编者按：原发部位不明黑色素瘤（Metastatic Melanoma of Unknown Primary, MUP）是一种少见的黑色素瘤类型，约占黑色素瘤的2~3%。MUP的特征是原发肿瘤位置未知，而转移灶通常主要出现在淋巴结、皮下组织或内脏器官。由于MUP的临床症状和影像学表现缺乏特异性，使得诊断过程相对复杂。目前，确诊MUP主要依赖于组织或细胞病理学活检、免疫组化检测以及分子病理学检测。

一、疾病特点

据估计，2020年全球黑色素瘤新发病例约32.5万人，死亡病例超过5.6万人^[1]。其中约2-3%黑色素瘤没有明确原发部位，主要累及淋巴结,最常涉及腋窝、腹股沟和腮腺淋巴结，其次皮下组织、内脏受累较多。患病年龄多处于40至50岁的年龄段，且男性患者数量多于女性^[2,3]。

二、诊断

根据1963年Das Gupta提出的诊断标准，MUP的诊断需明确组织病理学证实为转移性黑色素瘤，同时筛查全身各部位均不存在原发黑色素瘤^[4,5]。原发部位不明黑色素瘤（MUP）的诊断面临诸多挑战，主要由于其临床表现多样且缺乏特异性症状，导致早期诊断困难。尽管影像学检查有助于识别转移部位，但在确定原发灶方面存在局限^[6,7]。病理学诊断也较为复杂，常用免疫组化标志物在MUP中的表达可能不一致，需要与其他恶性肿瘤或良性病变进行区分^[8]。

三、发病机制

MUP的发病机制有三种主要假说。第一种假说认为黑色素瘤可能起源于淋巴结中的黑色素细胞痣或蓝痣^[9]，伴随着关键基因如BRAF、NRAS、PPP6C、TERT的突变，以及GNAQ和GNA11在蓝痣恶变中的作用^[10-21]；肿瘤细胞通过改变抗原表型和分泌免疫抑制因子逃避免疫监视^[22-26]。第二种假说提出原发灶可能在自身免疫介导下自发性消退，导致仅观察到转移灶^[27]。MUP患者的自发性消退现象与肿瘤的多个特征相关，如深度、大小和部位，这可能反映了宿主的免疫反应^[28,29]。第三种假说认为可能存在未记录的原发性黑色素瘤。这些理论为MUP的起源提供了可能的解释，但仍需通过进一步的临床研究和科学探索来加以证实。

四、治疗

（1）传统治疗方法

MUP患者治疗方法首选手术治疗，研究表明手术治疗患者5年生存率大约在47%到56%^[30-32]。然而，部分患者仍面临复发风险，与淋巴结转移的MUP患者相比，皮下转移的MUP患者复发率更高^[33]。因此，临床上广泛采用术后放疗或化疗作为治疗手段，但研究表明这些治疗与仅进行手术治疗相比，在预后上并没有显著差异^[34]。

（2）靶向治疗和免疫治疗

免疫治疗和靶向治疗可以显著提高MUP患者的生存率^[35-37]。一项回顾性研究中，Verver等纳入1032例MUP，其中有475名IV期MUP患者接受手术治疗联合或不联合化疗、放疗中位总生存期为4个月，557名IV期MUP患者接受免疫治疗或靶向治疗，靶向治疗中位总生存期延长至8个月，接受免疫治疗患者可达18个月^[38]。表明接受免疫治疗和靶向治疗有效延长MUP患者的生存期。

参考文献：

[1] Arnold M, Singh D, Laversanne M, Vignat J, Vaccarella S, Meheus F, Cust AE, de Vries E, Whiteman DC, Bray F. Global Burden of Cutaneous Melanoma in 2020 and Projections to 2040. JAMA Dermatol. 2022 May 1;158(5):495-503. doi: 10.1001/jamadermatol.2022.0160. PMID: 35353115; PMCID: PMC8968696.

[2] Kamposioras K, Pentheroudakis G, Pectasides D, Pavlidis N. Malignant melanoma of unknown primary site. To make the long story short. A systematic review of the literature. Crit Rev Oncol Hematol. 2011 May;78(2):112-26.

[3] Lee CC, Faries MB, Wanek LA, Morton DL. Improved survival after lymphadenectomy for nodal metastasis from an unknown primary melanoma. J Clin Oncol. 2008 Feb 1;26(4):535-41

[4] Dasgupta T, Bowden L, Berg JW. Malignant melanoma of unknown primary origin.  Surg Gynecol Obstet. 1963 Sep;117:341-5.

[5] Pack GT, Gerber DM, Scharnagel IM. End results in the treatment of malignant melanoma; a report of 1190 cases. Ann Surg. 1952 Dec;136(6):905-11.

[6]Mijnhout GS, Hoekstra OS, van Tulder MW, Teule GJ, Deville WL.Systematic review of the diagnostic accuracy of 18F-fluorodeoxyglucose positron emission tomography in melanoma patients. Cancer.2001;91:1530–42.

