間變型多形性黃色瘤型星形細(xì)胞瘤

邵立偉 王輔林

·臨床病理報(bào)告·

間變型多形性黃色瘤型星形細(xì)胞瘤

邵立偉 王輔林

目的報(bào)道1例男性間變型多形性黃色瘤型星形細(xì)胞瘤患兒的臨床資料，探討其臨床病理學(xué)、免疫表型、基因突變特征，以及診斷與鑒別診斷要點(diǎn)。方法與結(jié)果男性患兒，11歲，頭痛伴左上肢無(wú)力15 d。頭部CT和MRI顯示右側(cè)顳葉和基底節(jié)區(qū)巨大占位性病變，提示膠質(zhì)瘤。遂行右側(cè)顳葉和基底節(jié)區(qū)占位性病變切除術(shù)，術(shù)中可見(jiàn)腫瘤呈囊實(shí)性，實(shí)性部分呈灰黃色，質(zhì)地柔軟，血供豐富，無(wú)包膜，與周圍組織界限清晰。術(shù)中冰凍病理學(xué)提示低級(jí)別膠質(zhì)瘤，遂分塊全切除腫瘤。組織學(xué)形態(tài)觀察，腫瘤細(xì)胞呈多形性，由梭形和圓形星形膠質(zhì)細(xì)胞以及單核細(xì)胞和多核瘤巨細(xì)胞組成，核分裂象罕見(jiàn)；局部可見(jiàn)較成熟的神經(jīng)元或節(jié)細(xì)胞分化成分，伴淋巴細(xì)胞浸潤(rùn)；部分區(qū)域腫瘤細(xì)胞呈間變特征，細(xì)胞密度增加，異型性明顯，以圓形和梭形細(xì)胞為主，核分裂象＞5個(gè)/10高倍視野，血管內(nèi)皮細(xì)胞增生，伴血管周圍假“菊形團(tuán)”樣結(jié)構(gòu)，局灶性壞死。免疫組織化學(xué)染色，低級(jí)別腫瘤細(xì)胞胞質(zhì)表達(dá)膠質(zhì)纖維酸性蛋白（GFAP）和BRAF V600E、胞質(zhì)和胞核表達(dá)S?100蛋白、胞膜表達(dá)CD34，少數(shù)腫瘤細(xì)胞胞質(zhì)表達(dá)突觸素和非磷酸化神經(jīng)絲重鏈SMI?32，Ki?67抗原標(biāo)記指數(shù)為3%；低級(jí)別和高級(jí)別腫瘤細(xì)胞胞核均表達(dá)P53；高級(jí)別腫瘤細(xì)胞胞質(zhì)表達(dá)GFAP和BRAF V600E，Ki?67抗原標(biāo)記指數(shù)為30%。網(wǎng)織纖維染色可見(jiàn)腫瘤細(xì)胞周圍包繞基底膜樣物質(zhì)。基因檢測(cè)顯示，低級(jí)別和高級(jí)別腫瘤均存在BRAF V600E雜合突變。結(jié)論2016年世界衛(wèi)生組織中樞神經(jīng)系統(tǒng)腫瘤分類將間變型多形性黃色瘤型星形細(xì)胞瘤定義為核分裂象＞5個(gè)/10高倍視野，屬WHOⅢ級(jí)，預(yù)后較WHOⅡ級(jí)多形性黃色瘤型星形細(xì)胞瘤差。鑒別診斷主要包括膠質(zhì)母細(xì)胞瘤、毛細(xì)胞型星形細(xì)胞瘤和節(jié)細(xì)胞膠質(zhì)瘤，盡管上述腫瘤臨床表現(xiàn)、組織學(xué)形態(tài)、免疫表型和基因突變有重疊，但生物學(xué)行為、治療及預(yù)后各異。

黃瘤??； 星形細(xì)胞瘤； 間變； 免疫組織化學(xué)； 病理學(xué)

