nodal metastases, but additional studies are needed to identify a subgroup of patients (in particular for thin melanomas) with defined clinical-pathological parameters at risk of SL positivity.
Identification of clinical and pathological parameters predictive of non sentinel nodes positivity represents a crucial point to improve selection of patient candidates for CLND, as it is possible to spare un-necessary CLND in a defined quota of patients [44]. Several predictors of additional non-sentinel positive LNs have been identified, including those associated with primary tumor (i.e., melanoma thickness) or sentinel nodes (i.e. metastatic burden) [45, 46]. For instance, in patients with thin melanoma, the risk of additional lymph nodes in CLND is calculated 0.1% suggesting that the potential benefit of lymph node dissection after SLNB in this group should be balanced with the morbidity of CLND [47]. Histo-pathological parameters reflecting the pattern and amount of melanoma involvement in the SNs and the related risk-assessment systems able to predict the risk of additional non sentinel lymph node metastases in CLND are reported (table 3).
\n\t\t\t\tSystems\n\t\t\t | \n\t\t\t\n\t\t\t\tParameters\n\t\t\t | \n\t\t
Rotterdam system [48] | \n\t\t\tdimension of tumour deposit | \n\t\t
Starz classification [49] | \n\t\t\ttumor penetrative depth | \n\t\t
Hannover Scoring System (Hannover-II) [50] | \n\t\t\tdimension of the greatest deposit, tumor penetrative depth involvement of the capsula | \n\t\t
Non-Sentinel Node Risk Score (N-SNORE) [51] | \n\t\t\tsex regression, proportion of harvested SNs maximum size perinodal lymphatic invasion | \n\t\t
Rotterdam-Dewar Combined criteria (RDC) [52] | \n\t\t\tdimension of tumour deposit microanatomic location | \n\t\t
Risk assessment systems of Non-SLN involvement
As well as for predictors of SL positivity, these parameters need to be validated prospectively, and the ongoing research on new biological markers might predict the pathological status of the additional nodes, even more precisely in the near future.
The false negative rate (FNR) of SLNB probably represents the most important drawback for this procedure. The values reported in literature are wide ranging between 8.6 and 21% [10]. The main reason for this variability resides in the different methods to calculate this proportion after SLNB. In the past, many authors have erroneously considered the FNR as the ratio between the FN cases and the truly negative plus the truly positive instead the of truly positive plus false negative and, only recently, a standard definition has been adopted [53]. However, a recent meta-analysis shows a FNR of 12.5% [10]. This means that considering melanoma patients harbouring node metastases, approximately one out of ten of these patients has a negative SLNB. Furthermore, FNR tends to increase with the duration of follow-up and the quality of the study and is inversely correlated with the identification rate. Reasons for FNR after SLNB can involve different specialists at different steps of the SLNB procedure; lymphoschintigraphy evaluation (nuclear medicine physician), lymph node detection during surgery (surgeon) and node’s pathological examination (pathologist) [54]. The number of peri-tumoral injection seems to influence the outcome of lymphoscintigraphy but controlled studies are needed to confirm the real impact on FNR [9]. Failure in lymphoscintigraphy interpretation has been demonstrated to lead to in one third of false negative results after SLNB [54]. One third of cases, a FN result is explained by the failure of surgery to remove all the nodes identified at pre-operative lymphoscintigraphy, especially in neck and groin lymphatic basin. It should be noted that the ratio of marked on lymphoscintigraphy and excised sentinel lymph nodes is equal in only 38% of patients who underwent SLNB and that 20% of patients have fewer lymph nodes removed then those marked during lymphoscintigraphy [55]. FNR after SLNB seems higher in head and neck melanomas, confirming a greater complexity of SLNB in this body district, mainly for the proximity of primary tumor and lymphatic basin, the complexity of lymphatic drainage of neck and the higher risk of complications [56]. Moreover, a lack of standardization exists between centres on the threshold beyond which radioactivity of residual lymph nodes should indicate their excision. The 10 % rule (i.e., SN defined as all the lymph nodes with >10% radioactivity of the hottest SN removed) was proposed as standardization criteria and it was demonstrated to be able to reduce the rate of missing positive nodes, but a clear consensus on this is still lacking and further research is needed in this field [57, 58].
