臺灣博碩士論文加值系統

黑色素癌在亞洲人是一個少見的疾病，卻是惡性度最高的皮膚癌。黑色素癌可以發生在所有含有黑色素細胞的部位。皮膚的黑色素癌可以分成四大類：表淺蔓延性黑色素癌、結節性黑色素癌、惡性小痣性黑色素癌和肢端型黑色素癌。和白種人不同的是，肢端型黑色素癌是亞洲人最常見的一種黑色素癌。在我們的研究中，肢端型黑色素癌佔了約70%的案例。因為肢端型黑色素癌不容易發現，所以診斷時往往腫瘤已經很嚴重，預後也比較不好。目前關於亞洲的肢端型黑色素癌的研究報告並不多，如果我們的研究能找出能預測預後的基因變異、分子標記或者相關的病理與臨床特徵，相信在治療策略上可以提供患者更多的幫助。
在許多白人和少數亞洲人的黑色素癌有研究過BRAF和NRAS mutations的情形。但是關於台灣人BRAF和NRAS mutations的情形以及基因變異和臨床特徵相關性的研究很少。因此本論文先分析119位台灣人BRAF和NRAS mutations的情形以及基因變異和臨床病理特徵與預後的關係。我們發現BRAF mutations佔全部黑色素癌的14.3% (17/119)，而NRAS mutations佔10.1% (12/119)。17個有BRAF mutations的病患裡，有15個(88.2%)是V600E mutations。BRAF mutations比較常發生在年輕的患者(P=0.0035)、黑色素癌的腫瘤厚度較薄(P=0.0181)與較少潰瘍(P=0.0089)。NRAS mutations比較常發生在有淋巴結轉移的病患(P=0.0332)。不過BRAF和NRAS mutations和黑色素癌的預後並沒有顯著關係。雖然BRAF和NRAS mutations在台灣人是相對少見的，但可以針對有BRAF或NRAS mutations的病人，給予適合的標靶治療。
第二型似胰島素生長因子(IGF-II) mRNA結合蛋白-3 (IMP-3)乃是IGF-II mRNA結合蛋白家族的一員。最近發現IMP-3在轉移的黑色素癌中表現高於淺層黑色素癌，而在良性黑色素痣則不表現，顯示IMP-3是一個新的黑色素癌進展標記。我們之前的研究分析皮膚黑色素癌患者腫瘤的IMP-3免疫組織化學染色，發現IMP-3高表現和肢端型黑色素癌以及晚期黑色素癌有關，而且IMP-3高表現的患者五年存活率比較低。因此我們收集了93個肢端型黑色素癌做進一步分析，發現IMP-3在75.3%的腫瘤有高表現，而且IMP-3的高表現和腫瘤厚度較厚以及晚期腫瘤有關。IMP-3高表現的病患其overall, melanoma-specific, recurrence-free和distant metastasis-free survivals都比IMP-3低表現的病患顯著的差，顯示IMP-3會增加黑色素癌的惡性度。在腫瘤厚度小於4.0 mm的病患，如果有高表現IMP-3，melanoma-specific survival會比低表現IMP-3的病患差。多變量分析發現IMP-3是肢端型黑色素癌的melanoma-specific survival的獨立預後因子。肢端型黑色素癌的病患如果能檢驗IMP-3在腫瘤的表現量，可以預期他的預後並決定最適合的治療。
在西方國家有很多痣相關黑色素癌的討論，卻很少有關於亞洲人的痣相關黑色素癌的研究。因此，我們探討台灣的痣相關黑色素癌和原發黑色素癌在臨床表現、病理特徵以及預後的差異。本研究利用台大醫院病理部病理診斷資料庫以及台大醫院癌症防治中心癌症資料庫進行統計分析，在2010-2015年間共有103位皮膚黑色素癌病患，並追蹤患者預後至2016年11月。全部103位黑色素癌病患裡，有17.5%的黑色素癌是痣相關黑色素癌。在小於65歲的病患中，非肢端型黑色素癌和痣相關黑色素癌有統計上顯著的相關性。痣相關黑色素癌常合併的臨床病理特徵有：表淺蔓延性黑色素癌、患者年紀輕、腫瘤厚度薄、間歇性陽光曝曬的部位、和早期癌症。痣相關黑色素癌的recurrence-free survival比原發黑色素癌長。雖然肢端型黑色素癌佔了全部黑色素癌的70.9%，肢端型黑色素癌裡面只有9.6%是痣相關黑色素癌。關於臨床病理特徵或者是預後的表現，原發肢端型黑色素癌和痣相關肢端型黑色素癌是沒有顯著差異的。痣相關黑色素癌在肢端型黑色素癌裡是相對少見的。因為亞洲人大部份的黑色素癌都是肢端型黑色素癌，所以和西方國家相比，亞州人比較少有痣相關黑色素癌。
肢端型黑色素癌的病理發生機轉到現在還不清楚，最近有報告提到機械應力壓迫可能與黑色素癌的形成有關。所以我們收集了台大醫院和高雄長庚醫院2000-2015年間共153位足底肢端型黑色素癌的患者來做進一步的分析。探討發生在足底不同位置的肢端型黑色素癌是否臨床病理特徵或者是預後的表現有所不同。以goodness of fit分析發現，和non-stress-bearing areas相比，stress-bearing areas比較容易產生黑色素癌(P<0.0001)。跟arch相比，rear of the foot和front of the foot是比較容易產生黑色素癌的部位，且有達到統計上顯著差異。黑色素癌分布的位置和年紀、性別、左右腳、潰瘍、細胞分裂、淋巴結轉移、腫瘤厚度、癌症分期以及預後沒有顯著相關。
隨著更加了解台灣肢端型黑色素癌的基因變異、分子機轉、病理與臨床特性，可以幫助我們在診斷、治療的選擇、預後的評估等方面給予患者更全面的資訊，提供台灣的患者一個最好的機會來治療肢端型黑色素癌。