多形性黃色瘤型星形細(xì)胞瘤（PXA）是臨床罕見(jiàn)的原發(fā)性星形細(xì)胞腫瘤，占所有星形細(xì)胞腫瘤的1%以下，具有特征性臨床病理學(xué)和影像學(xué)特點(diǎn)，好發(fā)于兒童和青年，中位發(fā)病年齡為22歲，通常位于大腦淺表位置，累及軟腦膜和腦組織，約98%發(fā)生于幕上，尤以顳葉常見(jiàn)，多數(shù)患者存在長(zhǎng)期癲病史［1?2］。組織病理學(xué)以腫瘤細(xì)胞多形性為特征，伴單核細(xì)胞或多核瘤巨細(xì)胞、嗜酸性小體，血管周圍可見(jiàn)豐富淋巴細(xì)胞浸潤(rùn)，腫瘤組織附著于網(wǎng)狀纖維。2016年世界衛(wèi)生組織（WHO）中樞神經(jīng)系統(tǒng)腫瘤分類取消“伴間變特征的多形性黃色瘤型星形細(xì)胞瘤”命名，將核分裂象≥5個(gè)/10高倍視野（HPF）者定義為“間變型多形性黃色瘤型星形細(xì)胞瘤”，屬WHOⅢ級(jí)，伴或不伴壞死［1，3］。近年報(bào)道的間變型多形性黃色瘤型星形細(xì)胞瘤病例逐漸增多［4?11］。本文報(bào)道1例發(fā)生于顳葉和基底節(jié)區(qū)的間變型多形性黃色瘤型星形細(xì)胞瘤患兒，并復(fù)習(xí)相關(guān)文獻(xiàn)，初步探討其臨床病理學(xué)特點(diǎn)、免疫表型和BRAF V600E突變形式，并與組織學(xué)形態(tài)、免疫表型和基因突變相似的腫瘤進(jìn)行鑒別診斷。

病歷摘要

患兒 男性，11歲。主因頭痛伴左上肢無(wú)力15 d，于2016年1月15日入院?；颊?5 d前無(wú)明顯誘因出現(xiàn)頭痛伴左上肢無(wú)力，右側(cè)肢體正常，無(wú)肢體抽搐、意識(shí)障礙、大小便失禁。外院頭部CT檢查顯示，右側(cè)顳葉和基底節(jié)區(qū)巨大囊實(shí)性占位性病變伴幕上積水，考慮高級(jí)別膠質(zhì)瘤（圖1）。頭部MRI顯示，右側(cè)顳葉和基底節(jié)區(qū)巨大囊實(shí)性占位性病變伴幕上積水，T1WI可見(jiàn)病變界限相對(duì)清晰，呈以低信號(hào)為主的混雜信號(hào)影，周圍水腫帶呈低信號(hào)；T2WI可見(jiàn)病變呈不均勻高信號(hào)；FLAIR成像呈稍高信號(hào)；增強(qiáng)掃描病變呈環(huán)形和斑片狀不均勻明顯強(qiáng)化，囊性變區(qū)未見(jiàn)明顯強(qiáng)化（圖2）。為求進(jìn)一步診斷與治療，遂至我院就診，門診以“右側(cè)顳葉巨大占位性病變”收入院?；颊咦园l(fā)病以來(lái)，精神良好，睡眠、飲食可，體重?zé)o明顯變化，大小便正常。

既往史、個(gè)人史及家族史 既往身體健康，身高和體重發(fā)育正常，智力發(fā)育正常，否認(rèn)手術(shù)、外傷和輸血史，否認(rèn)藥物和食物過(guò)敏史，預(yù)防接種史不詳。生于山西省，久居本地，無(wú)疫區(qū)居住史，無(wú)疫情、疫水接觸史，無(wú)牧區(qū)、礦山、高氟區(qū)、低碘區(qū)居住史，無(wú)化學(xué)性物質(zhì)、放射物、毒物接觸史，無(wú)毒品接觸史，無(wú)吸煙、飲酒史。父母和兄長(zhǎng)身體健康，家族中無(wú)傳染性疾病和遺傳性疾病病史。

體格檢查 患兒體溫36.4℃，脈搏80次/min，呼吸 19 次/min，血壓 102/66 mm Hg（1 mm Hg=0.133 kPa）；身 高 150 cm，體 重 35 kg，體 重 指 數(shù)（BMI）15.60 kg/m2，發(fā)育正常，營(yíng)養(yǎng)良好，面容表情正常，自主體位；神志清楚，語(yǔ)言流利，查體合作，胸腹部檢查未見(jiàn)異常。神經(jīng)系統(tǒng)檢查：雙側(cè)瞳孔等大、等圓，直徑約2.50 mm，對(duì)光反射靈敏，眼球各向活動(dòng)充分；鼻唇溝對(duì)稱，口角無(wú)歪斜，伸舌居中；左上肢肌力4級(jí)、余肢體5級(jí)，肌張力均正常，無(wú)肌萎縮、肌束顫；痛溫覺(jué)和輕觸覺(jué)正常，兩點(diǎn)辨別覺(jué)、圖形覺(jué)、位置覺(jué)和音叉震動(dòng)覺(jué)正常；雙側(cè)快復(fù)輪替動(dòng)作、指鼻試驗(yàn)、跟?膝?脛試驗(yàn)穩(wěn)準(zhǔn)，Romberg征陰性，直線行走試驗(yàn)陰性；病理征陰性，腦膜刺激征陰性。自主神經(jīng)系統(tǒng)檢查：全身皮膚溫度和濕度適中，皮膚彈性好，皮膚劃痕試驗(yàn)陰性。