Pathologists can also contribute to FNR. In fact, the most appropriate pathologic protocol for SN examinations is still a matter of discussion. The number of sections to be stained and the optimal distance between them can significantly influence the metastases detection in SNs. Two main protocols have been popularized which seems to reach an acceptable compromise between diagnostic accuracy and costs [59, 60]. Although some evidence suggests that ultra-staging with polymerase chain reaction (PCR) of SNs represents an appealing prognostic tool and seems to improve melanoma cell detection in SNs, the clinical and prognostic value of molecular biology-based detection of melanoma cells in SNs needs to be further verified and supported by additional investigation in this field [61]
Fear of complication often influences surgeons’ and patients’ decision on whether or not to perform a lymphadenectomy in melanoma patients. Thus, to reduce morbidity is an important issue for surgical oncologists and for this purpose video-assisted surgery has recently been proposed for lymph node dissection. Considering the principal lymphatic basins, groin is indubitably associated with the greater incidence of wound complications. Wound infection, dehiscence/necrosis and seroma/lymphocele after traditional lymphadenectomy ranges between 15-55, 7-53 and 2-46%, respectively [62]. Videoscopic lymphadenectomy (VL) of the groin appears to be a promising tool in lowering the incidence of wound complication. Inguinal and iliac-obturator VL consists of two different surgical times. The inguinal part is performed using three trocars, placed at a variable distance from the apex of the femoral triangle (figure 5).
Trocar position for inguinal lymphadenectomy VL.
The working space is obtained after a skin incision and blunt dissection of the area under the Camper fascia. The creation of a working space using high pressure CO2 levels (25 mm/Hg) at the beginning of the procedure make dissection easier. The saphenous vein is generally sectioned with endostaplers or endoclips. Removal of the surgical specimen is performed using endobag.
For iliac and obturator VL (figure 6), the access is extraperitoneal with the first trocar being placed infraumbilical and two trocars between the umbilicus and the pubic symphysis.
Intraoperative view of iliac and obturator VL
The greatest advantage of VL is probably the virtual elimination of inguinal incision and (in case of iliac lymphadenectomy) the avoidance of the parietal abdominal muscles section. This potentially leads to a significant reduction of the post-operative wound related morbidity and pain. In one uncontrolled comparative study, the incidence of complications (infection and wound dehiscence) was significantly lower after VL (47.5% versus 80%, P=0.002) [63]. In another comparative study, although the incidence of infection and wound dehiscence was not statistically different after VL compared to open lymphadenectomy, in the open group wound infections appear more serious, requiring hospital readmission and intravenous antibiotics in five of the eight patients (62 %) [64]. Although the experiences are limited and the level of evidence is low, VL for melanoma is technically feasible, seems associated with a lower post-operative morbidity profile with comparable oncological outcomes (i.e. number of excised lymph nodes, loco-regional recurrence) (table 4). Before VL becomes suitable for routine clinical practice, the lower post-operative morbidity and safe oncological profile shown in retrospective and prospective series needs to be investigated within prospective RCTs.
