1. Abstract Background: Malignantmelanomaisahighlymalignanttu- mor caused by abnormal proliferation of melanoma cells in the skinandmucousmembranes,withapoorprognosisaftermetasta- sis. Skin melanocytes are gradually destroyed in vitiligo patients. Thereisacertaincorrelationbetweenthesetwodiseases:Inthese two conditions, cytotoxic T lymphocytes that target autoantigens shared by normal melanocytes and melanoma cells have been found. Spontaneous melanoma-associated vitiligo was relatively rare before melanoma was diagnosed, and its pathogenesis and prognosiswererarelystudied.Thecaseswereportedisextremely rareforapatienttohaveametastasisofmelanomathatlastsmuch longerthanthemoderatesurvivaltimeofapatientwithmalignant melanoma.
Case Presentation: A 63-year-old female patient who was treated in our hospital survived for up to seven years and five monthsafterbeingdiagnosedwithmalignantmelanoma.Thepri- mary symptom of the patient was skin darkening on the back of the right index finger. Within seven years, malignant melanoma metastases appeared sequentially in the right axillary region and in the small intestine region. The patient underwent right axillary tumor resection, right index finger distal segment amputation and smallboweltumorresection.Thepathologicalresultswereallma- lignantmelanoma.Patientswerenotreceivingsystemicimmuno- therapy, but the spontaneous melanoma-associated vitiligo made thepatientlivelongerthantheothermalignantmelanomapatients.
Conclusion: Spontaneous melanoma-associated vitiligo pro- longssurvivalinpatients withmalignant melanoma. Theemergence of spontaneous melanoma-associated vitiligo should be alerted and its pathogenesis should be studied.
Keywords: Metastatic melanoma; Spontaneous melanoma-associated vitiligo; Early diagnosis; Immune mechanism
2. Introduction Malignant melanoma (MM) is a kind of neural crest malignant tumor with strong aggressiveness and poor prognosis [1]. Hematogenous or lymphatic metastasis is prone to occur in the early stage of MM. Metastatic MM accounts for 1% to 3% of gastrointestinalmalignancies[2]andthefive-yearsurvivalrateforpatients with metastatic MM is only 5% [3]. Due to the lack of specific signs and symptoms, the pre-mortem diagnosis rate of patients with metastatic MM is only between 1.9% and 4.4% [4]. Vitiligo is an acquired depigmentation disease in which the skin melano- cytes are gradually destroyed. The pathogenesis of vitiligo and malignant melanoma is still unclear, however, there is a certain correlation between these two seemingly different diseases: Cy- totoxic T lymphocytes ( CTLs ) against autoantigens shared by normal melanocytes and melanoma cells were found in both cases,suggestingthecollapseofimmunetolerance[5,6].Inaddition, melanoma patients also develop lesions that are very similar to classicalvitiligo:melanoma-associatedvitiligo（MAV.MAVisdif- ferentfromclassicalvitiligo,andpeoplehavedifferentdefinitions ofit,whichareroughlydividedintothefollowingtwoviews.One idea has been mentioned in the literature by Hansje-EvaTeulings etal.thatmelanomapatientsmayexperienceskindepigmentation spontaneouslyoraftertreatment,calledMAV[7].However,Franciscoetal.definedMAVasalossofpigmentthatoccurswithin1 year before the detection of primary melanoma or 3 years before thediscoveryofMMwithanunknownprimarytumor[8].Inthis paper, in order to distinguish the vitiligo-like leukoplakia that appearsbeforeandaftertreatment,MAVisdividedintospontaneous melanoma-associatedvitiligo(SMAV),whichiswhatTeulingset al. call this condition， and reactive melanoma-associated vitili- go (RMAV), which is vitiligo-like leukoplakia that appears after treatment.Inrecentyears,ithasbeenfoundthatabout2%to16% ofMMpatientswillgraduallydevelopMAV[7].Currentresearch alsoshowsthatmostMAVoccursduringorafterimmunotherapy. MAVisasignofanti-tumoroftheautoimmunesystemandagood signal for immunotherapy [9,10]. It is worth mentioning that it is relativelyrareforSMAVtoappearbeforethedefinitediagnosisof MM, and there is no single research and report on SMAV in the literature.Inourcasereport,thisfemalepatienthadavitiligo-like discolorationspotbeforethemelanomawasdiagnosed,andithas appearedforatleastoneyear.Shedevelopedaxillarylymphnode metastasis 1 year after the initial diagnosis of malignant melanoma,andtheoverallsurvivaltimeafterdiagnosiswas7yearsand5 months. Her survival time far exceeded the median survival time of MM patients [11,12]. This phenomenon requires close attention of surgeons. Whether the emergence of SMAV can improve the prognosis of MM patients is worthy of our consideration. We recommendthatthefirstphysicianperformacarefulsystemicskin examinationofpatientswithvitiligo-likedepigmentation,consideringthepossibilityofmalignantmelanoma.Inaddition,in-depth research on the pathogenesis and immune process of MAV may open up new advances in the treatment of malignant treatment of melanoma.
