評估貓惡性乳腺腫瘤病理組織分型、分子表型與預後相關性

Pathological Study and Molecular Phenotyping of Feline Mammary Carcinomas: The Correlation of Phenotypes with Clinical Outcome

林之涵(Susanne Je-Han Lin)

指導教授 ： 鄭謙仁

共同指導教授 ： 龐飛 ； 張惠雯 ； 武敬和(Ching-Ho Wu)

國立臺灣大學/獸醫專業學院/分子暨比較病理生物學研究所/碩士(2017年)

https://doi.org/10.6342/NTU201703918

摘要

人類的乳腺腫瘤在全球都高居女性惡性腫瘤發生率的第一位，且發生人數與死亡人數逐年增加。過去的研究將乳癌當做單一疾病，有不同的組織分型與化療反應，但隨著近年基因體之解碼與蓬勃發展之癌症醫學研究，發現人類乳癌的基因表現有著不同的內在分子亞型，分別呈現了各自的臨床表徵、分子生物學特性與預後的差別，因此在臨床上進行亞型的區分相當具有意義。這幾種內在分子亞型，大致可分為Luminal A, Luminal B, HER2-enriched, Basal-like與Normal breast-like。貓是除了狗之外，少數會自發性長出乳腺腫瘤的家畜動物，而非強行致癌之實驗動物。乳腺腫瘤在母貓為第三常見的腫瘤，僅次於皮膚腫瘤與淋巴肉瘤，且高達85- 95%被診斷為惡性。越來越多研究者提出，貓乳腺腫瘤可作為人類乳腺腫瘤之動物模式，且研究其致癌機制，可以提供許多有價值的資訊。在本研究中，依循了人類腫瘤之分類，對於74個貓惡性乳腺腫瘤檢體進行了分子表型的區分，統計其與各臨床因子、病理組織因子之間的關聯性，並追蹤了51隻貓兩年的預後情形。結果顯示四種分子表型，依多寡順序分別為Luminal B/HER2−（37/74, 50.0%; 22/51, 43.1%）、Luminal B/HER2+（20/74, 27.0%; 16/51, 31.4%）、Luminal A （14/74, 18.9%; 11/51, 21.6%）及Triple negative（3/74, 4.1%; 2/51, 3.9%）。其分佈情形與過往之研究大相逕庭，三陰乳腺腫瘤表型之占比非常低，且主要導因於過高的PR（Progesterone）陽性率（94.6%），此或許與不同的地理位置、貓隻族群不同及荷爾蒙狀態等原因相關，需要進一步研究。此四種分子表型與病理組織分級有著相關性，以Luminal A惡性程度最低，Luminal B/HER2−惡性程度最高。在預後分析部分，雖然分子表型並無顯著的預測效果，但Luminal A之存活時間仍較久，而臨床與病理組織因子中，是否遠端轉移、腫塊潰瘍、臨床分級、病理組織分型、三種病理組織分級（Elston and Ellis、Revised Elston and Ellis、Mitotic-Modified Elston and Ellis grading systems）、淋巴血管轉移與炎症類型都在本研究中有著對預後的預測效果。本研究最終之結果與過去研究並不完全相同，但仍顯示出，貓惡性腫瘤並非性質單一的疾病，且可能在地域分佈上存在著差異。若能進一步探討其中之原因，對於理解貓惡性乳腺腫瘤及進一步對人類乳腺腫瘤的比較病理學，應具有正面意義。

關鍵字

乳腺腫瘤 ； 貓乳腺腫瘤 ； 分子表型 ； 荷爾蒙受體

並列摘要

Breast cancer is the most common cancer in women worldwide, and the incidence and mortality rates increase year by year. In the past, breast cancer was perceived as a single disease entity with different histological morphologies and chemotherapy responses, but nowadays breast cancer has been divided into several intrinsic molecular subtypes after the unraveling of human genome as well as many significant discoveries. The major intrinsic subtypes include: Luminal A, Luminal B, HER2-enriched, Basal-like and Normal breast-like, which each has its own clinical characteristics, molecular gene expressions, specific biological behavior, and prognosis, making it meaningful to figure out the subgroups clinically. Domestic cats, besides dogs, are the few animal species that will spontaneously develop mammary tumors instead of the laboratorial, artificial animal models. Mammary tumors are the third most common tumor in queens, only secondary to the skin tumors and lymphomas, and up to 85 to 95% cases are diagnosed as malignant cancers. In recent years, more and more researchers have proposed that feline mammary tumors can be used as animal models for human breast cancer. In the present study, we retrospectively classified 74 feline mammary carcinomas into different intrinsic molecular subtypes based on the surrogate immunohistochemical panel from human researches, and the survival status and clinical information were obtained in 51 cats. We have found four subtypes, including Luminal B/HER2− （37/74, 50.0%; 22/51, 43.1%）, Luminal B/HER2+（20/74, 27.0%; 16/51, 31.4%）, Luminal A （14/74, 18.9%; 11/51, 21.6%） and Triple negative （3/74, 4.1%; 2/51, 3.9%）. The considerable low percentage of triple negative subtype, owing to the high positive rate of progesterone receptor （PR） （94.6%）, is quite distinct from the previous reports in which it usually serves as the major component. The disagreement may be related to the different geological location, and the different feline breeds with diverse clinical and hormonal status, which need further study. The four subtypes were associated with the histological grades: the Luminal A showed the lowest malignancy, while the Luminal B/HER2− subtype usually exhibited higher grades. In the survival analysis, although the subgroups did not show survival prediction, the Luminal A subtype had the longest overall survival time. The clinical and pathological parameters, such as distant metastasis, tumor ulceration, clinical stage, histopathological classification, three pathological grading systems （Elston and Ellis, Revised Elston and Ellis, Mitotic-Modified Elston and Ellis）, lymphovascular invasion, and types of inflammation, were associated to the survival time. In spite of the fact that our results are distinct from previous studies, it still points out the heterogeneous characteristics of feline mammary carcinomas, which may have geological differences. Further clarifying the underlying cause may enable us to know more about the nature of feline mammary tumors and will provide prospective and interesting findings for comparative pathology.

並列關鍵字

breast cancer ； feline mammary tumor ； molecular phenotype ； hormone receptor

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