第六章、子宮頸小細胞神經內分泌癌 (NECC)

6.1 神經內分泌腫瘤特徵 [14]

• 異質性腫瘤：神經內分泌腫瘤 (Neuroendocrine Tumors, NETs) 在生物學、臨床表現以及組織病理學特徵上展現極高異質性的癌症。

• 分布：常見於肺、胃腸道及胰腺，但在婦科生殖道等較為罕見的部位亦有其蹤跡。

• WHO 分類：2014 年WHO分類已更新，採用「低分化NET (low-grade NET)」與「高分化神經內分泌癌 (high-grade NEC)」等術語。在子宮內膜與子宮頸中，高分化 NEC 較為常見，且多發於子宮頸。

• 盛行率： NECC 約佔所有子宮頸癌的 1% 至 1.5%，是一種具侵襲性的組織學變體。

6.1.1 NECC之表現

• 比率與分布：子宮頸小細胞神經內分泌癌 (Small Cell Neuroendocrine Carcinoma of the Cervix, NECC)：約佔所有子宮頸癌的1%至1.5%。儘管其發生率較低，卻算是女性生殖道中最好發神經內分泌癌的部位，其中又以小細胞型最為普遍，而大細胞神經內分泌癌、分化良好的NET G1 (典型類癌) 與NET G2 (非典型類癌) 則顯得異常罕見。

• 預後特徵：NECC的惡性程度極高，其預後遠遜於常見的子宮頸鱗狀細胞癌或腺癌，且有早期的廣泛轉移傾向，尤其是傾向於發生淋巴結與血行轉移。

• 組織型態與治療關聯：診斷初期，許多患者可能已有微小的遠端轉移病灶，使得局部治療 (如手術或放療) 往往不足以控制病情。NECC在組織形態學上與肺部的小細胞癌 (SCLC) 極為相似，目前的臨床治療策略，很大程度上是借鑑自SCLC的治療指引。

6.1.2 病理學原則與免疫組織化學分析

• 組織形態學特徵：細胞體積小、細胞質稀少、核染色質呈細粉末狀 (鹽胡椒狀) 、核仁不明顯，且細胞間界限不清，常形成緻密的巢狀或索狀結構。壞死與核分裂像極為常見，這反映了其快速增殖的生物學特性。

在診斷NECC時，多種IHC指標的組合應用能提高診斷的準確性：

• p16 指標：絕大多數NECC病例呈p16瀰漫性強陽性。這是因為其與高風險型人類乳突病毒 (HR-HPV) 感染高度相關，尤其是HPV 18型與16型 (18型比16型更常出現在神經內分泌亞型中) 。然而p16陽性不能作為區分腫瘤原發部位的唯一指標，因為來自其他部位的神經內分泌癌也可能因其他機制呈現p16陽性。

• 核心神經內分泌標記：

  • CD56 (NCAM)：這是最敏感的標記物，但在特異性方面較弱。

  • Synaptophysin：具備高度敏感性，是診斷神經內分泌分化的基石之一。

  • Chromogranin A：這是特異性最強的標記，但敏感度僅約50%至60%。如果此項呈陰性，並不能排除NECC的診斷。

  • INSM1 (Insulinoma associated protein 1)：作為較新型的標記，其在NECC中的陽性率約為80%，被認為是比 Chromogranin 更敏感且更具診斷價值的工具。

• TTF-1 (甲狀腺轉錄因子-1)：值得注意的是，高比例的子宮頸NECC也會表現出 TTF-1 陽性。這意味著在遇到臨床上同時存在肺部與子宮頸病灶的患者時，TTF-1無法用來區分這究竟是肺癌轉移至子宮頸，還是子宮頸癌原發。

• VRK1 (痘病毒相關激酶1)：最近的研究指出，VRK1在NECC 樣本中呈現穩定且高度的表達，與一般鱗狀細胞癌或腺癌的波動性表現不同。降低VRK1可導致腫瘤細胞粒線體功能障礙，這使其成為未來極具潛力的治療靶點。

6.2 臨床評估與分期治療 [14]

• 由於NECC較罕見，臨床數據相對匱乏，大規模的臨床試驗難以施行，因此NCCN專家委員會在制定指引時，除了參考既有的子宮頸癌指引外，亦大量採納了肺部神經內分泌與小細胞肺癌的管理經驗。

6.2.1 影像學評估的角色

由於NECC極易發生早期轉移，需藉由影像學評估以排除潛在的遠端擴散：

• 骨盆腔磁振造影 (Pelvic MRI)：MRI被認為是評估局部疾病範圍的最佳工具。它能精確顯示子宮頸原發腫瘤的體積、對陰道穹窿的侵犯程度、對子宮旁組織 (Parametrium) 的侵犯以及是否壓迫輸尿管導致水腎。對於計畫接受保留生育功能手術 (如根除性子宮頸切除術) 的少數極早期患者，MRI對於確保安全切緣至關重要。

• 全身FDG-PET/CT：PET/CT在NECC 的分期中扮演著不可或缺的角色。鑑於該病容易發生骨、肝、肺以及縱隔腔淋巴結轉移，PET/CT能偵測出隱匿性病灶，進而避免不必要的根除性手術。對於分期大於或等於IB1的患者，應強烈建議進行PET/CT。