3. Case Repot A63-year-oldfemalepatientwhohadbeentreatedinourhospital survivedforupto7yearsand5monthsafterbeingdiagnosedwith MM.A year before the diagnosis of MM, the patient began to developvitiligo-likedecolorization,initiallyontheface,followed by the same vitiligo-like decolorization lesions on her neck. It is worth mentioning that this patient has no family history of skin cancer and no family history of vitiligo. In March 2010, she went to the doctor for the first time because the skin on the back of the right index finger turned black as the first symptom. During the skin examination, the doctor found that, except the abnormalityoftherightindexfinger,thepatient'sfacehadvitiligolikediscol- oration skin lesions. After asking the medical history, he learned that the facial lesions had been more than one year, and it was earlier than the right index finger lesions. Doctors believed that the patient's diagnosis was melanoma with a righthanded index finger and recommended that she should undergo right-handed index finger amputation, but the patient refused surgery. In May 2011, the patient found a mass on the right armpit, about 2*3 cm insize,whichhadnotbeendiagnosedandtreated.After6months, thetumorhadprogressivelyincreasedto6*3cm.Thepatientwent to our hospital again and underwent a right axillary tumor resectioninNovember2011.Thepostoperativepathologicalresultwas MM.Immunohistochemicalresults: Vimentin(+),CK(-),CD34(- ), HMB45(+), MelanA(+), S-100(+), LCA(-). The patient's axillary melanoma was considered as axillary lymph node metastasis of the primary lesion. Therefore, after be tracked the primary tumor by the doctor, the patient underwent a right-handed index of the middle and distal finger amputation in December 2011. Combined with the results of postoperative pathological diagnosis, the patient was definitely diagnosed as stage IV MM of the right hand index finger.The doctor recommended that she should receive standardized immunotherapy after the operation, but she wasflatlyrejected,andthepatienthasnotbeenreviewedregularly since then. Until December 2,2017, the patient was treated again withintermittentepigastricpainfor1monthandaggravationwith 7 days of cessation of exhaust and defecation.Examination reveals a full abdominal bulge, hyperinvertine sounds, mild tender- ness in the left upper quadrant, and no mass touched.Abdominal Computer Tomography (CT) showed dilation of the small intes- tineintheabdominalcavity,multipleairliquidlevels(Figure1A), and local space-occupying lesions in the pelvic intestine (Figure 1B). On initial admission, the patient's initial clinical diagnosis was incomplete intestinal obstruction. Gynecological ultrasound examination suggests that there may be large pelvic intestinal space-occupying lesions (Figure 2). The patient had undergone a small bowel tumour resection. The postoperative histopathologicalresultsshowedsmallintestineMM(Figure3).Underthelight microscope, it could be seen that the submitted tumor cells were diffuselydistributed,withorgan-likestructuresinindividualareas. Thetumorcellsweremediuminsizeandrichincytoplasm.Some nucleiwereslightlyeosinophilic,andsomeweremoretranslucent. Thenucleuswasroundoroval,andthesizewasrelativelySmaller,splitelephantsweremorecommon(Figure3A-B).Theimmunohistochemical results displayed HMB45 (+), S-100 (+), MelanA(+), Vimentin (+) and CK (-) (Figure 3C). Owing to personal reasons, the patient and his family refused to undergo follow-up immunotherapy.Weconsideredthatthepatient'ssmallbowelmelanomawasstillasmallbowelmetastasisoftheprimaryfocus,and combinedwiththepathologicalresults,thepatientwasdiagnosed as small bowel malignant melanoma stage IV. Two years later, a progressively enlarging 4x4 cm tumour appeared in her abdomen (Figure4AC).Afteradmission,thispatientunderwentaphysical examination. She was clear-headed, poor in spirit, and general-ly in poor condition. The patient's superficial lymph nodes were not palpable and enlarged. We could see three old surgical scars about 5cm in size on her abdomen. Percussion of the abdomen revealedadrumsoundthroughouttheabdomen.Inaddition,inthe middle of her lower abdomen, we found a mass of approximately 4x4 cm, with hard texture, poor mobility and no tenderness. This patient has a distended abdomen with positive mobile turbid sounds.Finally,wealsofoundthatherrighthandindexfingerwas surgicallyremoved,andlargeareasofwhitespotsonbothsidesof herfaceandneck.Weconsiderthatthepatienthasadvancedmalignantmelanomawithextensivemetastasistotheabdominalcavity. Combinedwiththepatient'smedicalhistoryandgeneralstatus,the opportunity to re-operate had been lost. Patients were discharged after1cycleofcindilizumab200mgimmunotherapy.Thepatient died 1 month after discharge.
