ACTAS Dermo-Sifiliográficas

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1 ISSN: Pulicción Oficil de l Acdemi Espñol de Dermtologí y Venereologí Documento descrgdo de el 04/04/2017. Copi pr uso personl, se prohíe l trnsmisión de este documento por culquier medio o formto. Acts Dermosiiliogr. 2010;101(1):19-30 ACTAS Dermo-Sifiliográfics Full English text ville t AC TA S Dermo-Sifiliográfics Enero-Ferero Vol Núm. 1 Biosimilres o iosecuels en Dermtologí Agentes vesicntes de guerr Clsificción de Clrk de los melnoms Liquen escleroso Incidenci del cáncer de piel Etnercept en el trtmiento de l psorisis Quincrin y lupus eritemtoso cutáneo Epidemiologí de l dermtitis de contcto Free full English text ville t PuMed Incluid en: Index Medicus/MEDLINE CONTROVERSIES IN DERMATOLOGY But... Ws There Ever Clrk Clssifiction of Melnoms? E. Sánchez Yus,, * M. Herrer, R.S. Simón, c nd L. Requen d Deprt ment o de Medicin II (Dermt ologí), Fcult d de Medicin, Universidd Complut ense, Mdrid, Spin Servicio de Dermt ologí, Hospit l del Henres, Cosld, Mdrid, Spin c Servicio de Ant omí Pt ológic, Hospit l Virgen de l Slud, Toledo, Spin d Deprt ment o de Dermt ologí, Fundción Jiménez Díz, Fcult d de Medicin, Universidd Aut ónom, Mdrid, Spin Received Ferury 6, 2009; ccepted July 15, 2009 KEYWORDS Clrk clssiiction of melnom; Acrl lentiginous melnom; Breslow Astrct For the pst 40 yers, the Clrk clssiiction of cutneous melnom hs een ccepted nd used y the vst mjority of dermtologists nd pthologists throughout the world. However, fter creful rereding of the most relevnt rticles y Clrk nd his collortors, we cn firm tht the clssiiction ws only ever of pssing vlidity. After distinguishing etween nodulr melnom, supericil spreding melnom (SSM), nd lentigo mlign melnom (LMM) in 1968, the inclusion of crl-lentiginous melnom (ALM) in 1979 s new sutype ws the irst serious setck for the clssiiction; in contrst to ALM, lte-onset lentiginous melnoms, such s LMM, were situted on res of skin with less exposure to sunlight. Lter, the sme uthors found tht, contrry to their initil elief, the prognosis of LMM ws the sme s tht of other sutypes with the sme Breslow thickness. Finlly, numer of oservtions y the sme uthors mde ever clerer the incresing dificulty for distinguishing microscopiclly etween LMM, SSM, nd ALM, except y tking their locliztion into considertion. This mens tht, tody, the possile morphologicl differences etween one cse of cutneous melnom nd nother re of no proven prognostic impliction. In ddition, the morphologicl differences tht cn e found re much more closely relted to the different locliztion thn to the tumor itself Elsevier Espñ, S.L. nd AEDV. All rights reserved. *Corresponding uthor. E-mil ddress: evsyus@hotmil.com (E. Sánchez Yus) /$ - see front mtter 2009 Elsevier Espñ, S.L. nd AEDV. All rights reserved.

2 Documento descrgdo de el 04/04/2017. Copi pr uso personl, se prohíe l trnsmisión de este documento por culquier medio o formto. 20 E. Sánchez Yus et l PALABRAS CLAVE Clsiicción de Clrk de los melnoms; Melnom lentiginoso cro; Breslow Pero huo lgun vez un clsificción de Clrk de los melnoms? Resumen Desde hce 40 ños, l inmens myorí de los dermtólogos y los ptólogos de todo el mundo h ceptdo y h empledo l clsiicción de Clrk de los melnoms cutáneos. Sin emrgo, trs un cuiddos relectur de los rtículos fundmentles de Clrk y sus colordores, hemos podido compror que tl clsiicción h sido en relidd muy efímer. Trs distinguir en 1968 entre melnom nodulr, melnom de extensión supericil (MES) y melnom del lentigo mligno (MLM), l inclusión en 1979 del melnom lentiginoso cro (MLA) como un nuevo sutipo de melnom fue l primer verí seri de l clsiicción, y que un melnom lentiginoso y de prición trdí (como el MLM) se locliz, diferenci de éste, en ls zons menos fotoexpuests de l piel. Posteriormente, los mismos utores comproron que, contrrimente su ide inicil, el pronóstico del MLM er el mismo que el de los demás sutipos iguldd de espesor, según Breslow. Finlmente, diverss oservciones de los mismos utores fueron poniendo de mniiesto su creciente diicultd pr distinguir l microscopio entre MLM, MES y MLA, slvo que tuviesen en cuent l loclizción. Es decir, que hoy por hoy ls posiles diferencis morfológics entre uno y otro cso de melnom cutáneo no conllevn demostrds diferencis pronóstics, y ls diferencis morfológics que puedn encontrrse se deen más l diferente loclizción que l propi neoplsi Elsevier Espñ, S.L. y AEDV. Todos los derechos reservdos. Over the pst 40 yers, nerly ll the dermtologists nd pthologists in the world hve ctegorized, or ttempted to ctegorize, every cse of cutneous melnom they encountered ccording to Clrk s clssifiction. However, creful rereding of the most relevnt ppers on the suject y Clrk nd his collegues hs given rise in our minds to resonle dout not only concerning the prognostic usefulness of this clssifiction nd the criteri it is sed on, ut even concerning the very existence of this supposed clssifiction system. We hve in fct come to pose the question of whether there ever relly ws Clrk clssifiction of melnoms. The first interntionl consensus on the nomenclture nd clssifiction of cutneous melnom nd on the procedures tht physicins should follow in ptients with lesion of this type ws dopted t the Interntionl Cncer Conference held in Sydney, Austrli, in Mrch The results of tht meeting were pulished in nd the Tle 1 List of Terminology Recommended y the Interntionl Cncer Conference (Sydney, 1973) for the Denomintion of the Different Types of Melnom Recommended Terminology Hutchinson s melnotic freckle Supericil spreding melnom, noninvsive Melnom, invsive, with djcent intrepiderml component of Hutchinson s melnotic freckle type Melnom, invsive, with djcent intrepiderml component of supericil spreding type Melnom, invsive, without djcent intrepiderml component Adpted from McGovern et l. 1 Synonyms in Common Use Hutchinson s freckle Senile freckle Lentigo mlign Circumscried precncerous melnosis of Dureuilh Dureuilh s melnosis circumscript precnceros Pgetoid melnom Premlignnt melnosis Circumscried precncerous melnosis of Dureuilh Dureuilh s melnosis circumscript precnceros) In situ melnom Lentigo mlign melnom Supericil spreding melnom Pgetoid melnom Melnom with n in situ component Nodulr melnom Melnom d emlée

