台灣的慢性淋巴性白血病－流行病學，族群預後，細胞遺傳學，及新預後因子的探索

Abstract

緒論 慢性淋巴性白血病是一種和緩性的淋巴增生疾患。在西方已開發國家，慢性淋巴性白血病是最常見的成人白血病，然而，慢性淋巴性白血病在亞洲國家，發生率較西方低很多，包括台灣在內。目前有關慢性淋巴性白血病的資料，包括臨床描述，流行病學，及分子生物學研究，主要來自西方國家。很少有研究探討慢性淋巴性白血病在西方族群和東方族群之間的異同。 病患及研究方法 從台灣癌症登記資料庫中可以檢索出慢性淋巴性白血病的流行病學數據，包括發病率和病患存活狀況及時間。同一相對應時期的美國白人數據則由Surveillance, Epidemiology, and End Results資料庫中獲得。由這些資料可以估計兩個族群的慢性淋巴性白血病在不同診斷年代及不同世代中的年齡調整後之年齡別發生率，年代及世代效應的個別影響則使用年齡-年代-世代模型進行分析。將病患的實際存活率以相對應的一般健康族群預期存活率校正後，可以估計病患的相對存活率。在一個83人的台灣白血病患世代中，我們使用常規細胞遺傳學和螢光原位雜交兩種方式分析病患的細胞遺傳學異常，並和西方的資料進行比較。此外，我們也用慢性淋巴性白血病病患的骨髓切片標本，使用免疫組織化學染色，探討幹細胞因子(stem cell factor)的表現是不是一個可能的預後指標。 結果 過去20年，台灣的慢性淋巴性白血病發生率持續上升，而在美國白人則維持穩定，而60年代以後台灣的發生率趨勢有一個明顯的世代效應，時間正好跟台灣的生活方式西化的區間吻合。以相對存活率來看，整體而言，雖然慢性淋巴性白血病是一個和緩性的惡性腫瘤，這個疾病還是會大幅減短患者的壽命，而且在台灣病患中存活減少的幅度遠大於美國；在台灣，1995年之後診斷慢性淋巴性白血病的患者相對存活率有明顯改善，這個時間正好對應台灣全民健康保險計劃的啟動，這個相對存活率的改善主要發生在年齡少於65的病患，而在老年患者中則沒有改變。校正了年齡和性別影響後，診斷年代仍然對台灣患者相對存活率的改善有獨立的影響。在細胞遺傳學分析中，35例（42.2％）可由常規細胞遺傳學偵測出異常，58位（69.9％）則可以由螢光原位雜交偵測到。 不論是使用常規細胞遺傳學或螢光原位雜交，染色體17p或11q缺失者的總體存活率較差，而單獨13q缺失者存活率較佳。有５名病患在常規細胞遺傳學檢查中偵測到出現三條第３對染色體（三套染色體３），這５名患者病程都是Binet A期，但預後皆不佳，這個效應獨立於其他細胞遺傳學異常跟Binet臨床分期的影響。在初步實驗中觀察到，幹細胞因子在白血病細胞中的表達比較強的病患似乎預後較差，尤其是分期為Binet B及C的患者。 結論 除了發病率有種族差異外，台灣的慢性淋巴性白血病發病率有明顯越來越高的趨勢，而且有明顯的世代效應，暗示生活方式和環境因素可能影響台灣慢性淋巴性白血病的發生過程。台灣慢性淋巴性白血病患者的存活普遍較差，不如美國患者，然而，自1995年起，同時於醫療服務可近性的進步，年輕患者的存活已有所改善，暗示治療的進步可以增加慢性淋巴性白血病的存活，不過老年患者的存活仍然不佳，需要改善。雖然疾病的發病率不同，台灣病人細胞遺傳學異常的狀況跟西方病患類似，合併常規細胞遺傳學或螢光原位雜交分析也能夠預測台灣慢性淋巴性白血病病人的預後；至於三套染色體３作為一個不良的預後指標臨床意義則需要進一步驗證。最後，幹細胞因子的表現量可能是慢性淋巴性白血病一個新的預後指標，值得進一步用更多的檢體做確認。

Introduction Chronic lymphocytic leukemia (CLL) is an indolent clonal lymphoid neoplasm. In Western countries, CLL is the most common leukemia in adults. However, CLL is much less prevalent in Eastern countries, including Taiwan. At present, data on CLL, including the clinical picture, epidemiology, and molecular studies, are mainly derived from western countries. Few studies have addressed the similarities and differences of CLL between Western and Eastern countries. Patients and Methods Epidemiologic data for CLL in Taiwan, including the incidence rate and survival, were obtained from the Taiwan National Cancer Registry. The corresponding data for Caucasian Americans were obtained from the Surveillance, Epidemiology, and End Results database. The age-specific incidence rates of CLL for both populations were plotted by calendar year at diagnosis and by birth cohort. The individual effects of time period and birth cohort on the trends of the CLL incidence in both populations were analyzed using an age-period-cohort model. The relative survival (RS) of CLL patients in both populations was estimated as the observed survival among the cancer patients adjusted by the expected survival for a comparable group from the general population. Cytogenetic abnormalities (CA) were analyzed in a cohort of Taiwanese CLL patients (n=83) by both conventional cytogenetics (CG) and fluorescence in situ hybridization (FISH) and compared with data from Western countries. Furthermore, stem-cell factor (SCF) expression, a hypothesized prognostic marker, was also explored using immunohistochemical staining in bone marrow biopsy samples from CLL patients. Results The age-adjusted incidence rate of CLL for Taiwanese continuously increased during a 20-year period while that for Caucasian Americans remained steady. A much stronger birth-cohort effect was identified in Taiwanese compared with Caucasian Americans. This effect corresponded to the westernization of the lifestyle in Taiwan since 1960. Overall, despite its indolent course, CLL drastically shortened patients’ life expectancy in both Taiwan and the US, and the decrease in RS in Taiwan was much larger than that in the US. Intriguingly, RS in Taiwan improved in patients diagnosed after 1995, a time period corresponding to the introduction of Taiwan National Health Insurance. This improvement was observed mainly in patients younger than 65 years while RS in older patients remained unchanged. After adjustment for age and gender effects, the diagnosis period remained an independent factor contributing to changes in RS in Taiwanese patients. CA were seen in 35 patients (42.2%) by CG analysis and 58 (69.9%) patients by FISH analysis Both CG and FISH showed that deletion of 17p or 11q was associated with poorer overall survival (OS), whereas isolated 13q deletion was associated with better OS. Trisomy 3 was found in five patients by CG, all of whom were in Binet stage A but had very poor OS; this prognostic impact was independent of other CA and Binet stages. Strong SCF expression in CLL cells in a small cohort seemed to predict poor OS, especially in patients with Binet B/C disease. Conclusions In addition to the ethnic differences in the incidence, there was a distinct increased incidence trend of CLL in Taiwan. The strong birth-cohort effect underlying this trend suggests that lifestyle and environmental factors play a role in the development of CLL in Taiwanese. The survival of Taiwanese CLL patients was generally poor and inferior to that of US patients. However, the outcomes in younger patients have improved since 1995, possibly resulting from the availability of better medical care, suggesting that treatment advances have improved the outcome of CLL. Nevertheless, the survival of older patients remains poor and is in need of improvement. Although the disease incidences are different, the CA in Taiwanese patients with CLL are similar to those in the West; combined CG and FISH analysis is also able to predict outcomes in Taiwanese patients. The clinical significance of trisomy 3 as a poor prognostic factor warrants further validation. Finally, SCF expression might be a novel prognostic marker that warrants further verification with a larger cohort.