4. Discussion MM, a malignant tumor caused by the abnormal proliferation of melanocytesintheskinandmucousmembranes,istheleastcom- mon type of skin cancer, but Maccounts for75%of skin cancer deaths. In recent years, its incidence rate has been accelerating, second only to lung cancer [12].According to the latest U.S. data for 2020, it was estimated that 325,000 new cases of MM would beaddedlastyear,andthenumberofdeathsduetoMMwouldbe 57,000[13].Sofar,MMisthedeadliestskincancer,anditiseasy tometastasizeatanearlystage.TheprognosisofmetastaticMMis worse,withamediansurvivalofabout9monthsorless[11,12,14]. Atpresent,surgeryisstillanimportanttreatmentforMM.ForMM patients who are generally in good condition and have the possibilityofradicalcure,radicalsurgerycansignificantlyprolongthe overall survival and disease free survival time of MM patients[4, 15, 16]. Palliative surgery can also improve the complications of patientswithmetastaticMIM,evenifthegeneralconditionispoor and radical surgery cannot be performed for metastatic MM. The prognosis of untreated metastatic MM is extremely poor. Therefore,theearlydiagnosisofMMisparticularlyimportant.Currently,thereisalackofeffectivescreeningmethodsforMM.Thecase wereportedbecameintriguinguswithvitiligoandMM,andafter reviewingtheliteraturewefoundaninterestinglinkbetweenMM and vitiligo [6,8,10,17] and has been studied by scholars from all overtheworld.BothMMandvitiligoaremelanocyte-relateddiseases.MMisahighlymalignanttumorderivedfrommelanocytes, and the melanocytes of vitiligo patients are destroyed, resultingin skin discoloration [9]. Although the specific pathogenesis of both MM and vitiligo is not well understood, there is a common differentiating antigen between the two [10,20]. Most of the antigens recognized by CTL in melanoma patients are expressed by melanomacellsandnormalmelanocytes[5,6]andautoantibodies Therefore, the main purpose of this study is to remind clinicians of the following two points through this case report. First, the pathogenesis of SMAV may play an important role in inhibiting theoccurrenceanddevelopmentofMM.In-depthresearchonthe pathogenesisofSMAVwillmakeasignificantcontributiontothe treatmentofMM.Secondly,currentlyMAVisnotconsideredtobe asubtypeofvitiligo,andthedistinctionbetweenthetwoisofgreat significance to patients. For patients with initial vitiligo-like discoloration lesions, careful whole-body skin examinations should beperformedtobealerttothepossibilityofsufferingfrommalig- nant melanoma
5. Conclusion SMAV is the protective factor of MM.Its pathogenesis needs to be further studied, or it can provide new ideas for the treatmentofMMandbringgoodnewstoMMpatients.Forpatientswith symptomsofvitiligo-likedecolorization,vitiligocannotbeblindly diagnosed, and the first physician should conduct a careful systemic skin examination of the patient and ask him to follow up regularly to be alert to the possibility of SMAV.