圖1 頭部CT檢查顯示，右側(cè)顳葉和基底節(jié)區(qū)巨大囊實(shí)性占位性病變，呈不規(guī)則混雜密度影，其內(nèi)可見(jiàn)多房性低密度囊性變區(qū)，周圍可見(jiàn)片狀低密度水腫帶（箭頭所示）；右側(cè)側(cè)腦室受壓，中線結(jié)構(gòu)向左側(cè)偏移 圖2 頭部MRI檢查所見(jiàn) 2a 橫斷面T1WI顯示，病變界限相對(duì)清晰，呈以低信號(hào)為主的混雜信號(hào)影，周圍水腫帶呈低信號(hào)（箭頭所示） 2b 橫斷面T2WI顯示，病變呈不均勻高信號(hào)（箭頭所示） 2c 橫斷面FLAIR成像顯示病變呈稍高信號(hào)（箭頭所示） 2d 橫斷面增強(qiáng)T1WI顯示，病變呈環(huán)形和斑片狀不均勻明顯強(qiáng)化（箭頭所示），囊性變區(qū)未見(jiàn)明顯強(qiáng)化Figure 1 Cranial CT scan showed a huge space?occupying cystic?solid lesion in right temporal lobe and basal ganglia(arrow indicates),which was an irregular mixed density with multiple low?density cystic changes,surrounded by patchy low?density edema.Obvious space?occupying effect was found.The right ventricle was compressed and the midline was shifted to left. Figure 2 Cranial MRI findings.Axial T1WI showed the lesion boundary was relatively clear,and mixed signal lesion with predominant hypointense signal were seen(arrow indicates).Periphal edema zone with low?signal was seen(Panel 2a).Axial T2WI showed a heterogeneous hyperintense signal lesion(arrow indicates,Panel 2b).Axial FLAIR imaging displayed slight hyperintense signal lesion(arrow indicates,Panel 2c).Axial enhanced T1WI revealed heterogeneous ring or patchy enhancement lesion(arrow indicates),whereas enhancement was not seen in cystic region(Panel 2d).