Malignant melanoma is a rare disease in Asians but potentially the most aggressive form of skin cancer worldwide. Melanomas can develop in any melanocyte-containing anatomic site. Based on WHO classification, cutaneous melanoma can be classified into four main subtypes: lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma, and nodular melanoma. Superficial spreading melanoma is the most common type of melanoma in the West. In Asians, superficial spreading melanoma is less common than acral lentiginous melanoma, which is the most common subtype. In our study, acral lentiginous melanomas accounted for more than 70% of the cases. Because of their typically inconspicuous locations on the body, acral lentiginous melanomas are usually not noticed until the late stages, when they are ulcerated or large in size, so they tend to have a grave prognosis. However, only a few case series of acral lentiginous melanomas has been published in Asia and knowledge on its characteristics and prognosis factors is still limited. Hence, the establishment of more clinical, pathological, genetic or molecular markers for the prediction of invasiveness and metastatic potential of acral lentiginous melanomas will aid in the development of better strategies for patient management.
BRAF and NRAS mutations have been described in melanomas among Caucasians and some Asian populations. However, few large-scale studies have investigated the status and clinical significance of BRAF and NRAS mutations in a Taiwanese population. The incidence of somatic mutations within the BRAF and NRAS genes was 14.3% (17/119 patients) and 10.1% (12/119 patients), respectively. Among the 17 patients with BRAF mutations, 15 (88.2%) had V600E mutations. BRAF mutation was frequently detected in younger patients, in thin melanomas, and in melanomas with less ulceration. The NRAS mutation was more often seen in patients with lymph node metastasis. Both BRAF and NRAS mutations were not significantly correlated with overall survival and recurrence-free survival.
IGF-2 mRNA-binding protein 3 (IMP-3) is a member of the insulin-like growth factor-II mRNA-binding protein family. In our previous study, IMP-3 expression was much stronger in advanced-stage/metastatic melanomas and correlated with poor overall survival. First, we correlated IMP-3 expression with clinicopathological parameters as well as prognosis to further dissect the role of IMP-3 in a larger cohort of acral lentiginous melanomas. IMP-3 was over-expressed in 70 out of 93 tumors (75.3%). IMP-3 expression correlated with thick and high-stage tumor and predicted poorer overall, melanoma-specific, recurrence-free and distant metastasis-free survivals. Further analysis showed that patients with tumor thickness ≤ 4.0 mm and positive IMP-3 expression had a significantly worse melanoma-specific survival than those without IMP-3 expression. IMP-3 was confirmed to be an independent prognostic factor for melanoma-specific survival in multivariate survival analysis. Positive IMP-3 expression was an important prognostic factor for ALMs.