[7]Pfannenberg C, Aschoff P, Schanz S, Eschmann SM, Plathow C, Eigentler TK, Garbe C, Brechtel K, Vonthein R, Bares R, Claussen CD, Schlemmer HP. Prospective comparison of 18F-fluorodeoxyglucose positron emission tomography/computed tomography and whole-body magnetic resonance imaging in staging of advanced malignant melanoma. Eur J Cancer. 2007 Feb;43(3):557-64.

[8]Stante, M., de Giorgi, V., Carli, P., 2006. Possible role of dermoscopy in the detection of a primary cutaneous melanoma of unknown origin. J. Eur. Acad. Dermatol. Venereol. 20, 299–302.

[9] Shenoy BV, Fort L 3rd, Benjamin SP. Malignant melanoma primary in lymph node. The case of the missing link. Am J Surg Pathol. 1987 Feb;11(2):140-6.

[10] Gos A, Jurkowska M, van Akkooi A, Robert C, Kosela-Paterczyk H, Koljenović S, Kamsukom N, Michej W, Jeziorski A, Pluta P, Verhoef C, Siedlecki JA, Eggermont AM, Rutkowski P. Molecular characterization and patient outcome of melanoma nodal metastases and an unknown primary site. Ann Surg Oncol. 2014 Dec;21(13):4317-23. doi: 10.1245/s10434-014-3799-y. Epub 2014 May 28. PMID: 24866436; PMCID: PMC4218979.

[11] Egberts F, Bergner I, Krüger S, Haag J, Behrens HM, Hauschild A, Röcken C. Metastatic melanoma of unknown primary resembles the genotype of cutaneous melanomas. Ann Oncol. 2014 Jan;25(1):246-50. doi: 10.1093/annonc/mdt411. Epub 2013 Nov 24. PMID: 24276025.

[12]Hammond D, Zeng K, Espert A, Bastos RN, Baron RD, Gruneberg U, Barr FA. Melanoma-associatedmutations in protein phosphatase 6 cause chromosome instability and DNA damage owing to dysregulatedAurora-A. J Cell Sci. 2013 Aug 1;126(Pt 15):3429-40. 

[13] Stefansson, B., Brautigan, D.L., 2006. Protein phosphatase 6 subunit with conserved Sit4-associated protein domain targets IkappaBepsilon. J. Biol. Chem. 281, 22624–22634.

[14] Stefansson, B., Ohama, T., Daugherty, A.E., Brautigan, D.L., 2008. Protein phosphatase 6 regulatory subunits composed of ankyrin repeat domains. Biochemistry 47, 1442–1451.

[15]Liu R, Zhang T, Zhu G, Xing M. Regulation of mutant TERT by BRAF V600E/MAP kinase pathway through FOS/GABP in human cancer. Nat Commun. 2018 Feb 8;9(1):579.

[16]Li Y, Cheng HS, Chng WJ, Tergaonkar V. Activation of mutant TERT promoter by RAS-ERK signaling is a key step in malignant progression of BRAF-mutant human melanomas. Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):14402-14407.

[17] Gandini S, Zanna I, De Angelis S, Palli D, Raimondi S, Ribero S, Masala G, Suppa M, Bellerba F, Corso F, Nezi L, Nagore E, Caini S. TERT promoter mutations and melanoma survival: A comprehensive literature review and meta-analysis. Crit Rev Oncol Hematol. 2021 Apr;160:103288.

[18] Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA. Highly recurrent TERT promoter mutations in human melanoma. Science. 2013 Feb 22;339(6122):957-9.

[19] Costa S, Byrne M, Pissaloux D, Haddad V, Paindavoine S, Thomas L, Aubin F, Lesimple T, Grange F, Bonniaud B, Mortier L, Mateus C, Dreno B, Balme B, Vergier B, de la Fouchardiere A. Melanomas Associated With Blue Nevi or Mimicking Cellular Blue Nevi: Clinical, Pathologic, and Molecular Study of 11 Cases Displaying a High Frequency of GNA11 Mutations, BAP1 Expression Loss, and a Predilection for the Scalp. Am J Surg Pathol. 2016 Mar;40(3):368-77.

[20] Borgenvik TL, Karlsvik TM, Ray S, Fawzy M, James N. Blue nevus-like and blue nevus-associated melanoma: a comprehensive review of the literature. ANZ J Surg. 2017 May;87(5):345-349

[21] Suarez-Kelly LP, Levine KM, Olencki TE, et al. A pilot study of interferon-alpha-2b dose reduction in the adjuvant therapy of high-risk melanoma[ J]. Cancer Immunol Immunother, 2019,68(4):619-629.

[22] Chen, L. and X. Han, Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest, 2015. 125(9): p. 3384-91

[23] Sunshine J, Taube JM. PD-1/ PD-L1 inhibitors[ J]. Curr Opin Pharmacol, 2015, 23: 32-38. DOI: 10. 1016 / j. coph.2015. 05. 011.