3 Documento descrgdo de el 04/04/2017. Copi pr uso personl, se prohíe l trnsmisión de este documento por culquier medio o formto. But... Ws There Ever Clrk Clssiiction of Melnoms? 21 greed nomenclture is shown in Tle 1. The terminology recommended for the clssifiction of melnoms nd the other recommendtions, including the level of invsion, were lrgely sed on 4 ppers pulished in the yers leding up to the meeting, of which were uthored y Clrk s group. 2-4 The first of these ppers ws chpter in ook pulished in This ws followed in 1969 y 2 rticles (1 in Mrch signed y Clrk, From, Bernrdino, nd Mihm 3 nd nother in April signed y Clrk nd Mihm 4 ). The first of these rticles reported on 209 cses of which 114 were clssified s superficil spreding melnom (SSM), 66 s nodulr melnom (NM), nd 29 s lentigo mlign melnom (LMM). The uthors considered NM to e melnom in which they oserved fter exmintion of mny histologic sections tht intrepiderml growth, when present, did not extend more thn 3 rete ridges outside the intrderml component of the tumor in ny of the sections studied. In ppernce NM ws nodule, tht is, clerly elevted plque or n exophytic nd often ulcerted lesion without ny flt component round the centrl mss. This presenttion ws found in 30% of the ptients in tht cse series. The other 70% of cses ll presented more or less flt component of greter or lesser extension. The clinicl chrcteristics (shpe, surfce, nd color) of this component were then used to divide these nonnodulr cses into 2 groups, defined s SSM nd LMM. However, despite estlishing series of criteri with respect to these mcroscopic chrcteristics, the uthors lso stted tht: Histologic sections representing the vrious gross ptterns of the primry lesion re necessry for ccurte dignosis nd clssifiction of mlignnt melnom. Aout 70% of melnoms (SSM nd LMM) hve significnt portion of the primry lesion present either intrepidermlly or just elow the sement memrne. It is the evlution of these superficil cells tht determines the clssifiction of melnom [...]. 3 And wht re the chrcteristics of this superficil portion of the melnom whose scnt presence or totl sence would clssify cse of melnom s NM nd Tle 2 Chrcteristics of the Intrepiderml Component of Supericil Spreding Melnom nd Lentigo Mlign Melnom According to Clrk et l SSM LMM 1. Pgetoid growth 1. Pgetoid growth is very uncommon Individul cells There my e nests Nests Msses 2. Grdul increse in the numer of sl melnocytes 2. NA until these replce the whole sl lyer 3. Epithelioid melnocytes 3. Some cells re norml, others hve lrge nuclei, (undnt cytoplsm with dusty melnin) nd occsionlly some re multinucleted 4. While clerly norml, the melnocytes re 4. Cell pleomorphism c nonetheless similr one to nother c Arevitions: LMM, lentigo mlign melnom; NA, not pplicle; SSM, supericil spreding melnom. Dt derived from Clrk et l. 3 Pgetoid growth: reltively lrge single melnom cells distriuted throughout ll levels of the epidermis including the strtum corneum; generlly ssocited with clerly deined nests of such cells. Nests my merge nd even replce lmost the whole kertinocyte popultion (msses). c Cytology. Although the tumor cells of SSM re clerly norml, contiguous cells tend to e similr, which is in contrst to lentigo mlign melnom where there is more vrition in cell structure. In LMM, the melnocytes my vry mrkedly in form; some pper essentilly norml; others hve lrge nuclei or my e multinucleted. Tle 3 Levels of Invsion nd Outcomes No. of % (Yers of Follow-up) Dt derived from Clrk et l. 3 In 208 of the 209 ptients it ws possile to determine the level of invsion ccording to the criteri shown in the tle. The percentges of ptients who died nd survived on ech level do not dd up to 100. The missing cses re ptients who died from other cuses or were lost to follow-up. c Deths from melnom. d Survivors pprently free from neoplstic disese. Cses Deths c Survivors d,1. Level I (melnom in situ) 0 Level II (prtil invsion of the ppillry dermis) (1.5) 72.2 (6.8) Level III (totl invsion of the ppillry dermis ) (2.8) 46.5 (6.8) Level IV (invsion of the reticulr dermis) (2.2) 31.6 (5.2) Level V (invsion of the hypodermis) (1.8) 12.0 (3.5)

4 Documento descrgdo de el 04/04/2017. Copi pr uso personl, se prohíe l trnsmisión de este documento por culquier medio o formto. 22 E. Sánchez Yus et l whose presence llows us to distinguish etween SSM nd LMM? Tle 2 summrizes the chrcteristics ttriuted y the uthors to this intrepiderml component in SSM nd LMM nd includes their definitions of some terms we elieve to e essentil to good understnding of their hypothesis. As well s clssifying their cses y histology, they lso clssified the lesions ccording to the level of invsion Tle 4 Histologic Clssiiction of the 209 Cses of Melnom Studied y Clrk et l 3 with Age nd Outcome for Ech Type of Melnom No (%) Age, y % Arevitions: LMM, lentigo mlign melnom; NM, nodulr melnom; SSM, supericil spreding melnom. Dt derived from Clrk et l. 3 The percentges of deths nd surviving ptients for ech type of melnom do not dd up to 100. The missing cses re ptients who died from other cuses or were lost to follow-up. Men follow-up ws 6 to 6.5 yers for ptients with SSM nd NM, nd 4.75 yers for ptients with LMM. Survivors pprently free of neoplstic disese. c Deths from melnom. Rnge (men) Survivors Deths c SSM 114 (54.5) (52.9) NM 66 (31.6) (51.8) LMM 29 (13.9) (70.0) Tle 5 Distriution of Melnom in the Cses Studied y Clrk et l SSM NM LMM Totl Sclp Hed nd neck Chest Bck (ove wist) Upper rm Forerm nd dorsum hnd Hnd (plm) Hnd (suungul) Adomen Bck (elow wist) Genitls Thigh Lower leg Dorsum foot Sole of foot Foot (suungul) Unknown 4 4 Totl Arevitions: LMM, lentigo mlign melnom; NM, nodulr melnom; SSM, supericil spreding melnom. Dt derived from Clrk et l. 3 The totl numers do not coincide with those of erlier tles (there re 5 more melnom cses). This tle is sed on histogrm in which the rs re not ccompnied y igures nd the height of the r on the scle is often dificult to determine. This tle nd Tles 2-4 were compiled, sometimes with dificulty, using the dt reported in the pper y Clrk et l. 3 nd scertined tht the prognosis deteriorted with incresing depth of invsion (Tle 3). Tle 4 summrizes the histologic clssifiction of the 209 cses together with the ptients ges nd the outcome in ech cse. Tle 5 summrizes the dt on the sites of the tumors. On the sis of this study, the uthors concluded: The mjority of humn mlignnt melnoms (superficil spreding nd lentigo mlign melnom) re chrcterized y reltively long period of centrifuglly spreding, superficil growth (intrepiderml or just elow the sement memrne) [...] 3 Lentigo mlign melnom is iologic entity, ut re we justified in dividing the remining melnoms into two distinct groups? [ ] This view then regrds nodulr melnom s quite mlignnt neoplsm from the outset, ut it is proly not different iologic entity when compred with superficil spreding melnom. 