Controversies    in   melanoma Torello Lotti Department of Dermatologic Sciences University of Florence, Italy The Interna...
Controversies in melanoma’s… -   epidemiology :  Melanoma epidemic: true or false? -  etiopathogenesis :  The role of sun ...
- Epidemiology -
<ul><li>The presence of a true melanoma epidemic has been a controversial topic for the past decade. </li></ul><ul><li>A d...
They believe that this worldwide melanoma incidence increase represents a true epidemic take the statistics at face value,...
<ul><li>They pose multiple explanations for the incidence data, including: </li></ul><ul><li>length-time bias </li></ul><u...
Melanoma epidemic…?   In general, the question posed of whether a melanoma epidemic truly exists has not yet a definitive ...
- Etiopathogenesis -
<ul><li>Despite the evidence of an UV-induced damage to DNA, the exact relationship between melanoma risk and sun exposure...
Walker G. Cutaneous melanoma: how does ultraviolet light contribute to melanocyte transformation? Future Oncol 2008; 4: 84...
<ul><li>Stratospheric ozone thinning  has permitted that an increased number of rays, mainly the more carcinogenetic UVB, ...
Gradual and continuous exposure  can play a protective role for the photoexposed persons. Ricceri F. De Giorgi V. Lotti . ...
Benefits  of  a  gradual  and continuous  sun  exposure <ul><li>A correct, gradual and continuous sun exposure  starts a p...
Benefits  of  a  gradual  and continuous  sun  exposure <ul><li>A correct, gradual and continuous sun exposure  starts a p...
<ul><li>The question of whether hormones influence melanoma has been investigated for many years, often leading to inconsi...
Hormons  and  melanoma <ul><li>Some observations had led to speculation concerning a relationship between hormones and mel...
<ul><li>Recent clinical studies do not support a deleterious effect of  both exogenous hormones (OCs and HRT) and endogeno...
- Diagnosis  &  treatment -
The role of sentinel lymph node biopsy <ul><li>The term “sentinel node”(SN) is used to indicate the lymph node to which th...
<ul><li>Sentinel lymph node biopsy  ( SLNB ) is included in staging guidelines of  the American Joint Committee on Cancer ...
<ul><li>An early preoperative assessment of the lymph drainage pattern from the melanoma can be made through the  injectio...
<ul><li>A limited biopsy of the most likely node is performed rather than a more invasive removal of the entire regional l...
<ul><li>Mitotic rate has been added by the American Joint Committee on Cancer to their seventh edition staging system for ...
<ul><li>The question whether  SNLB influences positively the overall survival  is still the subject of debate .  </li></ul...
The postulate that all the positive sentinel nodes inevitably progress to nodal disease is not correct, because it can hap...
The postulate that all the positive SN inevitably progress to nodal disease is not correct, because it can happen that som...
<ul><li>Melanoma metastatization modalities limits  so much the diagnostical-therapeutical value of SN biopsy, and a follo...
<ul><li>malignant cells have not reached the node yet when the sentinel node is examined, because they are still inside th...
The role of CEUS in melanoma diagnosis  <ul><li>Contrast-enhanced ultrasound system  ( CEUS )  was recently introduced as ...
<ul><li>Electron paramagnetic resonance  ( EPR ) has been recently employed to melanoma field, because of its ability to d...
<ul><li>Whereas the surgical excision is accepted world wide as primary treatment for melanoma, the prognostic significanc...
<ul><li>Cutaneous melanoma is an emerging and complex health problem. </li></ul><ul><li>Management may require the experti...