診斷與治療經(jīng)過(guò) 實(shí)驗(yàn)室檢查各項(xiàng)指標(biāo)均于正常值范圍。結(jié)合外院影像學(xué)檢查，臨床診斷為膠質(zhì)瘤。完善術(shù)前準(zhǔn)備，于2016年1月19日在全身麻醉下行MRI導(dǎo)航下右側(cè)顳葉膠質(zhì)瘤切除術(shù)。術(shù)中可見(jiàn)腫瘤位于大腦皮質(zhì)下1 cm處，呈囊實(shí)性，實(shí)性部分呈灰黃色，質(zhì)地柔軟，血供豐富，無(wú)包膜，與周圍組織界限清晰，瘤體主要位于右側(cè)顳葉并突入側(cè)腦室，中線結(jié)構(gòu)向左側(cè)偏移。切取實(shí)性部分行快速冷凍病理學(xué)檢查，術(shù)中報(bào)告低級(jí)別膠質(zhì)瘤，遂于手術(shù)顯微鏡下分塊全切除腫瘤，行組織病理學(xué)檢查。（1）大體標(biāo)本觀察：術(shù)中和術(shù)后送檢標(biāo)本為灰白色破碎組織，大小分別為1.50 cm×1.00 cm×0.30 cm和9 cm×5 cm×2 cm，質(zhì)地柔軟，血供豐富，無(wú)包膜。經(jīng)體積分?jǐn)?shù)為10%中性甲醛溶液固定、常規(guī)脫水、石蠟包埋、4 μm連續(xù)切片，分別行HE染色、免疫組織化學(xué)染色和網(wǎng)狀纖維染色。（2）HE染色：腫瘤組織可見(jiàn)兩種組織學(xué)形態(tài)，術(shù)中送檢組織和部分術(shù)后送檢組織腫瘤細(xì)胞呈多形性，由梭形和圓形星形膠質(zhì)細(xì)胞以及單核細(xì)胞和多核瘤巨細(xì)胞組成，核分裂象罕見(jiàn)，可見(jiàn)較成熟的神經(jīng)元或節(jié)細(xì)胞分化成分，伴淋巴細(xì)胞浸潤(rùn)，局灶性泡沫樣細(xì)胞聚集，未見(jiàn)血管內(nèi)皮細(xì)胞增生和壞死灶，病變累及軟腦膜，呈現(xiàn)低級(jí)別腫瘤（WHOⅡ級(jí)）組織學(xué)形態(tài)改變（圖3，4）。部分術(shù)后送檢組織腫瘤細(xì)胞密度增加、異型性明顯，以圓形和梭形星形膠質(zhì)細(xì)胞成分為主，不典型核分裂象＞5個(gè)/10高倍視野，可見(jiàn)血管內(nèi)皮細(xì)胞增生，伴血管周圍假“菊形團(tuán)”樣結(jié)構(gòu)，局灶性壞死，呈高級(jí)別腫瘤（WHOⅢ級(jí)）組織學(xué)形態(tài)改變（圖5）。（3）免疫組織化學(xué)染色：采用SP二步法，檢測(cè)用試劑盒購(gòu)自北京中杉金橋生物技術(shù)有限公司，檢測(cè)用抗體包括突觸素（Syn，1∶100），膠質(zhì)纖維酸性蛋白（GFAP，1∶400），R132H?突變的異檸檬酸脫氫酶1（IDH1，1∶200），P53（1∶75），S?100 蛋白（S?100，1∶2000），CD34（1∶100），CD68（1∶100），神經(jīng)微絲蛋白（NF，1∶100），非磷酸化神經(jīng)絲重鏈 SMI?32（1∶7500），上皮膜抗原（EMA，工作液），BRAF V600E（工作液）和Ki?67抗原，均購(gòu)自北京中杉金橋生物技術(shù)有限公司。結(jié)果顯示，低級(jí)別腫瘤細(xì)胞胞質(zhì)表達(dá) GFAP（圖 6a）和 BRAF V600E（圖 6b）、胞質(zhì)和胞核表達(dá)S?100、胞膜表達(dá) CD34（圖6c），少數(shù)腫瘤細(xì)胞胞質(zhì)表達(dá) Syn（圖 6d）和 SMI?32（圖 6e），Ki?67 抗原標(biāo)記指數(shù)為3%（圖6f），不表達(dá)NF和EMA；高級(jí)別和低級(jí)別腫瘤細(xì)胞胞核均表達(dá)P53（圖7a）；高級(jí)別腫瘤細(xì)胞胞質(zhì)表達(dá)GFAP（圖7b）和BRAF V600E（圖7c），不表達(dá) R132H?突變的 IDH1和 CD34，Ki?67抗原標(biāo)記指數(shù)為30%（圖7d）。（4）特殊染色：網(wǎng)織纖維染色顯示腫瘤細(xì)胞周圍包繞基底膜樣物質(zhì)。（5）基因檢測(cè)：采用聚合酶鏈反應(yīng)（PCR）擴(kuò)增BRAF V600E位點(diǎn)，再行Sanger測(cè)序，結(jié)果顯示，低級(jí)別和高級(jí)別腫瘤均存在BRAF V600E雜合突變（圖8）。最終病理診斷為：（右側(cè)顳葉和基底節(jié)區(qū)）間變型多形性黃色瘤型星形細(xì)胞瘤（WHOⅢ級(jí)）。術(shù)后未輔助放射治療和藥物化療。患者共住院22 d，出院時(shí)病情平穩(wěn)，恢復(fù)良好。出院后9個(gè)月失訪。

圖3 術(shù)中送檢標(biāo)本組織學(xué)形態(tài)光學(xué)顯微鏡觀察所見(jiàn) HE染色 3a 腫瘤細(xì)胞呈多形性，由梭形細(xì)胞以及單核細(xì)胞和多核瘤巨細(xì)胞組成 ×100 3b 可見(jiàn)單核細(xì)胞和多核瘤巨細(xì)胞，腫瘤細(xì)胞異型性明顯 ×200Figure 3 Optical microscopy findings of histological patterns of sample of intra?operation HE staining Pleomorphic histological appearance of tumor was characterized by spindled cells being intermingled with mononucleated or multinucleated giant cells(Panel 3a). ×100 Nuclear pleomorphism and bizarre were seen in mononucleated or multinucleated tumor giant cells(Panel 3b). ×200