3 They summrized their clssifiction of melnom into 3 distinct forms s follows: First, we lso distinguish lentigo mlign melnom s slowly growing, reltively enign neoplsm usully on the exposed surfces of the elderly. 3 Secondly, we feel tht nother form of melnom, superficil spreding melnom, lso shows reltively long period (6 months to 5 yers) of superficil growth nd then develops tumor nodules nd deep invsion. 3 Third, those tumors showing nodulr form nd tendency to deep invsion from the outset were termed nodulr melnom. 3 The second rticle from 1969 is monogrph on 1 of the 3 types of melnom descried in the erlier rticle: LMM nd its initil phse, lentigo mlign. 4 The uthors strt y sying: This pper will descrie lentigo-mlign (L-M) melnom (Hutchinson s melnotic freckle or circumscried precncerous melnosis of Dureuilh). This kind of mlignnt melnom egins s smll, irregulr, freckle-like lesion nd then evolves over mny yers in distinctive wy to ecome n invsive mlignnt melnom distinguishle from the other forms of melnom. The erly, noninvsive stges of the process similr to freckle will e referred to s lentigo mlign nd the lter invsive stges s L-M melnom; this mlignnt melnom occurs lmost exclusively on exposed surfces of the ody nd hs etter prognosis thn other forms of melnom. 4 In the following descriptions lentigo mlign nd L-M melnom re t times considered seprtely, ut in spite of this division for descriptive purposes, we regrd these two lesions s representing the erly nd lte stges of single process. The sole criterion seprting lentigo mlign from L-M melnom is the presence of invsion in the ltter. 4 The study ws sed on 13 cses of lentigo mlign nd 35 of LMM. Tle 6, which is sed on the informtion reported

5 Documento descrgdo de el 04/04/2017. Copi pr uso personl, se prohíe l trnsmisión de este documento por culquier medio o formto. But... Ws There Ever Clrk Clssiiction of Melnoms? 23 Tle 6 Clinicl Fetures of the 13 Cses of Lentigo Mlign nd 35 Cses of Lentigo Mlign Melnom (LMM) Studied y Clrk nd Mihn Lentigo Mlign LMM Numer of cses 13 lesions/13 ptients 37 lesions/35 ptients Men ge on dignosis (45 96) Men ge t onset Intervl elpsed efore lentigo mlign ecme LMM 4 months 50 yers Men size, cm 2.7 ( ) 8.4 ( ) Site Fce nd neck Bck 1 1 Forerm 1 Dorsum of the hnd 2 Pretiil 2 Survivl Deths cused y LMM 3 Survivors with lymph node metstsis 3 Helthy survivors 18 Deths ttriutle to other cuses 9 Lost to follow-up 5 Arevitions: LMM, lentigo mlign melnom. Dt derived from Clrk nd Mihn. 4 At 8 yers nd 2 months, t 1 yer nd 10 months, nd t 1 yer nd 9 months fter histologic dignosis. Tle 7 Histologic Differences Between the Intrepiderml Components of Supericil Spreding Melnom nd Lentigo Mlign Melnom According to Clrk nd Mihm SSM LMM Pgetoid distriution Common Rre Nests Found in lmost ll sections Less common Melnocytes (typi) Although totlly norml, the cells re Mrked pleomorphism with cells rnging from similr one to nother (ll eqully d). norml to totlly typicl nd multinucleted Dominnt cytology Epithelioid Spindle-shped Cytology Lrge cells with undnt cytoplsm Lrge cells with scnt cytoplsm nd lrge nucleus nd lrge nucleus Arevitions: LMM, lentigo mlign melnom; SSM, supericil spreding melnom. Dt derived from Clrk nd Mihm. 4 in the rticle, summrizes the clinicl dt for these cses. The uthors undertook very meticulous histologic study of ech of the clinicl res of the lesion s identified y differences in tonlity (cinnmon, rown, reticulted lck, flt lck, etc). They then list the clinicl nd histologic differences etween LMM nd SSM. Tle 7 summrizes the histologic differences, which re the most importnt type since the uthors sserted tht numerous sections of these intrepiderml portions re necessry to differentite etween the 2 processes. They conclude y sying: Lentigo mlign nd lentigo-mlign melnom re nmes pplied to erly nd lte stges of the sme neoplstic system ffecting melnocytes; lentigo mlign pplies to the noninvsive stge nd lentigo-mlign melnom to the invsive neoplsm. 4 In 1977, on the sis of study of 33 plntr melnoms from the records of hospitl in New Orlens, Arrington et l 6 concluded tht: [...] there re vrints of cutneous melnom tht re not dequtely defined y the preceding prmeters nd hve not een included in current clssifictions. In prticulr, melnoms of soles re distinctive. Twenty-seven of the 33 cses hd lentiginous rdil component nd the other 6 were considered unclssifile. Tle 8 summrizes the clinicl chrcteristics nd outcomes of these 27 cses. The uthors of tht study remrked on the mrked histologic similrity etween these plntr melnoms nd lentigo mlign nd on the fct tht severl uthors hd reported on cses of lentigo mlign ffecting the mucosl memrnes nd suungul region. As result, they concluded tht there ws... nonctinic lentiginous vrint of melnom tht occurs on the plms nd soles, the suungul res, the muco-cutneous junction of the orl nd nsl cvities nd the nus. 6 They compiled tle to compre the histologic fetures of their cses of plntr lentiginous melnom with those of the other 2

6 Documento descrgdo de el 04/04/2017. Copi pr uso personl, se prohíe l trnsmisión de este documento por culquier medio o formto. 24 E. Sánchez Yus et l types of melnom with rdil component tht hd een descried y Clrk s group (Tle 9). In 1979, Clrk, Goldmn nd Mstrngelo edited ook entitled Humn Mlignnt Melnom 7 with chpters on ll spects of oculr nd cutneous melnom. In chpter 4, 8 Elder, Ainsworth, nd Clrk reviewed the histopthology of SSM, NM, nd LMM nd, in contrst to their erlier rticles, now sserted tht: Difficulty my e encountered from time to time in histologic distinction mong the vrious forms of melnom ctegorized ove, ut if clinicl s well s histologic prmeters re ssessed, differentitions is not usully prolem 8 In chpter 5 of the sme ook, Clrk, Berndino, Reed, nd Kopf 9 reviewed the clinicl nd histologic chrcteristics of wht they cll crl lentiginous melnom (ALM), which included, s Arrington et l 6 hd indicted, melnoms ffecting the plms, soles, nil ed, nd mucous memrnes, since: Tle 8 Clinicl Chrcteristics nd Outcomes of the 27 Cses of Plntr Melnom with Rdil Component Studied y Arrington et l Sex 16 M/11 F Men ge 63.4 t dignosis, y Men durtion 30.6 of lesions, mo Size, cm 2.7 ( ) Deths from melnom, n Level II 2 0 III 9 7 IV 6 6 V 10 5 Totl Arevitions: M, mle; F, femle. Dt derived from Arrington et l. 6 Mlignnt melnoms of the superficil spreding nd nodulr vrieties occur uncommonly in the volr nd suungul sites. 