\n\t\t\t | \n\t\t\t\tVideoscopic Lymphadenectomy\n\t\t\t | \n\t\t\t\n\t\t\t\tProcedures\n\t\t\t\t \n\t\t\t\t(N)\n\t\t\t | \n\t\t\t\n\t\t\t\tConversion rate\n\t\t\t\t \n\t\t\t\t(%)\n\t\t\t | \n\t\t\t\n\t\t\t\tWound complication rate\n\t\t\t\t \n\t\t\t\t(%)\n\t\t\t | \n\t\t\t\n\t\t\t\tLymph node excised\n\t\t\t\t \n\t\t\t\t(N)\n\t\t\t | \n\t\t\t\n\t\t\t\tLocal recurrence rate\n\t\t\t\t \n\t\t\t\t(%)\n\t\t\t | \n\t\t
Trias M, et al [65] | \n\t\t\tIliac | \n\t\t\t12 | \n\t\t\t0 | \n\t\t\t16.7 | \n\t\t\t10.2 | \n\t\t\tNot reported | \n\t\t
Schneider C, et al [66] | \n\t\t\tIliac | \n\t\t\t31 | \n\t\t\t0 | \n\t\t\t9.7 | \n\t\t\t4.6 | \n\t\t\t9.7 | \n\t\t
Abbott AM, et al [64] | \n\t\t\tInguinal | \n\t\t\t13 | \n\t\t\t7.7 | \n\t\t\t1.8 | \n\t\t\t13 | \n\t\t\tNot reported | \n\t\t
Martin BM, et al [63] | \n\t\t\tInguinal | \n\t\t\t40 | \n\t\t\t10 | \n\t\t\t15 | \n\t\t\t12.6 | \n\t\t\t2.5 | \n\t\t
Sommariva, et al. [unpublished data] | \n\t\t\tInguinal and Iliac | \n\t\t\t24 | \n\t\t\t16.5 | \n\t\t\t4 | \n\t\t\t20.4 | \n\t\t\t0 | \n\t\t
Summary of results on videoscopic groin lymphadenectomy for melanoma
Even in the present exciting era of discovering new drugs to cure patients with advanced melanoma, surgery still represents the most performed and effective treatment for this potentially lethal disease. Nevertheless, the effort to solve many controversies related to this important subject has been so far insufficient and the ongoing clinical practice guidelines often lack clear indications for an adequate clinical approach, in particular dealing with patients at high risk for or with lymph node metastasis. While waiting for the conclusion of the ongoing controlled clinical trials (MLST-2 and MiniTub), surgeons should look for new evidence based results strengthening support for indication of SLNB and lymph node dissection, completeness of the latter and QA parameters on which the surgical performance should be measured.
Indication to SLNB is accepted almost everywhere as a staging procedure. Moreover, a recent meta-analysis of retrospective studies and the last report on the long-term results of the MLST-1 controlled trial reinforce its curative value in patients with positive nodes who undergo immediate CLND. In perspective, a more precise patient selection, based on validation new statistical tools and/or identification of new molecular markers, and lowering its false negative rate might improve its efficiency and make this procedure even more appealing.
At present, LND represents the most controversial subject in the surgical treatment of melanoma, particularly in SN positive patients. Its indication can be further warranted by, besides the long-term results of the MLST-1, the demonstration of its essential role as staging procedure. A recent study shows that below the threshold of 11 excised lymph nodes an accurate sub-staging is impossible, and another one demonstrates that the status of the additional lymph nodes is an independent prognostic factor in stage III melanoma patients. These evidence-based results also prompt for their inclusion in the surgical QA process (the former), and in the forthcoming melanoma staging system (the latter). Even if the extension of each lymphadenectomy is still a matter of discussion, further evidence has been recently added to the need of its completeness, such as the demonstration that the lymph node ratio and the absolute number of excised lymph nodes are independently associated with survival. As for other solid tumours in which LND has an impact on staging and survival, melanoma surgeons are in search of simple and reproducible parameters to deem the procedure adequate. The minimum number of lymph nodes to be excised seems to meet this requirement, and the reproducible numbers provided as benchmark values by the 10th percentile method, for each type of LND, are likely to make this parameter the most reliable. Looking at the future, statistical tools and molecular markers for a better patient selection, randomized trials for devising the LND extent, and the mini-invasive surgical approach to reduce the fear of complication and improve patients’ quality of life, will probably fulfil the present lack of knowledge and make surgical treatment of melanoma more standardized and cost-effective. Nevertheless, since now surgeons can be helped by the new evidence-based results in the difficult process of building consensus on some important issues in melanoma surgery.
How do young scientists develop? What draws some people into science or engineering long before they realize there is something called a “career?” Why are some people, regardless of gender, attracted to science careers and some not? What stereotypes, both explicit and implicit, exist that contribute to one’s ideas and perceptions about scientists? These are some of the questions to be explored in this chapter.
\nIt is important to note that the intention of this chapter is to recognize that all children in early childhood are natural scientists. Two well-accepted ideas about how young children embrace science and interact with the environment come from Reggio Emilia and Maria Montessori. Both approaches support the child as their own scientist, and exploration is key in each of these approaches. The Reggio Emilia approach is an educational philosophy focused on preschool and early education that is student centered and uses self-directed, in relationship-driven environments. The Montessori method views the child as one who is naturally eager for knowledge and capable of initiating learning in a supportive, thoughtfully prepared learning environment. Regardless which curricula focus, the environment is the third teacher and science is taught in that environment. Thus, children assume the role of scientists naturally.