圖4 部分術(shù)后送檢標(biāo)本（低級(jí)別腫瘤）組織學(xué)形態(tài)光學(xué)顯微鏡觀察所見(jiàn) HE染色 4a 腫瘤組織由梭形細(xì)胞以及單核細(xì)胞和多核瘤巨細(xì)胞組成 ×200 4b 多核瘤巨細(xì)胞胞核呈“馬蹄”樣排列 ×200 4c 腫瘤位于腦表淺位置，侵及軟腦膜，與大腦皮質(zhì)分界清晰 ×100 4d 部分區(qū)域可見(jiàn)較多單核細(xì)胞和多核瘤巨細(xì)胞聚集 ×400Figure 4 Optical microscopy findings of histological patterns of sample(low grade tumor)of surgical excision HE staining Tumor was composed of spindled cells,mononucleated and multinucleated tumor giant cells(Panel 4a). ×200 Nuclei of multinucleated tumor giant cell were arranged in a horseshoe?like pattern at edge of the cell(Panel 4b). × 200 Tumor cells invaded pia mater(leptomeningeal)and clearly delineated from the underlying cerebral cortex(Panel 4c). ×100 Prominent mononucleated or multinucleated tumor giant cells were seen in part of the region(Panel 4d). ×400

圖5 部分術(shù)后送檢標(biāo)本（高級(jí)別腫瘤）組織學(xué)形態(tài)光學(xué)顯微鏡觀察所見(jiàn) HE染色 5a 可見(jiàn)典型多形性黃色瘤型星形細(xì)胞瘤成分 ×200 5b 腫瘤細(xì)胞呈相對(duì)一致的圓形或卵圓形，可見(jiàn)不典型核分裂象 ×400 5c 腫瘤細(xì)胞圍繞血管周圍排列，可見(jiàn)血管周圍假“菊形團(tuán)”樣結(jié)構(gòu) ×100 5d 可見(jiàn)局灶性壞死，腫瘤細(xì)胞呈“柵欄”樣排列 ×100Figure 5 Optical microscopy findings of histological patterns of sample(high grade tumor)of surgical excision HE staining Typical histologic feature of PXA,WHO gradeⅡwas seen(Panel 5a). ×200 Atypical mitotic activity was seen in the round or oval shape tumor cells(Panel 5b). ×400 Tumor cells were arranged around the vascular as perivascular pseudorosettes(Panel 5c). ×100 Focal necrosis was seen and tumor cells were arranged in column(Panel 5d). ×100

討 論

Kepes等［2］于1979年首次報(bào)告并命名多形性黃色瘤型星形細(xì)胞瘤，是臨床罕見(jiàn)的原發(fā)性星形細(xì)胞腫瘤，具有特征性組織病理學(xué)特點(diǎn)。腫瘤細(xì)胞呈梭形細(xì)胞、單核細(xì)胞和多核瘤巨細(xì)胞的多形性特點(diǎn)，伴胞體寬大的多核瘤巨細(xì)胞，胞質(zhì)表達(dá)GFAP，腫瘤細(xì)胞周圍包繞致密網(wǎng)織纖維，是一種特殊類型的星形細(xì)胞腫瘤，故命名為“多形性黃色瘤型星形細(xì)胞瘤”。多形性黃色瘤型星形細(xì)胞瘤僅占顱內(nèi)腫瘤的0.09%，占所有星形細(xì)胞腫瘤的＜1%［1］，好發(fā)于兒童和青年，亦有老年患者的報(bào)道［12］，無(wú)性別和種族差異。

多形性黃色瘤型星形細(xì)胞瘤組織病理學(xué)特點(diǎn)主要表現(xiàn)為［13］：（1）腫瘤細(xì)胞呈多形性，即梭形細(xì)胞、肥胖細(xì)胞以及單核細(xì)胞和多核瘤巨細(xì)胞多種成分，胞核和核仁大小不一，常見(jiàn)核內(nèi)包涵體（INIs）。（2）可見(jiàn)黃色瘤型星形細(xì)胞，即脂質(zhì)聚集于腫瘤細(xì)胞內(nèi)，融合并充滿或占據(jù)大部分胞質(zhì)，其星形膠質(zhì)細(xì)胞特性經(jīng)GFAP染色證實(shí)。（3）可見(jiàn)網(wǎng)織纖維，即腫瘤細(xì)胞周圍包繞的基底膜樣物質(zhì)，經(jīng)網(wǎng)織纖維染色證實(shí)。此外，還可見(jiàn)嗜酸性小體，間質(zhì)或血管周圍淋巴細(xì)胞和漿細(xì)胞浸潤(rùn)，后者形成血管周圍淋巴“袖套”或局灶性聚集。