 
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Controversies in melanoma -Professor Torello Lotti, MD - University G.Marconi, Rome, Italy - and Linda Tognetti, MD - Department of Dermatologic Sciences University of Florence, Italy

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etiopathogenesis: The role of sun exposure Hormons and melanoma
The role of Sentinel Lymph Node Biopsy The role of Contrast Enanched Ultra Sound The role of Electron Paramagnetic Resonance
Excisional VS incisional biopsy

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Controversies in melanoma -Professor Torello Lotti, MD - University G.Marconi, Rome, Italy - and Linda Tognetti, MD - Department of Dermatologic Sciences University of Florence, Italy

  1. 1. Controversies in melanoma Torello Lotti Department of Dermatologic Sciences University of Florence, Italy The International School of Vitiligo & Pigmentary Disorders Barcelona, 2-5 November 2011
  2. 2. Controversies in melanoma’s… - epidemiology : Melanoma epidemic: true or false? - etiopathogenesis : The role of sun exposure Hormons and melanoma - diagnosis & treatment : The role of S entinel Lymph Node Biopsy The role of Contrast Enanched Ultra Sound The role of Electron Paramagnetic Resonance Excisional VS incisional biopsy
  3. 3. - Epidemiology -
  4. 4. <ul><li>The presence of a true melanoma epidemic has been a controversial topic for the past decade. </li></ul><ul><li>A dramatic increase in the incidence of cutaneous malignant melanoma in developed countries is well documented, but mortality rates have not risen as rapidly. </li></ul><ul><li> The “melanoma epidemic theory” has generated much discussion. </li></ul>Melanoma epidemic: true or false? FAVOURABLE AUTHORS They assert there is a true increase in disease. CONTRARY AUTHORS They argument this is an apparent phenomenon that may be explained by multiple biases and other factors. Erickson C, Driscoll MS.  Melanoma epidemic: Facts and controversies. Clinic Dermatol 2010;28(3):281-286. Florez A, Cruces M. Melanoma epidemic: true or false? Int J Dermatol 2004;43:405-7.
  5. 5. They believe that this worldwide melanoma incidence increase represents a true epidemic take the statistics at face value, with the concept “ res ipsa loquitur”. FAVOURABLE Rigel DS, Friedman RJ, Kopf AW, et al. Melanoma incidence: if it quacks like a duck. Arch Dermatol 1997;133:656–658 Beddingfield FC, The melanoma epidemic: res ipsa loquitur. Oncologist 2003;8 :459–465 Melanoma epidemic…?
  6. 6. <ul><li>They pose multiple explanations for the incidence data, including: </li></ul><ul><li>length-time bias </li></ul><ul><li>increased surveillance intensity </li></ul><ul><li>diagnostic uncertainty </li></ul><ul><li>medico-legal climate </li></ul><ul><li>data quality </li></ul>They believe that this worldwide melanoma incidence increase represents a true epidemic take the statistics at face value, with the concept “ res ipsa loquitur”. FAVOURABLE CONTRARY LA Glocker-Reis, D Melber, M Krapcho, Editors et al., SEER Cancer Statistics Review, 1975-2005, National Cancer Institute (2008) Bethesda, MD Melanoma epidemic…? Rigel DS, Friedman RJ, Kopf AW. The incidence of malignant melanoma in the United States: issues as we approach the 21st century. J Am Acad Dermatol 1996;34:839-47 Florez A, Cruces M. Melanoma epidemic: true or false? Int J Dermatol 2004;43:405-7. Schaffer JV, Rigel DS, Kopf AW, et al. Cutaneous melanoma—past, present, and future. J Am Acad Dermatol 2004;51:S65-9. Rigel DS, Friedman RJ, Kopf AW, et al. Melanoma incidence: if it quacks like a duck. Arch Dermatol 1997;133:656–658
  7. 7. Melanoma epidemic…? In general, the question posed of whether a melanoma epidemic truly exists has not yet a definitive answer, because of the absence of randomized controlled trials which can evaluate the true effect of increased surveillance and biopsies on mortality rates. Erickson C, Driscoll MS.  Melanoma epidemic: Facts and controversies. Clinic Dermatol 2010;28(3):281-286.