\nIn the book, The Last Child in The Woods, the author, Richard Louv, even cautions against the opposite experience, “If education and other forces intentionally and unintentionally, continue to push the young away from direct experience in nature, the cost to science itself will be high. Most scientists today began their careers as children, chasing bugs and snakes, collecting spiders, and feeling awe in the presence of nature. Since such untidy activities are fast disappearing, how, then, will our future scientists learn about nature?”
\nHowever, we know that it is not practical that all children develop into scientists, but rather it is to not turn children off to science careers precisely when they are the most open to it. It appears that the more children go through formalized science in schools, the less they like and enjoy science and think about themselves in science careers. Therefore, the formative early childhood years become even more precious when it comes to lifelong aspirations. For example, we know that girls especially self-select out of math and science careers by age 10, which means what happens in early childhood years is extremely important [1]. While it is generally accepted that adolescents need to begin to think and plan for career choices, this suggests that even long before children are able to express or verbalize which careers may be interesting to them, they are processing information about their possible future.
\nAs young children gather lots of information from parents, media, books, and schools, they collect, reject, and store ideas about scientists conceptually. For these reasons, asking children to Draw-A-Scientist has become an accepted method to provide a glimpse into how children represent and identify with those in the science fields. This chapter looks broadly at the critical aspects involved in on the different phases of one’s academic life in order to observe how early childhood students take a variety of experiences with scientists and internalize them into their own science identities. Some of the central experiences discussed are perceptions of scientists at crucial developmental times in relation to formal schooling. For example, the biographies of Thomas Edison and Benjamin Franklin suggested that the very foundations of modern industry and design grew first in the waters and woods and farmlands of childhood [2]. This chapter will now discuss how to recognize stereotypes in science, what stereotypes mean, and how to combat these stereotypes.
\nStereotypes are what people think something is like with limited information. Unless one is presented with more information, they may never broaden or change an original idea or conception. They remain unfixed. Stereotypes can manifest in numerous different ways. Sometimes it is very obvious. In science, it can be as simple as hearing a parent say, “I was not good at science,” or “science is for boys.” At the early childhood age, it can be as simple as a child saying, “I want to dress as a mad scientist for Halloween.” Other times, it is more subtle, like the desire not to be like “the smart kids.”
\nSometimes children act a particular way, to reinforce a stereotype or to get a particular reaction from a parent or not. Young children use a variety of experiences to test out their identities in science and “check” with the adults in their lives for some sort of response, both positively and negatively. The teachers who unknowingly call on boys versus girls when asking science questions can reinforce a science stereotype. Parents’ expectations, society’s expectations, the media, and a teacher’s response are all the beginning of children testing out others’ ideas about their own science identity in early childhood. They will ultimately use these experiences to contribute to their identity in science in and outside the classroom and eventually a career. This suggests that what early childhood educators do is extremely important because they build the foundation for one’s entire career.
\nThe kinds of books teachers introduce and their assumptions must be explicitly challenged in early childhood classrooms. The kinds of television shows parents introduce must accompany some conversation about the scientists portrayed. Young children need to question and think through their ideas in order to broaden their idea about scientists. Children’s interests in science are formed by age 14, and therefore the early childhood years are extremely important [3, 4, 5].
\nScience capital, as described by [6], is the academic, social, and cultural aspects of a student’s life and how they may relate to a child’s science aspirations. The role of family should not be overlooked in terms of influence on the child; [6] found that parental attitudes to science play an important role in shaping children’s science aspirations. The survey data suggest that while a family’s social structure location is important, family attitudes to science and their encouragement and fostering or not to science in their everyday life seemed to have an important influence [7].
\nTherefore, scientists and engineers are “who we are” and “what we do” or who we are and what we do not do. These stereotypes may form early on in life, and they may seem so acceptable because they come from our family of origin and we cannot recognize them. Young children need to be challenged in the classroom on their ideas for just these very reasons.