9 Thirty-seven (5.6%) of the 636 cutneous melnoms studied y the Temple University Group occurred in volr (70%) nd suungul (30%) sites. At the end of the chpter the uthors summrized the histologic fetures of the rdil growth phses of ALM, SSM, nd LMM in tle (Tle 10). Hving reched this juncture the point y which Clrk nd his collegues hd recognized the 4 types of cutneous melnom tht mke up their fmous clssifiction we will once gin summrize the criteri they used to distinguish ech vrint: when little or no intrepiderml growth is present, the lesion is clssified s NM; nd when such growth extends eyond the width of 3 rete ridges, the histologic nd cytologic fetures of the intrepiderml component cn e used to clssify the nonnodulr melnom s SSM, LMM, or ALM. 2-4,8,9 In 1969, Clrk et l 3 nd Clrk nd Mihm 4 explined the chrcteristics tht llowed them to differentite etween SSM nd LMM; these re summrized in Tles 2 nd 7. Arrington nd collegues 6 (one of whom ws Reed) lter identified new vrint which, in their opinion, ws not dequtely covered y the estlished criteri. This new vrint, which they clled plntr lentiginous melnom, ws found only on the plms nd soles, the suungul res, nd the muco-cutneous junctions. In 1979, Clrk nd collegues 9 (once gin including Reed) ccepted this new vrint, which they clled ALM. Both working groups summrized in tulr form the histologic fetures of this new vrint nd the differences etween it nd the 2 forms defined erlier; these tles re reproduced in Tles 9 nd 10 of the present rticle. The first spect evluted in these 4 tles ws usully the growth pttern of the tumor cells within the epidermis. Clrk et l 3 used the term pgetoid distriution (single cells, nests, nd msses) in SSM nd compred this to grdul increse in the numer of sl melnocytes until they virtully replce the sl kertinocytes in LMM. Clrk nd Mihm 4 ssert tht pgetoid distriution is common in SMM nd rre in LMM. Arrington et l 6 contrst the pgetoid growth pttern in SSM to the lentiginous pttern in LMM nd plntr lentiginous melnom. Clrk et Tle 9 Histologic Fetures of Melnoms With Rdil Component According to Arrington et l SSM LMM PLM Pttern Pgetoid Lentiginous Lentiginous Shpe of melnocytes in epidermis Epithelioid Spindle nd epithelioid Spindle, epithelioid, nd izrre Atypi of melnocytes Uniform Vrile Vrile Dendritic processes Not prominent Prominent Prominent Epiderml invsion Prominent Not prominent Occsionlly prominent Epidermis Hyperplstic Atrophic Mrkedly hyperplstic Ppillry dermis Widened nd inlmed Norml thickness Widened nd inlmed Usul shpe of iniltrting melnom cell Epithelioid Spindle Spindle nd epithelioid Actinic dmge in dermis (occsionl, Occsionlly present Invrily present Asent invrile, or sent) Arevitions: LMM, lentigo mlign melnom; PLM, plntr lentiginous melnom; SSM, supericil spreding melnom. Source Arrington et l. 6

7 Documento descrgdo de el 04/04/2017. Copi pr uso personl, se prohíe l trnsmisión de este documento por culquier medio o formto. But... Ws There Ever Clrk Clssiiction of Melnoms? 25 Tle 10 Comprtive Histologic Fetures of the Rdil Growth Phses of Supericil Spreding, Lentigo Mlign, nd Acrl Lentiginous Types of Melnom ccording to Clrk et l SSM LMM ALM Loction of melnom cells All epiderml lyers Bsilr region Bsilr region within the epidermis Cytology of the individully Uniformly lrge epithelioid Pleomorphic norml nd Uniformly lrge with disposed intrepiderml cells without prominent izrre melnocytes mixed. prominent, complex dendrites melnocytes dendrites Dendrites inconspicuous Histology of the intrepiderml Nests quite lrge frequently Nests my e ellipsoidl in Nests tend to ulge into nests of melnocytes ridging the entire outline with the long xis dermis. thickness of the epidermis tending to prllel the epiderml surfce Cytology of the melnocytes Uniformly lrge epithelioid Cells re pleomorphic, Cells tend to e spindle-shped forming the intrepiderml cells form the nests. some quite smll, others nd my e epithelioid nests lrge nd izrre. Invsion of the ppillry dermis Esily demonstrted Essentilly sent Present, ut my require serch to ind it Solr chnges in connective Vrile Present Asent tissue Host response of lymphocytes Usully well developed Miniml to sent Present nd prominent with nd mcrophges extension into epidermis Arevitions: ALM, crl lentiginous melnom; LMM, lentigo mlign melnom; NM, nodulr melnom; SSM, supericil spreding melnom. Source Clrk et l. 9 The only difference etween this tle nd the originl is the order of the columns (in the originl the order ws ALM, LMM, nd SSM). This chnge ws mde to ensure tht ll the tles in the present rticle followed the sme order (SSM, NM, LMM, ALM) to fcilitte comprisons. Tle 11 Cytology of the Intrepiderml Melnocytes in Ech Type of Melnom According to Different Ppers SSM LMM ALM Clrk et l 3 Epithelioid? Clrk nd Mihm 4 Epithelioid Spindle-shped with scnt cytoplsm Arrington et l 6 Epithelioid without Spindle-shped nd epithelioid cells Spindle-shped, epithelioid, nd prominent dendrites with prominent dendrites izrre cells with prominent dendrites Clrk et l 9 Individul cells Epithelioid without Norml to izrre, without Epithelioid cells with prominent prominent dendrites conspicuous dendrites dendrites In Nest s Epithelioid From smll to lrge nd izrre Spindle-shped or epithelioid cells Arevitions: ALM, crl lentiginous melnom; LMM, lentigo mlign melnom; SSM, supericil spreding melnom. Plntr lentiginous melnom in the terminology used y Arrington. l 9 do not use the sme terms, ut do use equivlents when they sy tht typicl melnocytes re found throughout ll the lyers in SSM nd only in the silr region in LMM nd ALM (plntr lentiginous melnom ccording to Arrington s terminology). It ppers, therefore, tht the 4 tles re consistent in this respect nd tht we cn summrize y sying tht SSM is chrcterized y pget oid pt t ern wheres in LMM nd ALM prolifertion is sid to e lent iginous. And wht re they like, the tumor cells tht proliferte in this wy within the epidermis? In generl, the uthors cited ove ssess the chrcteristics of these cells oth collectively nd individully. When considering the cells collectively, they evlute whether the melnocytes constitute more or less uniform group or whether the popultion is essentilly heterogeneous. Clrk et l 3 (Tle 2) found the melnocytes in SSM to e uniformly typicl (tht is, ll of them were eqully d ). In LMM, on the other hnd, they found the popultion to e extremely vried in shpe nd they use the term cell pleomorphism. Clrk nd Mihm 4 used the sme terms, while Arrington et l 6 tlk out uniform melnocytic typi in SSM nd vrile typi in LMM nd plntr lentiginous melnom (Tle 9). In the lter pper, Clrk et l 9 sserted tht the typicl melnocytes were uniformly lrge in SSM nd ALM s opposed to pleomorphic in LMM, nd tht in ALM when the melnocytes formed nests the cells could e spindleshped or epithelioid (Tle 10).

