第九章、遺傳性腎細胞癌症候群之篩檢與診治

約3-5%的腎細胞癌源於遺傳性基因突變。辨識這些症候群不僅影響患者本身的治療 (如避免切除整個腎臟)，更關乎家族成員的早期篩檢與預防。

9.1 遺傳性腎癌的基因檢測與篩檢建議

住院醫師在臨床問診時，若發現患者符合以下任一條件，應轉介遺傳諮詢：

• 發病年齡： 診斷出腎癌時年齡 ≤ 46歲。

• 病理特徵： 雙側或多發性腎腫瘤；或具有特殊的病理型態 (如SDH缺乏型、混合型嗜酸細胞瘤) 。

• 家族史： 一等或二等親中有腎癌病史，或有已知的遺傳性腎癌綜合症。

• 臨床表徵： 合併有相關的腎外表現 (如自發性氣胸、多發性皮膚肌瘤、早發性子宮肌瘤、視網膜血管母細胞瘤) 。

9.1.1 帶因者的篩檢策略

對於已確診帶有致病突變但尚未發病的個體，篩檢的目的是「早期發現、保留腎元」。

• 影像工具：MRI是終身監測的首選工具。
  這些患者需要從年輕時進行數十年的影像追蹤，MRI可避免CT帶來的累積輻射暴露風險，且MRI對於鑑別囊腫與實質腫瘤優於超音波。

• 開始年齡：

  • 兒童期開始：VHL, HLRCC, TSC, SDH相關症候群。腫瘤可能在兒童或青少年出現。

  • 成年期開始：BHD, HPRC, BAP1症候群。通常建議從20-30歲開始篩檢。

9.2 確診遺傳性腎癌患者的腎臟專一性外科處置

對於遺傳性腎癌，手術決策與散發性腎癌截然不同。核心原則是推遲手術以保留腎功能。

9.2.1 3 公分準則 (The 3 cm Rule)

• 適用對象：VHL、HPRC、BHD、TSC患者。

• 執行方式：當實質腫瘤直徑小於3公分時，採取主動監測。直到最大腫瘤達到3公分時，才進行手術介入。

• 臨床解讀：因這些患者終其一生會不斷長出新腫瘤。若見影就開刀，患者將迅速面臨無腎狀態並依賴透析。研究顯示，這些症候群的腫瘤在3公分以下極少轉移。因此，3公分是一個安全閾值，旨在平衡預防轉移與延後洗腎。

• 手術方式：腎元保留手術 (Partial Nephrectomy) 是絕對標準。應避免根治性腎切除。

9.2.2 關鍵例外：HLRCC與SDH缺乏型RCC

• 不適用3公分原則：對於HLRCC (FH 突變) 與SDH缺乏型患者不適用。

• 立即手術：腫瘤具有高度侵襲性，即便微小也可能轉移。一旦影像學發現實質腫瘤，應立即手術切除，且需要較大範圍的切除邊界，甚至考慮根治性腎切除並廓清淋巴結。

9.3 確診遺傳性腎癌患者的腎臟專一性全身性治療

這是近年來進展最快的領域，從單純的手術切除轉向了精準藥物治療。

9.3.1 Von Hippel-Lindau (VHL)氏病：HIF-2α抑制劑的革命

Belzutifan (Welireg)的問世徹底改變了VHL的治療地圖。

• 推薦等級：Category 2A, Preferred Regimen (首選療法)。⁽³⁶⁾

• 適應症：用於治療VHL相關的腎細胞癌、中樞神經系統血管母細胞瘤、或胰臟神經內分泌腫瘤 (pNET)，且暫時不需要立即手術的患者。

• 試驗設計：單臂第二期LITESPARK-004試驗，納入61位VHL疾病患者，帶有至少一顆可測量的腎腫瘤且小於3公分；並給予Belzutifan 120 mg PO QD治療。

• 關鍵結果：腎癌ORR: 67%；CNS血管母細胞瘤ORR: 44-50%；胰臟pNET ORR:90%。

• 免除手術之可能： 許多患者在服用Belzutifan後，原本計畫的手術得以取消或無限期延後。這被視為一種化學減積手段。

• 安全性：主要副作用為貧血和缺氧。需監測Hb，必要時需輸血或使用紅血球生成素。

替代療法：Pazopanib (Category 2A, Useful in Certain Circumstances)

• 試驗設計：一項單中心第二期試驗納入37位VHL疾病患者；並給予Pazopanib (800 mg PO QD) 治療。

• 關鍵結果：Pazopanib在VHL腎癌中有52%的反應率，但對CNS病灶效果較差 (僅4%)，且肝毒性風險較高。目前僅在無法取得Belzutifan時考慮使用。⁽³⁷⁾

9.3.2 Hereditary Leiomyomatosis and RCC (HLRCC)

這類患者的腫瘤具有高度侵襲性，阻斷VEGF與EGFR能有效控制此類腫瘤

• 推薦療法：Bevacizumab + Erlotinib (Category 2A)。

• 試驗設計：一項單中心第二期試驗 (NCT01130519) 納入43位HLRCC相關的晚期papillary RCC患者。⁽³⁸⁾

• 關鍵結果：mPFS: 21.1 個月；mOS: 44.6個月。

9.3.3 結節性硬化症 (TSC, Tuberous sclerosis complex)

結節性硬化症為罕見疾病，可能導致嚴重失能，並伴隨多發性病灶，包括：腎血管平滑肌脂肪瘤 (AML)、腦部室管膜下巨細胞星狀細胞瘤 (SEGAs)、肺部淋巴管平滑肌瘤病 (LAM)。

TSC是由於mTOR通路過度活化所致。使用mTOR抑制劑能縮小腎臟血管肌肉脂肪瘤的體積，預防破裂出血，並控制TSC相關的腎細胞癌。

• 推薦療法：Everolimus。

• 試驗設計：EXIST-2試驗納入118位TSC患者且腫瘤至少一顆大於3公分，並讓患者隨機分派到Everolimus (10 mg PO QD) 或是安慰劑治療。⁽³⁹⁾

• 關鍵結果：48週腫瘤體積縮小至少50%之比率為：42% vs 0%。

總結 (Conclusion)

• 手術策略的精準化: 腎元保留手術 (PN) 已確立為T1期腫瘤的標準治療。而對於小型腎腫瘤 (<4 cm)，主動監測為避免過度治療的積極策略。

• 輔助治療的典範轉移: KEYNOTE-564試驗的成功，確立了Pembrolizumab在高風險ccRCC術後輔助治療的標準地位，這與過去TKI時代的挫敗形成了鮮明對比。

• 轉移性ccRCC的治療首選：所有風險患者建議使用VEGFR TKI+IO組合療法；而中高風險首選患者可選擇雙免疫。

• 後線治療新武器：除了轉換TKI，Belzutifan為ccRCC提供了精準打擊的新選擇。

• 非透明細胞癌的曙光：Cabozantinib成為首個具有高等級證據的標準治療。

• 對於VHL遺傳性腎癌，Belzutifan的出現讓患者有了免於手術的新希望。

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