\nScience identity, as defined by [8], demonstrates competent performance in relevant scientific practices with deep meaningful knowledge and understanding of science and recognizes oneself and gets recognized as a science person by others. The construction of this identity requires the participation of others as it is constructed socially within communities of practice [9]. Students develop identities through engaging with the practices and tasks of the science class upon entering a community of practice such as the science classroom [10]. Learning science in this community then becomes “a process of becoming to be, of forging identities in activity” ([10], p. 3).
\nRegrettably, in early childhood many students form perceptions of scientists and science that are narrow, inappropriate, and inaccurate [11, 12, 13, 14, 15, 16]. Older elementary students included more indicators of stereotypical images in their illustrations than did 5- to 7-year-olds, suggesting that by fourth and fifth grades, students already have formed their limited views of who a scientist is [12]. Inaccurate views of scientists are widely held by students from elementary through high school [12]. In 6 years of research, having children draw pictures of scientists that are stereotypical, male images of white men in the laboratory increased with age [17]. Therefore, the least stereotypes are drawn by the youngest children [18]. In the examination of gender differences, only girls draw female scientists, and the majority of the female scientists are drawn by Kindergarten to second grade students, meaning children are less aware of the gender stereotypes associated with scientists at the youngest of ages [18]. Parents and teachers should provide experiences for young children that lead them toward rich and rewarding experiences in science [19].
\nStarting at about second grade, one of the ways researchers have documented is that students possess stereotypical images of scientists by using paper and pencil/crayons methods [12, 15, 16]. This stereotype has been consistently portrayed by students for well 50 years [11, 12, 13, 14, 15, 16]. This suggests that, as teachers and parents, there is a very short window of time in which to address this stereotype as it is forming. While paper and pencil may not be developmentally appropriate, another way may be through informally interviewing or talking to children regarding their ideas about who can be scientists and engineers.
\nUnderstanding this limited view individuals have of scientists is important because these ideas relate to children’s science-associated educational and career aspirations. In other words, if children did not identify with such depictions, then they tend to not “see themselves” in these kinds of careers. A meta-analysis spanning five decades of Draw-A-Scientist studies studied that US children’s gender-science stereotypes are more closely matched with males versus females. This is interesting considering women’s representation in science has risen substantially in the United States, and mass media increasingly depict female scientists. Therefore, despite many efforts to attract females to science and make science a more diverse career field, children still associate science with mostly males.
\nEngineering is becoming increasingly popular in early childhood classrooms worldwide. Allowing students the opportunities to think and act like scientists goes hand and hand with the opportunities to play and build like engineers. For example, the Next Generation Science Standards (NGSS) has incorporated engineering throughout its K-12 standards. For example, one of the way to best describe how these two disciplines work together is to discuss one of the practices in the NGSS, Constructing Explanations (science) and Designing Solutions (engineering) [20]. Science is the way we make sense of the world or construct explanations, and engineering is the way we design solutions and/or solve problems and make the world better.
\nTherefore, research conducted on students’ perceptions of engineers [21, 22, 23] has used similar drawing methods, like the Draw-A-Scientist Test, of the past decades. The activity is called the Draw-An-Engineer Test (DAET) or Draw-An-Engineer-At-Work (DAEWT), and the purpose is to have students describe their knowledge about engineers and engineering through drawing and sometimes written responses. These illustrations are then analyzed for stereotypical features described in the previous studies much like the illustrations of scientists of Draw-A-Scientist Tests.
\nMuch in the same way, students have commonly associated beakers, chemicals, and lab coats with the tools scientists need to perform their duties. Students associate engineering with fixing, building, and working on things, and when asked to draw engineers, students portrayed engineers as physical laborers or working on cars [24, 25]. Students often associated engineers with blueprints, computers, and safety gear and believed that engineers needed these items in order to perform their work. For these reasons, the parallel between scientists and engineers is a closely linked one.
\nIt is not an uncommon idea for teachers to find ways for students to see scientists and engineers as individuals in a variety of settings and roles. Therefore, the most natural suggestion for broadening students’ ideas or perceptions about scientist might be to get them to meet a scientist or an engineer by bringing one into their classroom. While this sounds like a relatively easy task, there are several things to consider so that the teacher does not unknowingly reinforce the stereotype by recruiting a stereotypical scientist. The teacher should also be cautioned that there is tremendous value in meeting many scientists to appreciate the scope of many differences of scientists rather than limiting a scientist visit to one person.