8 Documento descrgdo de el 04/04/2017. Copi pr uso personl, se prohíe l trnsmisión de este documento por culquier medio o formto. 26 E. Sánchez Yus et l There ppers to e n inconsistency etween Tles 9 nd 10 concerning this spect of the cytology of melnom (in Tle 9, the cytology of plntr lentiginous melnom is vrile, while in Tle 10 the cytology of ALM the equivlent form is uniform). Aprt from this contrdiction, however, the terminology used is lrgely the sme: in some cses, the typicl melnocytes re similr or uniform nd in others the typi is vrile or pleomorphic. We cn, therefore, dopt the terminology of uniform t ypi s opposed to pleomorphic t ypi. Together with this collective evlution of the cytology we lso find description of the individul cells. In the cse of SSM, Clrk et l 3 repetedly cite the presence of epithelioid melnocytes with undnt cytoplsm nd dusty melnin grnules. In LMM, however, they descrie the melnocytes s pleomorphic nd sy tht some pper essentilly norml while others hve lrge nuclei or my e multinucleted. From this we deduce (lthough they do not explicitly sy s much) tht the cytoplsm of these cells is scnt with respect to the nucleus. Clrk nd Mihm 4 re more explicit nd descrie lrge, predominntly epithelioid cells with undnt cytoplsm nd lrge nuclei in SSM, nd lrge, predominntly spindle-shped cells with scnt cytoplsm nd lrge nuclei in LMM. Arrington et l 6 tlk out epithelioid melnocytes without prominent dendrites in SSM, spindle-shped nd epithelioid melnocytes with prominent dendrites in LMM, nd spindle-shped, epithelioid, nd typicl melnocytes, lso with prominent dendrites, in plntr lentiginous melnom. According to Clrk et l, 9 the isolted intrepiderml melnocytes re epithelioid nd without dendrites in SSM, norml to izrre without conspicuous dendrites in LMM, nd in ALM they re uniformly lrge with prominent dendrites nd the cells tht form nests tend to e spindle-shped lthough they cn e epithelioid. With respect to the cytology of the single cells found in the intrepiderml component of melnoms, there ppers to e considerle difference of opinion mong the different uthors. The only feture common to ll the ccounts is tht the melnocytes of SSM re epithelioid, tht is, they hve undnt cytoplsm nd no dendrites. According to Clrk nd Mihm 4 the melnocytes in LMM when not lmost norml hve lrge nucleus nd scnt cytoplsm nd re predominntly spindle-shped. However, Arrington et l 6 descrie these cells s spindle-shped nd epithelioid with prominent dendrites, nd Clrk et l 9 descrie them s norml to typicl, without conspicuous dendrites. Arrington et l 6 descrie the typicl melnocytes of plntr lentiginous melnom s spindle-shped nd epithelioid with prominent dendrites, wheres Clrk et l 9 descrie these cells s uniformly lrge with prominent dendrites when isolted ut tending to e spindle-shped when they re clustered in nests, lthough the cells in nests cn lso e epithelioid. These differences re summrized in Tle 11 for greter clrity. We cn summrize this tle y sying tht Arrington et l 6 found only slight differences etween LMM nd ALM, wheres Clrk et l 9 found differences, even though it is impossile to rrive t simple conclusion ecuse of the vriility of the cell morphology within ech type. However, if we confine ourselves to the repetition of the term spindle-shped with respect to LMM (Clrk nd Mihm 4 nd Arrington et l 6 ) nd to the terms epithelioid nd spindle-shped when tlking out ALM (Arrington et l 6 nd Clrk et l 9 ), we cn conclude tht the predominnt cytology in ech vrint of melnom my e epit helioid in SSM, spindle-shped in LMM, nd oth in ALM. In the cse of dendrites, these pper to e sent in SSM, present in ALM nd, t lest, vrile in LMM. Clrk et l 3 nd Clrk nd Mihm 4 contrst the frequent (lmost constnt) presence of int repiderml nest s (t times very lrge) of typicl melnocytes in SSM with the scnt presence (or lower frequency) of such nests in LMM. Arrington et l 6 do not ssess this spect (Tle 9), while Clrk et l 9 descrie seprtely, lthough with few differences, the cytology of the isolted typicl melnocytes nd tht of the melnocytes grouped into nests. They do not, however, report on the frequency with which nests pper in ech one of the 3 melnom sutypes (Tle 10). With respect to the size nd shpe of the nests, those found in SSM re descried s quite lrge ( frequently ridging the entire thickness of the epidermis ), while in LMM they my e ellipsoidl in outline with the long xis tending to prllel the epiderml surfce, nd in ALM they tend to ulge into the dermis (Tle 10). It is difficult to compre these 3 descriptions since the first refers to size, the second to shpe, nd the third to the loction of the nest. Extrpolting from the informtion provided, we could sy tht the nests found in LMM nd ALM re not usully lrge, nd tht those found in SSM nd ALM re not usully ellipsoidl in outline or horizontl (nd will therefore tend to e rounded). Likewise, we cn deduce tht in SSM nd LMM the nests do not usully ulge into the dermis nd will therefore tend to e locted within the strtum spinosum. We hve tried to summrize this informtion in Tle 12. Only Arrington et l 6 ssessed the epidermis, which they found to e hyperplstic in SSM, trophic in LMM, nd very hyperplstic in plntr lentiginous melnom. Tle 12 Chrcteristics of the Intrepiderml Nests of Melnoms According to the Authors Cited Arevitions: ALM, crl lentiginous melnom; LMM, lentigo mlign melnom; SSM, supericil spreding melnom. Dt derived from Clrk et l, 3 Clrk nd Mihm, 4 Arrington et l, 6 nd Clrk et l. 9 Hnging = ulging into the dermis. SSM LMM ALM Numer More common Less common? Size Lrge Not lrge Not lrge Shpe Round Ellipsoidl nd horizontl Round Site Not hnging Not hnging Hnging