圖6 低級(jí)別腫瘤光學(xué)顯微鏡觀察所見(jiàn) 免疫組織化學(xué)染色（SP二步法） 6a 腫瘤細(xì)胞胞質(zhì)表達(dá)GFAP ×200 6b 腫瘤細(xì)胞胞質(zhì)表達(dá)BRAF V600E ×200 6c 腫瘤細(xì)胞胞膜表達(dá)CD34 ×200 6d 少數(shù)腫瘤細(xì)胞胞質(zhì)表達(dá)Syn ×200 6e 個(gè)別神經(jīng)元樣細(xì)胞胞質(zhì)表達(dá)非磷酸化神經(jīng)絲重鏈SMI?32 ×400 6f Ki?67抗原標(biāo)記指數(shù)約3% ×100Figure 6 Optical microscopy findings of low grade tumor Immunohistochemical staining(SP) The cytoplasm of tumor cells was positive for GFAP(Panel 6a)and BRAF V600E(Panel 6b). ×200 Tumor cells membrane was positire for CD34(Panel 6c). ×200 The cytoplasm of a few tumor cells was positive for Syn(Panel 6d). × 200 The cytoplasm of individual neuron?like cells was positive for SMI?32(Panel 6e). × 400 Ki?67 labeling index was about 3%(Panel 6f). × 100

圖7 高級(jí)別腫瘤光學(xué)顯微鏡觀察所見(jiàn) 免疫組織化學(xué)染色（SP二步法） 7a 腫瘤細(xì)胞胞核表達(dá)P53 ×100 7b 腫瘤細(xì)胞胞質(zhì)表達(dá)GFAP ×200 7c 腫瘤細(xì)胞胞質(zhì)表達(dá)BRAF V600E ×200 7d Ki?67抗原標(biāo)記指數(shù)約30% ×100Figure 7 Optical microscopy findings of high grade tumor Immunohistochemical staining(SP) Tumor cells nucleus was positive for P53(Panel 7a). ×100 The cytoplasm of tumor cell was positive for GFAP(Panel 7b)and BRAF V600E(Panel 7c). ×200 Ki?67 labeling index was about 30%(Panel 7d). ×100

在2007年WHO中樞神經(jīng)系統(tǒng)腫瘤分類中，多形性黃色瘤型星形細(xì)胞瘤屬WHOⅡ級(jí)，伴明顯核分裂象或壞死者命名為“伴間變特征的多形性黃色瘤型星形細(xì)胞瘤”［14］。2016年WHO中樞神經(jīng)系統(tǒng)腫瘤分類取消該命名，將間變型多形性黃色瘤型星形細(xì)胞瘤（WHOⅢ級(jí)）列為一種明確類型，其診斷標(biāo)準(zhǔn)為：核分裂象≥5個(gè)/10高倍視野，可伴壞死［13］。間變型多形性黃色瘤型星形細(xì)胞瘤病變部位、臨床表現(xiàn)和影像學(xué)特點(diǎn)均與WHOⅡ級(jí)的多形性黃色瘤型星形細(xì)胞瘤相似［13］。組織病理學(xué)典型特征是核分裂活躍，呈局灶性或彌漫性分布。常見(jiàn)的壞死灶與高核分裂活性密切相關(guān)。微血管增生不明顯，常與核分裂活性和壞死相關(guān)。與WHOⅡ級(jí)的多形性黃色瘤型星形細(xì)胞瘤相比，間變型多形性黃色瘤型星形細(xì)胞瘤細(xì)胞多形性不明顯，突出表現(xiàn)為彌漫性和浸潤(rùn)性生長(zhǎng)模式［13］。有文獻(xiàn)報(bào)道，間變型多形性黃色瘤型星形細(xì)胞瘤可見(jiàn)小細(xì)胞、纖維樣、上皮樣/橫紋肌樣成分［15?17］。

多形性黃色瘤型星形細(xì)胞瘤細(xì)胞表達(dá)GFAP和S?100［1］；存在明顯的神經(jīng)元分化特征，表達(dá)相應(yīng)的神經(jīng)元標(biāo)志物［18］，如 Syn、嗜鉻素 A（CgA）、NF、β?微管蛋白（β?tubulin）和微管相關(guān)蛋白?2（MAP?2）；部分表達(dá)P53。大多數(shù)多形性黃色瘤型星形細(xì)胞瘤核分裂象罕見(jiàn)或缺如，Ki?67 抗原標(biāo)記指數(shù) ＜ 2%［1］且隨著腫瘤惡性程度的增加而升高，間變型多形性黃色瘤型星形細(xì)胞瘤達(dá)10%甚至20%［5］。多形性黃色瘤型星形細(xì)胞瘤細(xì)胞表達(dá)CD34，陽(yáng)性率達(dá)84%，但間變型多形性黃色瘤型星形細(xì)胞瘤CD34陽(yáng)性率下降，僅為44%，可資鑒別［19］。