\nClassroom teachers are limited by time. Not only do they struggle to meet day-to-day responsibilities of instruction, but also local, state, and national requirements, as well as other expectations, placed upon them. As a result, teachers need guidance in selecting appropriate scientists and engineers (visitors) for their students. However, it is not clear that matching mentors to students based on race or gender is necessary or more beneficial for early childhood classrooms. However, the number of studies that used visiting scientists with early childhood students has been small for a variety of reasons. These sorts of visits take time to set up, and the relationship between the scientist and even several scientists takes time to develop and establish. A well-educated scientist does not always make an appropriate person to discuss science topics in a developmentally appropriate way to early childhood students.
\nVisiting scientist programs are built on the assumption that a visiting scientist will benefit children’s perceptions of who scientists are and the work they do. For students at this age, the best bet for the classroom teacher would be to ask for parent participation and engage parents in science and engineering careers in their classrooms. However, this can have drawbacks too, as the classroom changes year after year. Even if scientists and the engineer are carefully screened and properly trained for the classroom (and they would need to be for early childhood classrooms), there are simply not enough scientists to fill the need nationwide. Even when the resource pool is expanded to include such professionals as radio/TV meteorologists, county extension agents, and wildlife management professionals, the availability of scientists is still limited by their own work schedule and restrictions of geography. An oceanographer, for example, would be ready in one part of the country but not another. This would be something to consider.
\nBe sure to prepare your class with questions before the visiting scientists or engineer comes and after he/she leaves. This will get the students thinking about the kind of work the scientist does. Be sure to cue the students into things like how the scientist dresses, etc., to start addressing the stereotypes. Did he/she wear a lab coat? Did they work in a lab? Did they work from home? Once the visiting scientist/engineer leaves, be sure to process the visit with the students aloud and discuss their expectations versus what really happened, what surprised them, and how did they see this scientist/engineer as a “real” person?
\nMake no mistake; authentic experiences with successful scientists and engineers who can relate to early childhood students can be powerful. If there are opportunities to do so, teachers need to restructure their learning environment so that students’ beliefs about science, scientists, and themselves lead to positive attitudes and to less-sex-role stereotypic views concerning the nature of science and the physical attributes of scientists. However, the time, opportunity, or desire is not available; the remainder of the chapter will discuss two other ways to combat stereotypes if no visiting scientists are available: trade books and televisions shows.
\nBecause young children do not have the paper and pencil option available to them before second or third grade, a nonfiction historical trade book or television show may be used to prompt explicit discussion. In this section, how to use trade books with early childhood students will be discussed.
\nLinking nonfiction historical trade books and science content uniquely enables the teacher to model scientific thinking to stories of scientists and engineers in science lessons. This idea is that biographies of scientists can allow the teacher to highlight the human dimension of scientists and engineers while you encourage science learning. These stories will help broaden students’ perceptions of scientists and engineers as real people and will add explicit and implicit opportunities for your students to consider science and engineering careers.
\nA book series that guides teachers in addressing non-stereotypical scientists [26, 27] has lessons linking the biographies of scientists and science content. This is one example of using nonfiction historical trade books in science teaching as a way to invite scientists and engineers into the classroom without the hassle of finding and scheduling guest speakers. Each chapter of this book presents three lessons based on children’s literature biography of a scientist. Each lesson is organized according to NGSS [20] alignment, the character trait or disposition of the scientist, recommended science teaching strategies, and the learning cycle. However, if you decide to select the biographies for yourself, the following selection has guidelines for selecting biography-themed trade books for a science classroom.