9 Documento descrgdo de el 04/04/2017. Copi pr uso personl, se prohíe l trnsmisión de este documento por culquier medio o formto. But... Ws There Ever Clrk Clssiiction of Melnoms? 27 Tle 13 Summry of the Structurl nd Cytologic Fetures of the Intrepiderml Component of Primry Nonnodulr Cutneous Melnoms According to Clrk et l, 3 Clrk nd Mihm, 4 Arrington et l, 6 nd Clrk et l 9 SSM LMM ALM Pttern Pgetoid Lentiginous Lentiginous Melnocytic typi Uniform Pleomorphic Uniform (Clrk). Pleomorphic (Arrington) Predominnt cytology Epithelioid Spindle-shped Epithelioid nd spindle-shped Dendrites Asent Vrile Prominent Nests Numer Very common Less common? Size Lrge Not lrge Not lrge Shpe Round Ellipsoid nd horizontl Round Site Not hnging Not hnging Hnging Epidermis Hyperplstic Atrophic Very hyperplstic Actinic dmge to the dermis Occsionl Present Asent Arevitions: ALM, crl lentiginous melnom; LMM, lentigo mlign melnom; SSM, supericil spreding melnom. Hnging = ulging into the dermis Tle 14 Summry of the Structurl nd Cytologic Fetures of the Intrepiderml Component of Primry Nonnodulr Cutneous Melnoms According to Clrk et l, 3 Clrk nd Mihm, 4 Arrington et l, 6 Clrk et l, 9 nd Clrk et l 10, Arevitions: ALM, crl lentiginous melnom; LMM, lentigo mlign melnom; SSM, supericil spreding melnom. The words in itlics re fetures reported y Clrk et l in tht differ from those descried in his erlier ppers (see Tle 13). This pttern is uncommon in melnom in situ. 10 c Hnging = ulging into the dermis SSM LMM ALM Pttern Pgetoid. Lentiginous Lent iginous. Somet imes Not except ionlly, pget oid sl nd 1-4 cells t hick Melnocytic typi Uniform Pleomorphic. Slight ly Uniform (Clrk). Pleomorphic pleomorphic (Arrington) Predominnt cytology Epithelioid Spindle-shped Epithelioid nd spindle-shped Dendrites Asent Vrile. Asent Prominent Nests Numer Very common Less common. Common Scnt? Size Lrge Not lrge Not lrge Shpe Round Ellipsoidl nd horizontl Round Site Not hnging c Not hnging. Hnging Hnging Epidermis Hyperplstic Atrophic Very hyperplstic Actinic dmge to the dermis Occsionl Present. Modert e t o severe Asent Neither Clrk et l 3 nor Clrk nd Mihm 4 ssessed ctinic dmge in the dermis. However, fter Arrington et l 6 pulished their ssessment of ctinic dmge, Clrk et l 9 lso evluted this spect. Both groups found ctinic dmge to e occsionl or vrile in SSM, lwys present in LMM, nd invrily sent in ALM. Tle 13 summrizes ll the ove findings. In order to check whether Clrk nd his group susequently chnged, clrified, or refined ny of the criteri they hd defined etween 1969 nd 1979, we reviewed chpter 49 (entitled Dysplstic Nevus nd Mlignnt Melnom) of the ook Pt hology of t he Skin edited y Frmer nd Hood in 1990; Clrk, Elder, nd Guerry re the uthors of the chpter in question. 10 In this chpter, the description of the histology of SSM is similr to tht pulished in the erlier rticles, with 2 exceptions: 1. It is uncommon to see this distinctive pttern of melnom [tht of SSM] without invsion One importnt vrint histology of this prticulr rdil growth phse lcks the distinctive pttern of pgetoid intrepiderml growth [of SSM]. [ ] The melnom cells re usully seen s lyer of contiguous cells t the dermoepiderml interfce. [ ] More commonly there is lyer two to four cells thick seprting the kertinocytic epidermis, ove, from the dermis, elow [...] frequently ssocited with effcement of the rete ridges. In such cses, the cells re [...] somewht smller thn those of the clssic histologic picture. [ ] This vrint pttern is commonly, ut not exclusively, seen in lesions of the lower lims. 10 With respect to LMM, the uthors once gin refer to the silr distriution of the norml cells. They stte tht:

10 Documento descrgdo de el 04/04/2017. Copi pr uso personl, se prohíe l trnsmisión de este documento por culquier medio o formto. 28 E. Sánchez Yus et l [...] [the epidermis] my e of norml thickness, or trophic, reflecting the cutneous phenotype, solr dmge, nd the ge of ptients who develop this form of melnom. The tumor cells re disposed in smll nests, which extend down from the epidermis into the ppillry dermis without overt invsion. [ ] The cells composing the nests tend to e smll, slightly pleomorphic, nd exhiit diminished cohesiveness. [ ] [The isolted single cells] my e numerous nd lmost contiguous ut re often moderte in numer nd clerly seprte from ech other. [...] The dermis lmost lwys shows moderte to dvnced solr degenertion. 10 In the cse of ALM, they sy: The cells tend to e in the silr epiderml region [...]. The individul cells my show well-preserved dendrites [...]. Epithelioid melnocytes re lso seen nd [...] my grow upwrd nd e similr in ppernce to superficil spreding melnom. 10 We see, in light of these descriptions, tht we cn mke some modifictions to Tle 13 nd dd some detils: The distinctive pttern of SSM is uncommon in melnom in situ. An undetermined numer of cses of SSM (ut not smll numer ecuse this histologicl vrint is commonly seen in the lower lims, one of the min sites for melnom, prticulrly mong women) feture distinctive lentiginous pttern tht tkes the form of lyer of contiguous cells t the dermoepiderml junction (which we cll sl frieze pttern). Melnocytic typi is only slightly pleomorphic in LMM (wheres the presence of cell pleomorphism hd, since 1969, een one of the chrcteristics tht distinguished LMM from SSM). Dendrites re not chrcteristic of LMM. Nests re only rrely found in ALM. The nests in LMM re now descried s hnging from the epidermis (extending down into the ppillry dermis) wheres in previous ppers this hd only een chrcteristic of ALM. Now, with respect to ALM, the uthors only sy tht nests re rre. The thickness of the epidermis in LMM ppers to e independent of the tumor nd consequence of other, essentilly exogenous, fctors. The severity of ctinic dmge in LMM is quntified, lthough logiclly such dmge is consequence of the site of the lesion nd not of the melnom itself. Tle 14 is repetition of Tle 13 with the ddition, in itlics, of