有50%～78%的WHOⅡ級(jí)多形性黃色瘤型星形細(xì)胞瘤存在BRAF基因突變，尤以BRAF V600E突變最為常見(jiàn)，故腫瘤細(xì)胞表達(dá)BRAF V600E，免疫組織化學(xué)染色檢測(cè)BRAF V600E敏感性和特異性均較高［20］。研究顯示，約75%WHOⅡ級(jí)多形性黃色瘤型星形細(xì)胞瘤存在BRAF V600E突變，WHOⅢ級(jí)間變型多形性黃色瘤型星形細(xì)胞瘤BRAF V600E突變率較低（47.4%）［10］，且兒童與成人無(wú)明顯差異［3］。BRAF V600E突變亦見(jiàn)于其他原發(fā)性中樞神經(jīng)系統(tǒng)腫瘤，特別是膠質(zhì)母細(xì)胞瘤（GBM）、毛細(xì)胞型星形細(xì)胞瘤（PA）和節(jié)細(xì)胞膠質(zhì)瘤（GG）［21］。

圖8 Sanger測(cè)序顯示，BRAF基因存在第15外顯子雜合突變c.1799A＞TFigure 8 The 1799 basic group of 15th exon of BRAF occurred heterozygosis mutation:A＞T.

應(yīng)注意與膠質(zhì)母細(xì)胞瘤兩種亞型巨細(xì)胞型膠質(zhì)母細(xì)胞瘤和上皮樣膠質(zhì)母細(xì)胞瘤、毛細(xì)胞型星形細(xì)胞瘤及節(jié)細(xì)胞膠質(zhì)瘤相鑒別。（1）巨細(xì)胞型膠質(zhì)母細(xì)胞瘤：腫瘤組織以大量異形多核瘤巨細(xì)胞、豐富網(wǎng)狀纖維和淋巴細(xì)胞浸潤(rùn)為特征，亦可見(jiàn)血管周圍假“菊形團(tuán)”樣結(jié)構(gòu)，與多形性黃色瘤型星形細(xì)胞瘤組織學(xué)形態(tài)相重疊，應(yīng)予以鑒別［22］。多形性黃色瘤型星形細(xì)胞瘤核分裂象罕見(jiàn)，未見(jiàn)壞死，Ki?67抗原標(biāo)記指數(shù)＜2%，易區(qū)分。間變型多形性黃色瘤型星形細(xì)胞瘤和巨細(xì)胞型膠質(zhì)母細(xì)胞瘤均表現(xiàn)為核分裂活躍，特別是當(dāng)前者出現(xiàn)廣泛壞死時(shí)，難以區(qū)分。Reifenberger等［19］研究顯示，多形性黃色瘤型星形細(xì)胞瘤表達(dá)CD34，而巨細(xì)胞型膠質(zhì)母細(xì)胞瘤不表達(dá)，可資鑒別。此外，與多形性黃色瘤型星形細(xì)胞瘤不同，巨細(xì)胞型膠質(zhì)母細(xì)胞瘤幾乎不表達(dá)神經(jīng)元標(biāo)志物［NF、神經(jīng)元核抗原（NeuN）、Syn等］，可資鑒別［22］。（2）上皮樣膠質(zhì)母細(xì)胞瘤：好發(fā)于兒童和青年，腫瘤細(xì)胞可見(jiàn)多核瘤巨細(xì)胞、脂肪化、促纖維增生反應(yīng)，約 50%患者存在 BRAF V600E 突變［23?24］。二者不同之處在于，間變型多形性黃色瘤型星形細(xì)胞瘤缺乏腫瘤細(xì)胞形態(tài)一致性特點(diǎn)，可見(jiàn)嗜酸性小體［25?26］和局灶性典型低級(jí)別多形性黃色瘤型星形細(xì)胞瘤成分［13］。（3）毛細(xì)胞型星形細(xì)胞瘤：約9%患者存在BRAF V600E突變，主要見(jiàn)于幕上毛細(xì)胞型星形細(xì)胞瘤患者［27］，免疫組織化學(xué)染色BRAF V600E陽(yáng)性。二者鑒別診斷要點(diǎn)在于，毛細(xì)胞型星形細(xì)胞瘤的致密纖維區(qū)域由特征性細(xì)長(zhǎng)突起的雙極腫瘤細(xì)胞組成，含豐富Rosenthal纖維；稀疏區(qū)可見(jiàn)微囊結(jié)構(gòu)和規(guī)則的假少突膠質(zhì)細(xì)胞結(jié)構(gòu)［28］，并伴透明樣變性的厚壁血管和海綿狀血管瘤樣等退行性變成分。（4）節(jié)細(xì)胞膠質(zhì)瘤：系發(fā)育異常的神經(jīng)元和腫瘤性膠質(zhì)細(xì)胞組成的神經(jīng)元及混合性神經(jīng)元?膠質(zhì)腫瘤，約70%以上的WHOⅠ級(jí)節(jié)細(xì)胞膠質(zhì)瘤位于顳葉，臨床癥狀主要為局限性癲發(fā)作［29］。腫瘤性神經(jīng)元的大小和分布差異較大，可見(jiàn)雙核神經(jīng)元、鈣化、促纖維增生反應(yīng)、淋巴細(xì)胞浸潤(rùn)和嗜酸性小體；梭形細(xì)胞成分與彌漫性星形細(xì)胞瘤、毛細(xì)胞型星形細(xì)胞瘤或多形性黃色瘤型星形細(xì)胞瘤等組織學(xué)形態(tài)相似。腫瘤性神經(jīng)元成分表達(dá)神經(jīng)元標(biāo)志物，如MAP?2、NF、CgA、Syn和CD34；腫瘤性膠質(zhì)細(xì)胞表達(dá)GFAP［29?31］。有 20% ～ 60%的節(jié) 細(xì) 胞 膠質(zhì) 瘤 存 在BRAF V600E 突變［27，32?33］。節(jié)細(xì)胞膠質(zhì)瘤細(xì)胞成分缺乏多形性黃色瘤型星形細(xì)胞瘤的細(xì)胞多形性特點(diǎn)，即梭形細(xì)胞及單核細(xì)胞和多核瘤巨細(xì)胞的混合成分，以及特征性富含脂質(zhì)的多核瘤巨細(xì)胞，可資鑒別。