\nThe Science Trade Book Evaluation Rubric [28] can help teachers evaluate science trade books for use in their classroom. This rubric assesses the science- and literature-related appropriateness for trade books. It includes two main sections: literacy and science content. With respect to literacy, the rubric looks at plot development, imagination, and continuity if the story is fictional or whether the book contains sufficient information that is clearly organized in appropriate text structures if the story is nonfiction. The rubric further looks at the writing style, the suitability of the book’s illustrations and graphics for the text it relates to, and the presentation of positive ethical and cultural values, including gender and racial representation. With respect to science content criteria, the rubric’s key elements address the following: whether the science content is substantial, accurate, and current, whether the content has a “human face” (is personalized), and whether the content is intellectually and developmentally appropriate for the target audience. However, one aspect of science trade books not clearly addressed in the Science Trade Book Evaluation Rubric is the representation of scientists, particularly within the context of “science as a human endeavor.”
\nSome places to begin looking for quality books include the National Science Teachers Association (Yearly Trade Book Awardees) and the Caldecott, Newbery, and Orbis Pictus Award lists.
\nWhen selecting science trade books with a focus on science as a human endeavor for their classroom science instruction, teachers may want to consider the following ideas below (in no particular order). The trade book should focus mostly on one particular scientist. The gender and/or ethnicity of the person(s) included within its pages may or may not be related. Meaning, the book is selected because of the work of the scientist, not necessarily the ethnicity or gender; however, there is nothing wrong with selecting a book to explicitly teach that someone besides a white male can do science. Trade books, by their very nature, evoke a storytelling aspect of the book that undoubtedly reflects the human endeavor of science versus a presentation of sets of facts.
The trade book must contain accurate information. There are two things to consider: (1) the accuracy of the scientific information and (2) the attributes of the process(es) of science as delineated by the NGSS [20].
The trade book must include a nonstereotypical representation of a scientist. The trade book should include images of both men and women while remaining historically accurate.
The story presented in the trade book should illustrate the roles of people engaging in the scientific enterprise.
The illustrations in the trade book should be artwork that is esthetically pleasing in a way that encourages children to want to enjoy the book over and over again. Books with high-quality illustrations will help achieve this goal. These trade books stand out because they are so different from the typical information texts currently found in the science sections of the bookstore. Informational texts are read for information, and we encourage students to read trade books for enjoyment.
The trade book must be age appropriate, and the practice of science must include students’ practice and learning. The content of the trade book must be both age and developmentally appropriate for its intended audience so that readers can cognitively connect with what is being presented.
Gather the science trade books, and then consider the following:
\nAssess their science content for accuracy and developmental appropriateness, so the books clearly suit your students’ reading ability ranges, interests, and abilities. Students should be able to grasp the scientific concepts that are being presented.
Assess the books’ literacy qualities, including the narrative, style of writing, and cultural appropriateness.
Determine how well the books show the personal side of science for the main characters (i.e., determine how well the books describe science as being a human endeavor).
Consider the quality of the illustrations that help tell the story. For the age and developmental levels of your students, consider the brightness of the colors and whether the photographs or other types of illustrations are understandable and appropriate.
Young children do not have the paper and pencil option available to them before second or third grade, a nonfiction historical trade book or television show may be used to prompt explicit discussion. In this section, how to use a television show with early childhood students will be discussed.
Select a television show that has a scientist included. The stereotypical or non-stereotypical portrayal of the scientist is not as important as the discussion that will follow between you and the young scientist.
Discuss with your child or your class some explicit assumptions about the scientist* on the show. For example, does the scientist wear a lab coat? Do they always work in a basement? What activities are they doing that considered science?
Just start asking the child questions about scientists, and see where it leads. Try to listen to the child and know that you do not have to answer every question.
*This can also work for field trips or visits like the zoo or science centers that have places where scientists are working on site.
\nSid the Science Kid was selected as an example in the section because this author has used this television show for a research study to understand what aspects of science preschoolers were exposed to during the 1 and 30 minute episode. The goals of this particular study were (1) to analyze process skills: observing, inferring, classifying, measuring, predicting, and communicating within each episode; (2) to evaluate the number of questions asked within an episode; and (3) to evaluate and analyze how and who used the word “scientist” during each episode. Overall study findings (about the use of process skills) suggested preschoolers are exposed to observation and predicting most often while watching the television show and are exposed to an average of fifteen questions per 30-min episode. The explicit and implicit use of the word scientist (an average of five times per episode) might actually help young children visualize themselves as scientists [29].