  8. 8. - Etiopathogenesis -
  9. 9. <ul><li>Despite the evidence of an UV-induced damage to DNA, the exact relationship between melanoma risk and sun exposure is not yet optimally known . </li></ul>Walker G. Cutaneous melanoma: how does ultraviolet light contribute to melanocyte transformation? Future Oncol 2008; 4: 841-56 The role of sun exposure in melanoma <ul><li>Considering mechanisms that allow UV radiations to induce melanoma, is now generally accepted that the sun exposure is one of the most relevant risk factor for melanoma. </li></ul>Narayanan DL, Saladi RN, Fox JL. Ultraviolet radiation and skin cancer. Int J Dermatol 2010; 49: 978-986 <ul><li>The controversy lies in the assessment of what kind of sun exposure, intermittent and intense versus continuous and gradual, causes cell degeneration. </li></ul>
  10. 10. Walker G. Cutaneous melanoma: how does ultraviolet light contribute to melanocyte transformation? Future Oncol 2008; 4: 841-56 UVA rays <ul><li>free radical damage to DNA </li></ul><ul><li>immunosuppression : diminishing of the antigen-presenting cell function </li></ul><ul><li>modulation of hypersensitivity reactions </li></ul><ul><li>facilitation of immunosuppressive cytokines </li></ul><ul><li>contribute to 10-20% of all UV ray effects </li></ul>UVB rays <ul><li>erythema, tanning, sunburn, photoaging </li></ul><ul><li>carcinogenic effect </li></ul><ul><li>DNA damages : formation of cyclobutane pyrimidine </li></ul><ul><li>dimers and6-4 photoproducts genetic transitions </li></ul><ul><li>(cysteine to thymine) </li></ul><ul><li> mutations to p53 gene </li></ul>UV radiation effects
  11. 11. <ul><li>Stratospheric ozone thinning has permitted that an increased number of rays, mainly the more carcinogenetic UVB, reach the earth’s surface. </li></ul><ul><li> 1% of ozone layer’s depletion ccauses to an increase of 1-2% in melanoma mortality </li></ul><ul><li>Altitude and latitude role: </li></ul><ul><li>1000 meters in elevation correspond to an increase of UV intensity of 10% </li></ul><ul><li>incidence rates for melanoma correlate with latitude. </li></ul>Narayanan DL, Saladi RN, Fox JL. Ultraviolet radiation and skin cancer. Int J Dermatol 2010; 49: 978-986 UV radiation effects <ul><li>Patient-related factors making patients more or less susceptible to UV effects: </li></ul><ul><li>pigmentation features </li></ul><ul><li>melanocyte proliferative response </li></ul><ul><li>DNA repair capability </li></ul><ul><li>cutaneous microenvironmental capacity in contrasting </li></ul><ul><li>the proliferation of first mutated melanocytes. </li></ul>
  12. 12. Gradual and continuous exposure can play a protective role for the photoexposed persons. Ricceri F. De Giorgi V. Lotti . Melanoma:un’ipotesi eretica relativamente alla fotoesposizione cronica. In: De Giorgi V, Aricò M, Lotti T, eds. Il melanoma. Prevenzione, diagnosi e terapia. Tortona: Fernando Folini; 2008. pp:15-20. intermittent exposure Intermittent, acute and intense exposure increases the possibility to develop melanoma and basal cell carcinoma (BCC). Chronic intense UV exposure is more typically associated with the squamous cell carcinoma (SCC) and actinic keratosis. Among children, melanoma risk is most associated with intermittent sunburns. De Giorgi V, Gori A, Grazzini M et al. Sun exposure and children: what do they know? An observational study in an Italian school. Prev Med 2011; 52: 186-187. continuous exposure vs It is though to be harmless for the melanoma. It is defined as “recreational” or “vacation exposure”: melanoma often appears in sites not usually covered by the seasonal habits and therefore attainable by UVR Moan J, Porojnicu AC, Dahlback A et al. Where the sun does not shine: Is sunshine protective against melanoma of the vulva? J Photochem Photobiol B 2010; 101: 179-183