Statistical data regarding melanomas associated with melanocytic nevi in Asia appears to be limited, although we did discover such information with regard to populations in the West. We examined whether nevus-associated melanomas differ from de novo melanomas in terms of their associations with clinical factors, histologic characteristics, and patient survival in Taiwan. Approximately 17.5% of the melanomas in question were associated with a nevus. In patients under 65 years of age, non-acral lentiginous melanomas were significantly associated with a higher percentage of nevus-associated melanomas. The superficial spreading subtype, younger patient age, thinner tumor, intermittent solar exposure, and early stage were significant predictors of a melanoma being histologically associated with a nevus. The appearance of a nevus associated with a melanoma predicted better recurrence-free survival compared with de novo melanomas. Although acral lentiginous melanomas (70.9%) constituted the most common histologic subtype, only 9.6% of the acral lentiginous melanomas were associated with a nevus. Furthermore, there was no statistically significant difference between the nevus-associated and de novo acral lentiginous melanomas with regard to clinicopathological factors and survival. In conclusion, nevus-associated melanomas were uncommon among acral lentiginous melanomas.
The pathogenesis of melanomas emerging in plantar surfaces remains unclear; however, mechanical stress has been reported to increase the formation of melanomas. We examined whether melanomas which developed in different areas of the patients’ soles differed in their associations with various clinicopathological characteristics and survival. Testing by goodness of fit indicated that stress-bearing areas were significantly more conducive to the generation of melanomas than non-stress-bearing areas. More specifically, compared to the arch, the rear of the foot and front of the foot were significantly more conducive to the generation of melanomas. The distribution pattern was not associated with differences in age, gender, right/left foot involvement, ulceration, mitosis, lymph node metastasis, tumor thickness, or stage. The overall, distant metastasis-free, and recurrence-free survival rates did not differ significantly between the stress-bearing and non-stress-bearing areas.
We conclude that increased understanding of the mutations, clinicopathologic factors and molecular markers of acral lentiginous melanomas will allow for dramatic improvement in the treatment strategies, providing the best chance for long-term palliation or cure of acral lentiginous melanomas in Taiwan.

口試委員會審定書…………………………………………………….............………...i
誌謝…………………………………………………………………………….…..........ii
中文摘要………………………………………………………………………..............iii
英文摘要…………………………………………………………………....…….….....vi
第一章 前言（Introduction）...……………………........................................................1
1.1 BRAF and NRAS mutations………….........................................................................3
1.2 IMP-3 expression in melanomas...………..................................................................3
1.3 Nevus-associated melanomas...……………………...................................................4
1.4 Mechanical stress and melanomas…………………...................................................5
第二章 材料與方法（Materials and Methods）……………………..............................5
2.1 Patients and tissues of the BRAF and NRAS mutations study………...……………..5
2.2 Patients and tissues of the IMP-3 study...……………………....................................5
2.3 Patients and tissues of the nevus-associated melanomas study………………...……6
2.4 Patients and tissues of the mechanical stress study………………………………….7
2.5 Immunohistochemical analysis..……………………..................................................7
2.6 Mutation analyses of BRAF, NRAS and KIT genes in melanoma tissues……………9
2.7 Statistical analysis..…………………........................................................................10
第三章 實驗結果 (Results)…………………………...................................................10
3.1 BRAF and NRAS mutations in cutaneous melanoma patients...................................10
3.2 Expression of IMP-3 protein in ALM…………...……………………………........13
3.3 Clinicopathological and prognostic significance of IMP-3 expression. …………...14
3.4 Concomitant effects of IMP-3 expression with thickness on the prognosis of ALM............................…………………………………………………………………15
3.5 IMP-3 Expression is an Independent Prognostic Factor in ALM……………….…15
3.6 Nevus-associated melanomas in Taiwan…………………………………………...16
3.7 Clinicopatholigical factors of nevus-associated melanomas………………….……17
3.8 Prognosis of nevus-associated melanomas…………………………………………17
3.9 Clinicopathological factors and prognosis of nevus-associated acral melanomas....18
3.10 Clinicopathological analysis of acral melanomas and the relevance of mechanical stress……………………………………………………………………………………18
第四章 討論 (Discussion) …………………………....................................................20
4.1 Prevalence of BRAF and NRAS mutations in melanoma patients in Taiwan……………………………………………………………………………….…21
4.2 IMP-3 expression correlates with poor prognosis in acral lentiginous melanoma…23