\nAnother research study about Sid the Science Kid found that the show successfully engaged both preschool children and their adult caregivers. It also reported that during and after viewing Sid the Science Kid, children asked more questions related to the concepts from the programs [2cite]. This is not surprising since children’s exposure to particular topics would naturally lead to the questioning of new information in which they were exposed. It was found that when comparing viewers and non-viewers when presented with similar materials to those they had watched on Sid the Science Kid, the children in the viewer’s category replicated the activities and use terminology they heard on the show, while nonviewers did not [30]. In a study with adult viewers, adults reported increased confidence with science content and increased comfort and interest in engaging in science activities with their preschool-aged children (2cite). Another reason this show would be good to have a discussion about the role of the scientist was that it was specifically found in a research study to measure the impact of the show on caregivers’ reports of low-income children’s science talk at home and found that watching the show had a positive impact on children’s science talk [31].
\nSid is a “Science Kid” who wants to be a scientist when he grows up! The television show produced by the Public Broadcasting System first began in 2008; since then they have aired about 70 episodes about the 4-year-old Sid. The main character, Sid, is an inquisitive preschooler who is always asking questions about how things work and the world around him. As he goes to preschool each day, he tries to answer these questions using the nature of science and basic science principles along with the help of his classmates (May, Gerald, and Gabriela).
\nThe idea for the show was created around Sid and his question for each episode, and every show has basically the same blueprint. There is a brief description of the show as Sid begins each day with a question on his mind. As he greets his family for breakfast, he includes them in his science experiment. Then, he is off to school, and he brings the same question he is wondering about to the school playground usually in the form of a survey. His teacher, then, investigates whatever the particular question he has on his mind for that day at school. After school his grandmother reinforces what he has learned that day on the ride home from school.
\nThe conceptual content of Sid is based in the National Science Standards [32], Cognitive Learning Theory, and on the preschool science curriculum, Preschool Pathways to Science [33]. The topics discussed on the show include earth, life, and physical science. Preschool specific topics per episode include tools and measurement, changes and transformation, senses, health, simple machines, backyard science, weather, the body, force and motion, environmental systems, light and shadow, technology and engineering, and living things.
\nIt is recommended that teachers restructure their learning environment so that student beliefs about science, scientists, and themselves will lead to positive attitudes and to less-sex-role stereotypic views concerning the nature of science and features of a typical scientist [34]. This chapter has suggested that teachers can successfully address stereotypes in existing early childhood science classroom without restructuring their entire classrooms. Simple addition and/or modifications of trade books and/or television episodes (or visits from scientists) will serve their students well, by creating opportunities for discussions to broadening early childhood students’ ideas about who can be scientists and engineers.
\nThis chapter examined the development of the young scientists. It is often accepted that approaches to teaching young children in general include science and seeing themselves as scientists. However, as children progress through the school years, something happens with traditional schooling, and children often lose their curiosity and their sense of being scientists. They tend to try in fit in traditional idea of what others believe they should be a scientists or not, and this contributes to their science identity beginning as in early childhood.
\nIn early childhood settings, children must be supported in their own role as scientist, and exploration is key to seeing themselves as a scientists. The Reggio Emilia approach and the Montessori method both were mentioned earlier in this chapter as examples of learning environments where children can “see themselves as scientists”. Thus, children assume the role of scientists naturally.
\nYoung children are impressionable and are forming images of not only their own identity but also their science identity. This is an important realization for teachers and parents of young children to recognize so that they can have fruitful discussions to uncover any stereotypes or limited thinking on the part of the young child. As previously discussed in this chapter, this can be accomplished through several ways that include trade books, trips to the zoo, or television shows. The most important aspect is that it is intentional on the part of the adult to try and build a communication stream between the child and the adult to discuss the implicit and explicit assumptions that will inevitably come with age and culture.
\nEarly investment and exposure to scientists and engineers can inspire many years of discovery, even if children do not enter science careers. Finding developmentally appropriate trade books and television shows to address stereotypes can be both meaningful and relevant to the everyday lives of young children and their teachers. In addition, science content is framed in relatable ways to its characters yet investigated through the nature of science, through posing questions and investigating objects and events that can be directly observed and explored for young scientists.
\nThis chapter offered some practical tips for teachers because there is a real need for professional development for early childhood teachers on the issues of stereotypes in general.
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