  13. 13. Benefits of a gradual and continuous sun exposure <ul><li>A correct, gradual and continuous sun exposure starts a protective, negative-feedback mechanism which permits to stimulate melanin and vitamin D production. </li></ul>Abdel-Malek ZA, Kadekaro AL, Swope VB. Stepping up melanocytes to the challenge of UV exposure. Pigment Cell Melanoma Res 2010; 23: 171-186 Ivry GB, Ogle CA, Shim EK. Role of sun exposure in melanoma. Dermatol Surg 2006; 32: 481-492 Maddodi N, Setaluri V. Role of UV in cutaneous melanoma. Photochem Photobiol 2008; 84: 528-536 <ul><li>has photoprotective properties: </li></ul><ul><li>greater resistance to degradation than pheomelanin </li></ul><ul><li>antioxidant activity  direct correlation between eumelanin amount and catalase levels </li></ul><ul><li>free radicals scavenger  preserving DNA from pyrimidine base formation </li></ul><ul><li>filtering and absorbing UV photons and transforming the UV energy into heat </li></ul><ul><li> forming a supranuclear cap between the nucleus and the extracelluar environment </li></ul>Eumelanin can halt malignant cells’ proliferation, facilitating tissue differentiation and limiting UV-induced damages. Vitamin D
  14. 14. Benefits of a gradual and continuous sun exposure <ul><li>A correct, gradual and continuous sun exposure starts a protective, negative-feedback mechanism which permits to stimulate melanin and vitamin D production. </li></ul>Abdel-Malek ZA, Kadekaro AL, Swope VB. Stepping up melanocytes to the challenge of UV exposure. Pigment Cell Melanoma Res 2010; 23: 171-186 Ivry GB, Ogle CA, Shim EK. Role of sun exposure in melanoma. Dermatol Surg 2006; 32: 481-492 Maddodi N, Setaluri V. Role of UV in cutaneous melanoma. Photochem Photobiol 2008; 84: 528-536 <ul><li>Evidences supporting the hypothesis of a protective role of gradual sun exposure against melanoma development: </li></ul><ul><li>low melanoma incidence in darker-skinned persons is due to the photoprotection </li></ul><ul><li>guaranteed by increased epidermal melanin. </li></ul><ul><li>cutaneous melanoma is more common among indoor workers than in outdoor ones. </li></ul><ul><li>solar elastosis is often associated with better melanoma prognosis and shows an inverse </li></ul><ul><li>correlation with melanoma mortality </li></ul><ul><li>there are studies showing a reversed latitude gradient for melanoma </li></ul>Rigel DS. Cutaneous ultraviolet exposure and its relationship to the development of skin cancer. J Am Acad Dermatol 2008; 58: s129-132
  15. 15. <ul><li>The question of whether hormones influence melanoma has been investigated for many years, often leading to inconsistent conclusions. </li></ul>Hormons and melanoma <ul><li>Early case reports of the ‘80s and case series suggested a negative impact of hormones on the prognosis of melanoma. </li></ul>Bain C, Hennekens CH, Speizer FE, et al. Oral contraceptive use and malignant melanoma. J Natl Cancer Inst 1982;68 :537–539. Holly EA, Weiss NS, Liff JM. Cutaneous melanoma in relation to exogenous hormones and reproductive factors. J Natl Cancer Inst 1983; 70:827–831. Beral V, Evans S, Shaw H, et al. Oral contraceptive use and malignant melanoma in Australia. Br J Cancer 1984; 50  :681–685. Adam SA, Sheaves SA, Wright NH, et al. A case-control study of the possible association between oral contraceptives and malignant melanoma. Br J Cancer 1981;44 :45–50. <ul><li>Some observations had led to speculation concerning a relationship between female hormones and melanoma. </li></ul>Beral V, Ramcharan S, Faris R. Malignant melanoma and oral contraceptive use among women in California. Br J Cancer 1977; 36:804–809.