the informtion tht represents divergence etween the content of Tle 13 nd the lter chpter y Clrk et l. 10 In light of the ove, we cn conclude tht our ttempts to determine the chrcteristics which, ccording to Clrk nd his collegues, llow us to differentite with some precision etween one type of nonnodulr melnom nd nother hs filed: the distinctive pttern of SSM is uncommon nd, furthermore, new pttern hs een identified tht tkes the form of sl lyer of cells 2 to 4 cells thick in frieze pttern. In other words, the most common type of melnom (>60%) often lcks ny unique histologic chrcteristics. With respect to the other 2 sutypes (LMM nd ALM), only the thickness of the epidermis nd the presence or sence of ctinic dmge to the dermis re sid to e conclusive, ut oth these chrcteristics re consequence of the site of the lesion nd not of the melnom itself. In view of this filure to estlish histologic clssifiction we must, s Elder et l 8 stted in 1978, turn to the clinicl picture. However, they do not tell us how to do this. When does histology override the clinicl findings? When is the clinicl presenttion more importnt thn histology? When 1 of the 2 predomintes over the other? Which cses cn e considered unclssifile when we hve no cler clssifiction criteri? A susequent review of the iliogrphy discussed ove led us to identify further contrdictions which we hd previously overlooked. 1. In the cse series tht formed the sis of the first rticle y Clrk et l 3 none of the cses were descried s unclssifile or difficult to clssify. Of the 209 cses studied, 32% were NM, 54% were SSM, nd 14% were LMM (Tle 4). 2. The clssifiction, s the uthors explined, ws definitively histologic: It is the evlution of these superficil cells tht determines the clssifiction of melnom [...]. 3 Although they concluded tht LMM ppers usully on the exposed surfces of the elderly, 3 the uthors do not tke site into ccount s fctor differentiting SSM from LMM: Of the 51 melnoms of the sclp nd neck, 18 were SSM nd 25 LMM. 4 LMM were locted on the lims: 2 on the forerm nd the dorsum of the hnd nd 2 on the legs They lso concluded tht lentigo mlign melnom ws slowly growing, reltively enign neoplsm [...]. 3 However, if we look more closely t Tle 4, we see tht the supposed enign nture of LMM is not supported y their dt since the percentge of disese-free survivors of SSM (46.5%) does not differ significntly from tht of disese-free survivors of LMM (55.2%). Moreover the 8.7% difference cn e ccounted for y the fct tht the men follow up ws 6 yers in SSM nd only 4.75 yers in LMM. Yers lter, Koh et l 11 (with Clrk nd Mihm mong the couthors) rectified this ssertion tht LMM is reltively enign neoplsm when they found the prognosis to e the sme for LMM s for other types of melnom of the sme thickness. 4. But the detil in this first rticle 3 tht prticulrly climed our ttention ws tht 6 of the 209 melnoms were locted on the plm, 25 on the soles, nd 4 in the nil ed. Of these 35 cses, 20 were clssified s SSM nd 15 s NM (none s LMM). Eight yers lter when Arrington et l 6 studied plntr melnoms, they highlighted the mrked histologic

11 Documento descrgdo de el 04/04/2017. Copi pr uso personl, se prohíe l trnsmisión de este documento por culquier medio o formto. But... Ws There Ever Clrk Clssiiction of Melnoms? 29 similrity etween such cses nd lentigo mlign nd concluded tht: [] nonctinic lentiginous vrint [of melnom] occurs on the plms nd soles, the suungul res, the muco-cutneous junction of the orl nd nsl cvities, nd the nus. 6 Those uthors used the term plntr lentiginous melnom to designte such cses. 6 Two yers lter, Clrk, Bernrdino, Reed, nd Kopf 9 integrted plntr lentiginous melnom into the roder concept of ALM, designtion tht included melnoms of the plms, soles of the feet, nil ed nd mucous memrnes, since: mlignnt melnoms of the superficil spreding nd nodulr vrieties occur uncommonly in the volr nd suungul sites. 9 In the cse series studied 8 yers erlier, ll the cses of melnom ffecting the plms, soles, nd nil ed (35 cses) were clssified s either nodulr (15 cses) or superficil spreding melnom (20 cses) Another interesting fct tht cn e glened from the dt shown in Tle 4 is tht the ptients with LMM re significntly older thn the other 2 groups of ptients. This is the finding tht gve rise to the conclusion in the rticle cited tht lentigo mlign melnom ws slowly growing, reltively enign neoplsm usully on the exposed surfces of the elderly. 3 However, the verge ge in the group of 27 ptients with plntr melnom studied y Arrington et l 6 ws 63.4 yers, nd this finding hs een clerly confirmed y lter studies In other words, LMM is not differentited from other melnoms in terms of prognosis 11 nd nor is it differentited from ALM y either ge of onset, 6,12-14 or structurl pttern (lentiginous in oth cses). 6,9 6. In the sme ook 7 tht includes the study y Clrk et l 9 on ALM, Elder, Ainsworth, nd Clrk 8 ssert tht: Difficulty my e encountered from time to time in histologic distinction mong the vrious forms of melnom ctegorized ove, ut if clinicl s well s histologic prmeters re ssessed, differentition is not usully prolem. 8 They do not, however, explin which clinicl prmeters should e tken into ccount in cses tht re difficult to clssify on the sis of histology: site, ge, morphology of the lesion, rte of evolution? 