4.3 Clinicopathological features and prognosis of patients with de novo versus nevus-associated melanoma in Taiwan………………...................................................26
4.4 Acral melanomas and the relevance of mechanical stress.........................................29
第五章 展望 (Perspectives) ………………………......................................................31
第六章 參考文獻 (Reference) ………………………………………….....................33
第七章 附圖及說明 (Figures and figure legends) ………………………...................52
Fig 1. Kaplan-Meier curves of survival associated with mutations in 119 melanoma patients.............................................................................................................................52
Fig 2. Representative sections with immunohistochemical staining intensity against IMP-3………………………….......................................................................................53
Fig 3. IMP-3 was expressed in ALM and associated with its progression……..………54
Fig 4. Kaplan-Meier curves of survival associated with IMP-3 expression in 93 primary ALMs…………………………………………………………………….………..……55
Fig 5. Kaplan-Meier analysis of survival in patients with or without IMP-3 expression in relation to thickness…………………………............................................................56
Fig 6. Superficial spreading melanoma arising from a nevus….....................................57
Fig 7. Kaplan-Meier curves of survival for 103 primary melanoma patients………….59
Fig 8. Kaplan-Meier curves of survival for 73 patients with primary acral lentiginous melanomas………………………………………………………………………..…….60
Fig 9. Study flow diagram…………………………………………………………...…61
Fig 10. Distribution of acral melanomas in the plantar area……………………...……62
Fig 11. Distribution of 114 primary acral melanomas in the plantar area…...…………63
Fig 12. Kaplan-Meier curves of survival in 114 primary acral melanomas……………64
Fig 13. Distribution of primary acral melanomas in the palmar area……………..……65
第八章表格 (Tables) ………………………….............................................................66
Table 1. BRAF and NRAS mutations identified in 119 primary melanomas...................66
Table 2. Association of BRAF and NRAS mutation status with patient and melanoma characteristics..................................................................................................................67
Table 3. Summary of BRAF and NRAS mutation in primary cutaneous melanoma in Asians..............................................................................................................................69
Table 4. Univariate and multivariate analyses of risk factors associated with overall survival............................................................................................................................70
Table 5. Univariate and multivariate analyses of risk factors associated with recurrence-free survival ..................................................................................................70
Table 6. Clinical and histologic prognostic factors and IMP-3 expression……….……71
Table 7. Univariate and multivariate analysis of risk factors associated with melanoma-specific survival in acral lentiginous melanoma patients……….……….…73
Table 8. Univariate and multivariate analysis of risk factors associated with overall survival in acral lentiginous melanoma patients…………….………………..……..…74
Table 9. Univariate and multivariate analysis of risk factors associated with recurrence-free survival in acral lentiginous melanoma patients………………………75
Table 10. Univariate and multivariate analysis of risk factors associated with distant metastasis-free survival in acral lentiginous melanoma patients………………….……76
Table 11. Clinical and histologic characteristics in nevus-associated melanomas..........77
Table 12. Univariate and multivariate analysis of risk factors associated with overall survival…………………………....................................................................................79
Table 13. Univariate and multivariate analysis of risk factors associated with distant metastasis-free survival…………………………...........................................................80
Table 14. Univariate and multivariate analysis of risk factors associated with recurrence-free survival……………...............................................................................81
Table 15. Clinical and histologic characteristics in acral lentiginous melanomas…..…82
Table 16. Patient clinicopathological data………………………………...……………84
Table 17. Factors associated with the stress- and non-stress-bearing areas……………86
Table 18. Univariate and multivariate analyses results of risk factors associated with overall survival……………............................................................................................87
Table 19. Univariate and multivariate analyses results of risk factors associated with distant metastasis-free survival……………....................................................................88
Table 20. Univariate and multivariate analyses results of risk factors associated with recurrence-free survival……………...............................................................................89
附錄：已發表之論文 (Publication list)………………………………………….…….90

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