  16. 16. Hormons and melanoma <ul><li>Some observations had led to speculation concerning a relationship between hormones and melanoma. </li></ul><ul><li>melanoma incidence is rare before puberty, rises throughout the reproductive years until approximately age 50, and then decreases during menopausal years. </li></ul><ul><li>changes in pigmentation, such as melasma, are associated with pregnancy, oral contraceptives (OCs), and hormone replacement therapy (HRT). </li></ul><ul><li>the recently identified estrogen receptor β , has been shown </li></ul><ul><li>to be expressed in benign nevi, dysplastic nevi, lentigo maligna, </li></ul><ul><li>and melanmas of varying depth. </li></ul>Strouse JJ, Fears TR,Tucker MA, et al. Pediatric melanoma: risk factor and survival analysis of the surveillance, epidemiology, and end results database. J Clin Oncol 2005;23:4735–4741. R.P. Gallagher, J.M. Elwood and G.B. Hill, et al. Reproductive factors, oral contraceptives and risk of malignant melanoma: Western Canada melanoma study. Br J Cancer 1985;52:901–907. Schmidt A, Nanney LB, Boyd AS, et al. Oestrogen receptor- β expression in melanocytic lesions. Exp Dermatol 2006;15:971–980. Ohata C,Tadokoro T, Itami S. Expression of estrogen receptor beta in normal skin, melanocytic nevi and malignant melanomas. J Dermatol 2008;35:215–221 .
  17. 17. <ul><li>Recent clinical studies do not support a deleterious effect of both exogenous hormones (OCs and HRT) and endogenous hormones (pregnancy) on melanoma . </li></ul><ul><li>According to a recent review of all the controlled studies to date, OCs and HRT do not appear to increase a woman's risk for MM; however, there </li></ul><ul><li>is more extensive evidence concerning OCs than HRT. Pregnancy </li></ul><ul><li>does not appear to influence a woman's risk of melanoma, nor does </li></ul><ul><li>to affect prognosis. </li></ul>Driscoll MS, Grant-Kels JM. Hormones, nevi and melanoma: an approach to the patient. J Am Acad Dermatol 2007; 57: 919–931. Kaae J, Andersen A, Boyd HA, et al.Reproductive history and cutaneous malignant melanoma: a comparison between women and men. Am J Epidemiol 2007;165 :1265–1270. Lea CS, Holly EA, Hartge P, et al. Reproductive risk factors for cutaneous melanoma in women: a case-control study. Am J Epidemiol 2007;165:505–513. Koomen ER, Joosse A, Herings RM, et al. Estrogens, oral contraceptives and hormonal replacement therapy increase the incidence of cutaneous melanoma: a population-based case-control study. Ann Oncol 2009:20,358–564. Gupta A, Driscoll MS. Do hormones influence melanoma? Facts and controversies. Clin Dermatol 2010;28(3):287-92. Hormons and melanoma
  18. 18. - Diagnosis & treatment -
  19. 19. The role of sentinel lymph node biopsy <ul><li>The term “sentinel node”(SN) is used to indicate the lymph node to which the afferent lymphatic vessels drain first in the regional lymph node basin. </li></ul><ul><li>SN represents the first lymphatic station which receives </li></ul><ul><li>the metastasizing cells coming from the primitive tumour. </li></ul>Leong SPL, Zuber M, Ferris RL et al. Impact of nodal status and tumor burden in sentinel lymph nodes on the clinical outcomes of cancer patients. J Surg Oncol 2011; 103: 518-530 <ul><li>For this reason, the assessment of the sentinel node’s histological features allow the physician to predict the status of the other neighboring structures of the lymphatic basin. </li></ul>
  20. 20. <ul><li>Sentinel lymph node biopsy ( SLNB ) is included in staging guidelines of the American Joint Committee on Cancer and in treatment guidelines of the National Comprehensive Cancer Network , and most of the surgical physicians who treat melanoma adopt it, especially in United States and Australia. </li></ul>Ross MI . Sentinel node biopsy for melanoma: An update after two decades of experience.Semin Cutan Med Surg 2010; 29:238-248 <ul><li>Several studies have confirmed that SLNB is the most likely site of metastasis, therefore: </li></ul><ul><li>when it is histologically negative , no further interventions are required </li></ul><ul><li>when it is positive , a complete regional lymphadenecetomy is suggested because the other nodes of that lymphatic area probably contain disease. </li></ul>The role of sentinel lymph node biopsy