6.2.2 臨床分期系統

• 臨床分期：時而會參考小細胞肺癌中退伍軍人管理局肺癌研究小組 (VALG) 兩級分期法 (分侷限期與廣泛期)，但NCCN指引建議使用2018年國際婦產科聯盟 (FIGO) 分期系統。研究顯示，FIGO分期在計算預後上比VALG兩級法具備更為準確。(參考第2.5章)

• 對於NECC患者，即便分期較早 (如Stage IA-IB1) ，亦應將其視為高度全身性風險族群進行管理。

6.3 NECC不同期別之治療

6.3.1 侷限於子宮頸的早期病變 (≤ 4 cm)

對於腫瘤直徑小於或等於4 cm的患者，建議手術合併輔助化療 ± 放療：

• 根除性子宮切除術 (Radical hysterectomy)：需配合前哨淋巴結 (SLN) 定位或雙側骨盆腔淋巴結摘除 (Pelvic lymphadenectomy)。術後通常需要輔助治療，以降低極高的局部復發與遠端轉移風險。

• 術後輔助化療 (Adjuvant EP)：即使手術邊緣乾淨且淋巴結陰性，仍建議追加輔助化療。首選療法為Etoposide + Cisplatin/Carboplatin (EP) *5療程。根據回溯性研究之結果，進行五次以上的Adjuvant EP療法，其預後較僅做四次以下的患者為佳。且EP療法的效果相較於其他療法(如：Paclitaxel + Carboplatin) 為佳，且研究及臨床經驗較多。[51]

6.3.2 較大病變 (> 4 cm) 或局部晚期 (Stage IIA-IVA)

對於腫瘤體積較大或已擴散至子宮旁的患者，單純手術通常不足夠，需合併放療及化療：

• 同步化放療 (CCRT)：合併Cisplatin/Carboplatin與Etoposide進行化放療，並配合近接放射線治療 (Brachytherapy) 是標準做法。

• 術前輔助化療 (Neoadjuvant Chemotherapy)：可考慮先進行數個療程的含鉑化療以縮小腫瘤體積，再評估是否能進行手術切除或放療。

6.3.3 全身性藥物治療與關鍵臨床試驗解析

在復發性或轉移性NECC的治療，全身性療法是唯一的長期控制手段。然而晚期NECC的治療，大多借鑑於廣泛期SCLC中重要試驗之結果，並加以外推適用於NECC。以下是影響當前治療標準的重要療法與其臨床試驗結果。

• Durvalumab + EP 療法：CASPIAN試驗確立了免疫療法合併標準化療作為高惡性度NECC的一線治療標準。這為患者提供了在傳統化療外更具希望的生存選項。[52]

• Atezolizumab + EP 療法：IMpower133研究鞏固了PD-L1抑制劑在一線神經內分泌癌治療中的地位。值得注意的是，後續的 IMscin001 研究證明 Atezolizumab 的皮下注射劑型具備與靜脈注射相當的暴露量與安全性，可大幅縮短治療時間至7分鐘。[53]

• TPB (Topotecan + Paclitaxel + Bevacizumab) 組合療法：NeCTuR登錄研究對一線鉑類藥物產生耐藥，或在短時間內復發的NECC患者，分析TPB組合療法與含鉑雙藥化療之療效。結果顯示TPB組之存活期顯著較長。其藥理基礎在於NECC具有高VEGFR表現，因此加入抗血管生成藥物Bevacizumab，能有效抑制腫瘤血管新生。[54]

• Nivolumab + Ipilimumab：雙免疫檢查點阻斷療法 (PD-1 + CTLA-4) 在子宮頸癌中展現了持久的反應，且這種反應不完全依賴於PD-L1的表現水平，為NECC患者提供了後線治療的新方向。[47]

表6.3 NECC全身性療法關鍵試驗 (由SCLC經驗外推適用)

mPFS: median progression free survival; mOS: median overall survival; ORR: objective response rate; RCT: randomized controlled trial. SAEs: severe adverse events.

結語

• 子宮頸癌主要由高風險HPV持續感染所致，透過定期抹片、HPV DNA檢測與九價疫苗接種，能有效阻斷癌前病變進展。

• 子宮頸癌的正確診斷仰賴陰道鏡、切片與病理評估。FIGO 2018分期納入影像與病理淋巴結證據及組織學型別 (鱗狀、腺癌、腺鱗癌) 有助精準風險分層與個別化治療規劃。

• 早期子宮頸癌首選手術治療，低風險患者可採用A型單純子宮切除合併前哨淋巴結評估。術後輔助療法依病理中度與高度風險決定是否追加放療或化放療。

• 晚期與復發性疾病以同步化放療為首選治療；全身性療法則結合含鉑類化療、免疫檢查點抑制劑、bevacizumab；標靶藥物如RET抑制劑更能針對特定突變延長存活時長。

• 子宮頸小細胞神經內分泌癌雖罕見但高度侵襲，治療上多參考小細胞肺癌模式，以化療合併免疫治療為主，需多學科團隊嚴密追蹤管理。

作者：傅彥崴 藥師

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