References 1. Bassi M. Metastases of malignant melanoma to gastrointestinal tract:arareevent.Giornaleitalianodidermatologiaevenereologia. 2012; 147(2): p. 208.
2. Blecker D. Melanoma in the gastrointestinal tract. 1999; 3427-33.
3. CoitDG,Melanoma.JournaloftheNationalComprehensiveCancerNet work: JNCCN. 2009; 7(3): p. 250-75.
4. Ollila DW. Surgical resection for melanoma metastatic to the gastrointestinal tract. Archives of surgery (Chicago, Ill: 1960). 1996.131(9): p. 975-9; 979-80.
5. Garbelli S. Melanocyte-specific, cytotoxicTcell responses in vitiligo: the effective variant of melanoma immunity? Pigment cell research. 2005; 18(4): p. 234-42.
6. FaillaCM.MelanomaandVitiligo:InGoodCompany.Internationaljour nal of molecular sciences. 2019; 20(22): p.5731.
7. Teulings H. The antibody response against MART-1 differs in patients with melanoma-associated leucoderma and vitiligo. Pigmentcell & melanoma research. 2014; 27(6): p. 1086-96.
8. FranciscoG,BK.RaoandFCVictor.Tworeportsofmalignantmelanoma arising within a new vitiligo-like depigmented patch. 2018; p. 573-575.
9. Quaglino P, Vitiligo is an independent favourable prognostic factorinstageIIIandIVmetastaticmelanomapatients:resultsfroma singleinstitution hospital-based observational cohort study. AnnOncol. 2010; 21(2): 409-414.
10. HuaC.Association ofVitiligo withTumor Response in Patients withMetastaticMelanomaTreatedWithPembrolizumab.JAMADerm a-tol. 2016; 152(1): 45-51.
11. Markovic SN. Metastatic malignant melanoma. Giornale italianodi dermatologia e venereologia: organo ufficiale, Societa italiana didermatologia e sifilografia. 2009; 144(1): p. 1-26.
12. Califano J, M Nance, Malignant melanoma. Facial plastic surgery clinics of North America. 2009. 17(3): p. 337-48.
13. Ferlay J. Cancer statistics for the year 2020:An overview. International journal of cancer. 2021.
14. LensM,VBataille,ZKrivokapic.Melanomaofthesmallintestine.The Lancet. Oncology, 2009; 10(5): p. 516-21.
15. Akaraviputh T. Surgery for gastrointestinal malignant melanoma:experiencefromsurgicaltrainingcenter.Worldjournalofga stroen-terology, 2010; 16(6): p. 745-8.
16. MarianiP.Surgicalmanagementoflivermetastasesfromuvealmelanoma: 16 years’experience at the Institut Curie. European journalof surgical oncology : the journal of the European Society of Sur-gical Oncology and the British Association of Surgical Oncology,2009; 35(11): p. 1192-7.
17. WenY.Cancerrisksinpatientswithvitiligo:aMendelianrandomization study. Journal of cancer research and clinical oncology.2020; 146(8): p. 1933-1940.
18. Cohen BE. Vitiligo and Melanoma-Associated Vitiligo: UnderstandingTheir Similarities and Differences.American journal of clinicaldermatology. 2020; 21(5): p. 669-680.
19. Bergqvist C, K Ezzedine,Vitiligo:AReview. Dermatology (Basel, Switzerland). 2020. 236(6): p. 571-592.
20. Nakamura Y. Correlation between vitiligo occurrence and clinicalbenefit in advanced melanoma patients treated with nivolumab: Amulti-institutional retrospective study.The Journal of dermatology.2017; 44(2): p. 117-122.
21. Elias GJ. Circulating tissue inhibitor of matrix metalloproteinase-4 (TIMP-4)insystemicsclerosispatientswithelevatedpulmonaryarterial pressure. Mediators of inflammation. 2008. 2008: p. 164134.
22. Francisco G, BK Rao, FC Victor. Two reports of malignant melanoma arising within a new vitiligo-like depigmented patch. 2018; p. 573-575.
Enhong Zhao. A Metastatic MelanomaPatient with Spontaneous Melanoma-Associated Vitiligo Survived for up to 7 Years and 5 Months:ACase Report. Annals of Clinical and Medical Case Reports 2022