  21. 21. <ul><li>An early preoperative assessment of the lymph drainage pattern from the melanoma can be made through the injection of 99m Tc-HSA colloid and the succeeding lymphoscintigraphyic analysis some hours before the sentinel node biopsy. </li></ul><ul><li>Combination of the highest radioactivity detected and the presence of the dye under the incised area, increases the accuracy through which the physician identifies SN. </li></ul>From: http://blogs.nejm.org/now/index.php/sentinel-lymph-node-biopsy/2011/05/06/ <ul><li>The identification of the sentinel node is permitted also injecting a blue dye at the tumour site and visually identifying it later inside the first draining node. </li></ul>Gershenwald JE, Ross MI . Sentinel-lymph-node biopsy for cutaneous melanoma.N Engl J Med 2011; 364: 1738-45 Lens M . Sentinel lymph node biopsy in melanoma patients. J Eur Acad Dermatol Venereol 2010; 24: 1005-1012 The role of sentinel lymph node biopsy
  22. 22. <ul><li>A limited biopsy of the most likely node is performed rather than a more invasive removal of the entire regional lymphatic chain. </li></ul><ul><li>SN biopsy is often performed because it provides: - detailed nodal staging </li></ul><ul><li>- regional disease control </li></ul><ul><li>- possible overall improved survival </li></ul><ul><li>Roughly 20% of melanoma patients show presence of malignant cells’deposits in SN. </li></ul><ul><li>Histopathological examination allows dermatologist to know: </li></ul><ul><li>the presence of metastasis inside the SN </li></ul><ul><li>relevant features of the metastatic deposit (e.g., </li></ul><ul><li>extension, location, extracapsular spreading </li></ul>From: http://blogs.nejm.org/now/index.php/sentinel-lymph-node-biopsy/2011/05/06 / Gershenwald JE, Ross MI . Sentinel-lymph-node biopsy for cutaneous melanoma.N Engl J Med 2011; 364: 1738-45 Prieto VG . Sentinel lymph nodes in cutaneous melanoma. Arch Pathol Lab Med 2010; 134: 1764-1769 The role of sentinel lymph node biopsy
  23. 23. <ul><li>Mitotic rate has been added by the American Joint Committee on Cancer to their seventh edition staging system for melanomas, replacing the Clark level of invasion. </li></ul><ul><li>Otherwise, the exact significance of mitotic rate in melanoma is still controversial. </li></ul><ul><li>Some author consider it weakly predictive of SN status and argument it is not an independent predictor of survival for melanomas of 1 mm or thicker. </li></ul><ul><li>Criteria for SNLB : </li></ul><ul><li>melanoma ≥1 mm in Breslow thickness with no clinically involved nodes </li></ul><ul><li>melanoma ≥0,75 mm in Breslow thickness with ulceration </li></ul><ul><li>mitotic rate ≥ 1/mm 2 </li></ul>Sekula-Gibbs SA, Shearer MA , Sentinel node biopsy should be offered in thin melanoma with mitotic rate greater than one. Dermatol Surg 2011; 37: 1080-8 Roach BA, Burton AL, Mays MP et al.Does mitotic rate predict sentinel lymph node metastasis or survival in patients with intermediate and thick melanoma?Am J Surg 2010; 200: 759-764 Thompson JF, Shaw HM . Should tumor mitotic rate and patient age, as well as tumor thickness, be used to select melanoma patients for sentinel node biopsy?Ann Surg Oncol 2004; 11: 233-5 The role of sentinel lymph node biopsy
  24. 24. <ul><li>The question whether SNLB influences positively the overall survival is still the subject of debate . </li></ul><ul><li>All the authors admit the value of SLNB as a widespread prognostic tool, able to stage patients with cutaneous melanoma. </li></ul>To date, a rising part of authors is sceptical of this position, and adduces a series of evidences, which can be summarized in 5 points. Some authors has argued in favor of this technique by postulating that removal of a SN that resulted positive at histologic examination, followed by lymphadenectomy, has a therapeutic effect. The role of sentinel lymph node biopsy