[24] Goto M, Chamoto K, Higuchi K, et al. Analytical performance ofa new automated chemiluminescent magnetic immunoassays for soluble PD-1, PD-L1, and CTLA-4 in human plasma [ J]. Sci Rep, 2019,9(1):10144.

[25]  Liu Y, Liang X, Dong W, Fang Y, Lv J, Zhang T, Fiskesund R, Xie J, Liu J, Yin X, Jin X, Chen D, Tang K, Ma J, Zhang H, Yu J, Yan J, Liang H, Mo S, Cheng F, Zhou Y, Zhang H, Wang J, Li J, Chen Y, Cui B, Hu ZW, Cao X, Xiao-Feng Qin F, Huang B. Tumor-Repopulating Cells Induce PD-1 Expression in CD8+ T Cells by Transferring Kynurenine and AhR Activation. Cancer Cell. 2018 Mar 12;33(3):480-494.e7.

[26]Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 2014;25(6):846–59.

[27] Fujiwara T, Yakoub M, Chandler A, et al. CSF1 /CSF1R signaling inhibitor pexidartinib (PLX3397)reprograms tumor-associated macrophages and stimulates T-cell infiltration in the sarcoma microenvironment[J]. Mol Cancer Ther, 2021, 20(8): 1388-1399.

[28] Smith JL Jr, Stehlin JS Jr. Spontaneous regression of primary malignant melanomas with regional metastases. Cancer. 1965 Nov;18(11):1399-415.

[29] Smith JL Jr, Stehlin JS Jr. Spontaneous regression of primary malignant melanomas with regional metastases. Cancer. 1965 Nov;18(11):1399-415. 

[30] McGovern VJ. Spontaneous regression of melanoma. Pathology. 1975 Apr;7(2):91-9.

[31] Aivazian K. Regression in cutaneous melanoma: histological assessment, immune mechanisms and clinical implications. Pathology. 2023 Mar;55(2):227-235.

[32] Cormier JN, Xing Y, Feng L, Huang X, Davidson L, Gershenwald JE, Lee JE, Mansfield PF, Ross MI. Metastatic melanoma to lymph nodes in patients with unknown primary sites. Cancer. 2006 May 1;106(9):2012-20.

[33] Prens SP, van der Ploeg AP, van Akkooi AC, van Montfort CA, van Geel AN, de Wilt JH, Eggermont AM, Verhoef C. Outcome after therapeutic lymph node disp in patients with unknown primary melanoma site. Ann Surg Oncol. 2011 Dec;18(13):3586-92.

[34] Utter K, Goldman C, Weiss SA, Shapiro RL, Berman RS, Wilson MA, Pavlick AC, Osman I. Treatment Outcomes for Metastatic Melanoma of Unknown Primary in the New Era: A Single-Institution Study and Review of the Literature. Oncology. 2017;93(4):249-258

[35]  Vijuk G, Coates AS. Survival of patients with visceral metastatic melanoma from an occult primary lesion: a retrospective matched cohort study. Ann Oncol. 1998 Apr;9(4):419-22.

[36] Del Fiore P, Rastrelli M, Dall'Olmo L, Cavallin F, Cappellesso R, Vecchiato A, Buja A, Spina R, Parisi A, Mazzarotto R, Ferrazzi B, Grego A, Rotondi A, Benna C, Tropea S, Russano F, Filoni A, Bassetto F, Tos APD, Alaibac M, Rossi CR, Pigozzo J, Sileni VC, Mocellin S. Melanoma of Unknown Primary: Evaluation of the Characteristics, Treatment Strategies, Prognostic Factors in a Monocentric Retrospective Study. Front Oncol. 2021 Mar 5;11:627527.

[37] Del Fiore P, Rastrelli M, Dall'Olmo L, Cavallin F, Cappellesso R, Vecchiato A, Buja A, Spina R, Parisi A, Mazzarotto R, Ferrazzi B, Grego A, Rotondi A, Benna C, Tropea S, Russano F, Filoni A, Bassetto F, Tos APD, Alaibac M, Rossi CR, Pigozzo J, Sileni VC, Mocellin S. Melanoma of Unknown Primary: Evaluation of the Characteristics, Treatment Strategies, Prognostic Factors in a Monocentric Retrospective Study. Front Oncol. 2021 Mar 5;11:627527.

[38] Verver D, van der Veldt A, van Akkooi A, Verhoef C, Grünhagen DJ, Louwman WJ. Treatment of melanoma of unknown primary in the era of immunotherapy and targeted therapy: A Dutch population-based study. Int J Cancer. 2020 Jan 1;146(1):26-34. Beasley GM. Melanomas of Unknown Primary May Have a Distinct Molecular Classification to Explain Differences in Patient Outcomes. Ann Surg Oncol. 2020 Dec;27(13):4870-4871.