7. Ten yers lter, Clrk, Elder, nd Guerry 10 told us tht the distinctive histologic pttern of SSM is uncommon in the sence of invsion, in other words, in melnom in situ, nd tht, in ddition, other cses of SSM lck the distinctive pttern of pgetoid intrepiderml growth even during the rdil growth phse. They go on to sy tht the rdil growth phse is chrcterized y the horizontl plque-like growth tht we cll sl frieze pttern, which they descrie in detil. Nevertheless, they do not explin which ptterns they find in those melnoms in situ tht do not present the distinctive SSM pttern, ut which they, nonetheless, clssify s SSM, leding us to pose the question: On wht sis do they mke such clssifiction? Conclusions NM is only distinguished from SSM y the numer of ridges ffected y the in situ component: if 3 or less ridges re ffected, disese is clssified s NM nd if 4 or more re ffected, s SSM. LMM nd ALM re only differentited y site: if the melnom ffects the plms, soles, nil ed, or semimucosl memrnes, it is ALM, if it occurs in ny other prt of the ody, it is clssified s LMM. The distinctive pgetoid pttern of SSM is uncommon in melnom in situ. A not insignificnt numer of cses of SSM re chrcterized y distinctive horizontl lentiginous growth pttern, which we cll sl frieze pttern. This historicl review of Clrk s supposed clssifiction of cutneous melnoms rose when one of our group (MH) ttempted to clssify cses of melnom using Clrk s criteri in the course of doctorl thesis. After mny ded ends nd returns to squre one, we were mzed to discover tht Clrk s criteri did not in fct relly exist or, more precisely, tht they hd chnged over time nd, even more worrying, hd een progressively diluted. Once it hd een estlished tht melnoms ffecting the lest exposed res of our skin the soles of the feet were similr to those of the fce in oth clinicl nd histologic morphology nd with respect to ge of onset nd prognosis, the ttempt to clssify melnoms using Clrk s criteri should hve een ndoned forthwith. The only ctegory still extnt t this point ws SSM, ut even Clrk 8,10 himself progressively questioned nd douted the histologic uniqueness of this ctegory. After this review of the history of this clssifiction, our response to the question posed in the title of this rticle must e tht yes, in Clrk et l 2-4 clssified cutneous melnoms into 3 groups MN, SSM, nd LMM ut tht in succeeding yers fter this the sme group of uthors dismntled the clssifiction piece y piece. 8,10 Wht remins inexplicle is why most uthors, with few exceptions, hve continued to use Clrk s clssifiction system in their ppers to the present dy. We elieve tht it ws the identifiction of LMM, thought to e type of melnom with distinctive clinicl chrcteristics (slow growing with long in situ phse nd frequent zones of regression, lte onset in photoexposed res of the ody nd supposedly with etter prognosis), tht led Clrk nd his collegues to ttempt to drw up clssifiction with prognostic implictions. However, s we hve seen, mny melnoms ffecting nonphotoexposed res (the soles of the feet) hve the sme clinicl nd histologic (lentiginous) fetures supposedly chrcteristic of LMM, nd t the sme thickness there is no difference in prognosis etween the 2 vrints. When this fct ws estlished in 1984, 11 the clssifiction system first devised in 1964 y Clrk should hve een

12 Documento descrgdo de el 04/04/2017. Copi pr uso personl, se prohíe l trnsmisión de este documento por culquier medio o formto. 30 E. Sánchez Yus et l ndoned. 2 Recent studies pper to indicte tht melnoms will in future e clssified on the sis of genetics nd moleculr iology. 21 We encourge our reders to never lose their criticl sense when evluting new hypotheses s we elieve most clinicins did when evluting Clrk s supposed system for clssifying melnoms. Conlict of Interest The uthors declre no conflicts of interest. References 1. McGovern VJ, Mihm MC, Billo C, et l. The clssiiction of mlignnt melnom nd its histologic reporting. Cncer. 1973;32: Clrk WH. A clssiiction of mlignnt melnom in mn correlted with histogenesis nd iologicl ehviour. In: Montgn W., Hu F., editors. Advnces in iology of the skin, the pigmentry system. London: Pergmon Press Ltd.; p Clrk WH, From L, Bernrdino E, Mihm MC. The histogenesis nd iologic ehviour of primry humn mlignnt melnoms of the skin. Cncer Res. 1969;29: Clrk WH, Mihm MC. Lentigo mlign nd lentigo mlign melnom. Am J Pthol. 1969;55: Mc Govern VJ. The clssiiction of melnom nd its reltionship with prognosis. Pthology. 1970; 2: Arrington JH, Reed RJ, Ichinose H, Krementz ET. Plntr lentiginous melnom. A distinctive vrint of cutneous mlignnt melnom. Am J Surg Pthol. 1977;1: Clrk WH, Goldmn LI, Mstrngelo MJ. Humn mlignnt melnom. New York: Grune & Strtton; Elder DE, Ainsworth AM, Clrk WH. The surgicl pthology of cutneous mlignnt melnom. In: Clrk W.H., Goldmn L.I., Mstrngelo M.J., editors. Humn mlignnt melnom. New York: Grune & Strtton; p Clrk WH, Bernrdino EA, Reed RJ, Kopf AW. Acrl lentiginous melnoms. In: Clrk WH, Goldmn LI, Mstrngelo MJ, editors. Humn mlignnt melnom. New York: Grune & Strtton; p Clrk WH, Elder DE, Guerry DP. Dysplstic nevi nd mlignnt melnom. In: Frmer E.R., Hood A.F., editors. Pthology of the skin. London: Prentice-Hll Interntionl; p Koh HK, Soer AJ, Lew RA, Dy CL, Clrk WH, Mihm MC, et l. Lentigo mlign melnom hs no etter prognosis thn other types of melnom. J Clin Oncol. 1984;2: Weedon D. Skin pthology. 2. Edinurgh: Churchill Livingston; p Mssi G, LeBoit PE. Histologic dignosis of nevi nd melnom. Germny: Steinkopff Verlg Drmstdt; Nestle FO, Kerl H Melnom. In: Bologni JL, Jorizzo JL, Rpini RP, et l, editors. Dermtology. Edinurgh: Moshy; Herrer M. L clsiicción de Clrk de los melnoms, reconsiderd. Tesis doctorl. Mdrid, Ackermn AB. Mlignnt melnom. A unifying concept. Humn Pthol. 1980;111: Ackermn AB, Dvid KM. A unifying concept of mlignnt melnom: Biologicl spects. Humn Pthol. 1986;17: Mize JC, Burgdorf WHS, Hurt MA, LeBoit PE, Metclf JS, Smith T, et l. Cutneous pthology. Phildelphi: Churchill Livingston; p Brnhill RL. Tumors of melnoccytes. In: Brnhill R.L., editors. Textook of dermtopthology. New York: McGrw-Hill; p Frmer ER, Hood AF. Melnocytic tumors. In: Frmer ER, Hood AF, editors. Pthology of the skin. 2. New York: McGrw-Hill; p Puig S, Puig-Butille JA, Bdens C, Cúellr F, Mlvehy J. Noveddes en genétic del melnom. Piel. 2006;21:272-4.