  25. 25. The postulate that all the positive sentinel nodes inevitably progress to nodal disease is not correct, because it can happen that some micrometastases in the sentinel node can disappear for host immune processes or can remain in a dormancy state. De Giorgi V, Grazzini M, Papi F et al. Sentinel lymph node biopsy: Is it an evolution of the management of cutaneous melanoma?Ann Surg Oncol 2011;18:597 De Giorgi V, Grazzini M, Massi D. Sentinel-lymph-node biopsy for cutaneous melanoma. N Engl J Med 2011; 365: 570-571 Thomas JM . Caution with sentinel node biopsy in melanoma.Br J Surg 2006; 93: 129-130 1 2 It has never been shown that the lymphadenectomy performed after a positive SN finding really improves the survival of melanoma patients. Thomas JM. Time to re-evaluate sentinel node biopsy in melanoma postmulticenter selective lymphadenectomy trial. J Clin Oncol 2005; 23: 9443-4 The role of sentinel lymph node biopsy
  26. 26. The postulate that all the positive SN inevitably progress to nodal disease is not correct, because it can happen that some micrometastases in the sentinel node can disappear for host immune processes or can remain in a dormancy state. 1 2 3 It has never been shown that the lymphadenectomy performed after a positive SN finding really improves the survival of melanoma patients. Results from Multicentre Selective Lymphadenectomy Trials (MSLT-I and II) have showed that SLNB do not significantly improve overall survival , by comparing the observation group and the biopsy group, but it helps reducing time for lymph node metastases detection  earlier identification of the natural disease progression Amersi F, Morton DL . The role of sentinel lymph node biopsy in the management of melanoma. Adv Surg 2007; 41: 241-256 De Giorgi V, Leporatti G, Massi D et al. Sentinel lymph nodes in melanoma patients: evaluating the evidence. Oncology 2006; 71: 460-2 De Giorgi V, Leporatti G, Massi D et al. Outcome of patients with melanoma and histologically negative sentinel lymph nodes: one institution’s experience.Oncology 2007; 73: 401-6 The role of sentinel lymph node biopsy
  27. 27. <ul><li>Melanoma metastatization modalities limits so much the diagnostical-therapeutical value of SN biopsy, and a following potential lymphadenectomy. </li></ul><ul><li>Indeed, a melanoma can produce: </li></ul><ul><li>cutaneous metastases , satellitosis or in-transit ( 20% of cases of initial melanoma) </li></ul><ul><li>regional nodal metastases ( 50% of cases) </li></ul><ul><li>distant metastases ( 30% ) </li></ul><ul><li> In half cases, there could be previous cutaneous and distant metastases not yet detected at SN biopsy time. </li></ul>4 The role of sentinel node biopsy 5 Amersi F, Morton DL . The role of sentinel lymph node biopsy in the management of melanoma. Adv Surg 2007; 41: 241-256 De Giorgi V, Leporatti G, Massi D et al. Sentinel lymph nodes in melanoma patients: evaluating the evidence. Oncology 2006; 71: 460-2 De Giorgi V, Leporatti G, Massi D et al. Outcome of patients with melanoma and histologically negative sentinel lymph nodes: one institution’s experience.Oncology 2007; 73: 401-6 SNLB frequently gives false negatives and false positives results . Van Akkooi ACJ, Voit CA, Verhoef C et al. New developments in sentinel node staging in melanoma: controversies and alternatives. Curr Opin Oncol 2010; 22: 169-177
  28. 28. <ul><li>malignant cells have not reached the node yet when the sentinel node is examined, because they are still inside the lymphatic vessels. </li></ul><ul><li>not all the sentinel nodes are reached by 99m Tc-HSA colloid during the lymphoscintigraphy. </li></ul><ul><li>part of the radiocolloid has cross the sentinel node arriving up to other nodes, or it could enter inside “second line” bigger nodes. </li></ul><ul><li>there is reduced lymphatic flow to the sentinel node due to the obstruction by the metastatic bulk. </li></ul>5 Causes of a possible false negatives result of SLNB techinque: Van Akkooi ACJ, Voit CA, Verhoef C et al. New developments in sentinel node staging in melanoma: controversies and alternatives. Curr Opin Oncol 2010; 22: 169-177 The role of sentinel node biopsy
  29. 29. The role of CEUS in melanoma diagnosis <ul><li>Contrast-enhanced ultrasound system ( CEUS ) was recently introduced as an alternative and less invasive procedure, in spite of SLNB, for the detection of SN. </li></ul><ul><li>Sometimes there is a reduced lymphatic flow to the sentinel node due to the obstruction given by the metastatic bulk. </li></ul><ul><li>In such cases, using an ultrasound-based evaluation can </li></ul><ul><li>successfully identify the node’s involvement. </li></ul><ul><li>CEUS has demonstrated a negative predictive value of 100%, </li></ul><ul><li>so that all negative results were confirmed by negative SN </li></ul><ul><li>histological examination. </li></ul><ul><li>CEUS has shown an high diagnostic accuracy in detecting </li></ul><ul><li>occult non-palpable metastases in regional lymph nodes. </li></ul>De Giorgi V, Gori A, Grazzini M, et al. Contrast-enhanced ultrasound: a filter role in AJCC stage I/II melanoma patients. Oncology 2010; 79: 370-5. Catalano O, Setola SV, Vallone P, et al. Sonography for locoregional staging and follow-up of cutaneous melanoma: how we do it. J Ultrasound Med 2010;29(5):791-802.
  30. 30. <ul><li>Electron paramagnetic resonance ( EPR ) has been recently employed to melanoma field, because of its ability to detect free radicals trapped in melanin pigments by using their paramagnetic properties. </li></ul><ul><li>EPR can localize melanoma metastases with high precision and </li></ul><ul><li>can help assessing the contribution of UV rays to the initiation of melanoma. </li></ul><ul><li>EPR spectrometry and imaging largely improve the detection and mapping of melanin pigments inside ex vivo and in vivo melanomas. </li></ul><ul><li>However, this method has some limitations, and further investigations are needed. </li></ul>The role of EPR in melanoma diagnosis Melanoma mtx in the lungs of mice and the respective 2D transversal EPR image. Godechal Q, Gallez B. The contribution of electron paramagnetic resonance to melanoma research. J Skin Cancer 2011;2011:273-280. Godechal Q, Defresne F, Danhier P. Assessment of melanoma extent and melanoma metastases invasion using electron paramagnetic resonance and bioluminescence imaging. Contrast Media Mol Imaging 2011;6(4):282-8.
  31. 31. <ul><li>Whereas the surgical excision is accepted world wide as primary treatment for melanoma, the prognostic significance of incisional bopsy is discussed controversially, and so far, no international consensus has been reached. </li></ul><ul><li>Incisional biopsies are currently recommended for the histopathologic diagnosis of large tumors in facial, mucosal, and acral locations. </li></ul><ul><li>Evidence from latest trials and studies is that incisional biopsies of malignant melanoma are not associated with an unfavorable prognosis for patients. </li></ul><ul><li>Anyway, complete excision of primary melanoma is still the recommended standard of care and is a precondition for accurate histopathologic diagnosis. </li></ul>Excisional VS incisional biopsy Pflugfelder A, Weide B, Eigentler TK. Incisional biopsy and melanoma prognosis: Facts and controversies. Clin Dermatol 2010;28(3):316-8. Leiter U, Eigentler TK, Forschner A, et al. Excision guidelines and follow-up strategies in cutaneous melanoma: Facts and controversies. Clin Dermatol. 2010 ;28(3):311-5. From: http://www.glowm.com/resources/glowm/cd/pages/v1/v1c011.html?SESSID=cvrcbl8q7c00h40nmlti9r0na3
  32. 32. <ul><li>Cutaneous melanoma is an emerging and complex health problem. </li></ul><ul><li>Management may require the expertise of multiple specialties. </li></ul><ul><li>Although the outlook for advanced disease remains very poor, there are major advances in the understanding of melanoma. </li></ul><ul><li>As technology improves and information continues to accrue, our increased understanding of melanoma will lead to improved treatment of advanced disease. </li></ul>Take home messages
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