多形性黃色瘤型星形細(xì)胞瘤有相對(duì)良性的臨床病程。一項(xiàng)納入74例多形性黃色瘤型星形細(xì)胞瘤患者的研究顯示，5年無(wú)進(jìn)展生存率和總生存率分別為70.9%和90.4%；手術(shù)切除范圍是最具意義的腫瘤復(fù)發(fā)預(yù)測(cè)因素［3］。間變型多形性黃色瘤型星形細(xì)胞瘤患者預(yù)后較差、生存期較短，5年總生存率顯著低于多形性黃色瘤型星形細(xì)胞瘤患者（55.6%對(duì)89.4%），且伴壞死的患者5年總生存率低于不伴壞死的患者（42.2%對(duì)90.2%）。兒童和成人的5年無(wú)進(jìn)展生存率（67.99%對(duì)62.4%）和總生存率無(wú)顯著差異（87.4%對(duì)76.3%）；BRAF V600E突變的預(yù)后意義不明［3］。多形性黃色瘤型星形細(xì)胞瘤患者應(yīng)進(jìn)行長(zhǎng)期隨訪。

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Anaplastic pleomorphic xanthoastrocytoma

SHAO Li?wei,WANG Fu?lin
Department of Pathology,Chinese PLA General Hospital,Beijing 100853,China
Corresponding author:WANG Fu?lin(Email:wfl301@yeah.net)

ObjectiveTo investigate the clinicopathological features,immune phenotype and gene mutation characteristics,and diagnosis or differential diagnosis of anaplastic pleomorphic xanthoastrocytoma(PXA).Methods and ResultsA 11 ?year?old male patient presented with more than half month of headache,and left upper limb weakness.Cranial CT and MRI revealed a large space?occupying lesion in the right parietal lobe and basal ganglia which was suggested as glioma.During operation the tumor was examined.It was a cystic?solid lesion.The solid part was soft and greyish yellow with rich blood supply and without membrane,and the boundary was clear.Intraoperative freezing pathologic examination showed the tumor was a low grade glioma.The right parietal glioma was completely removed piece by piece under the microscopy.Histologically,the tumor cells were polymorphism,including spindle or round astrocytes,monocytes and multinuclear tumor giant cells.Mitoses were rarely seen.Differentiation of mature neuronal cells or ganglion cells with lymphocyte infiltration were seen in focal region.In some regions,tumor cells were anaplastic,and cellularity were increased.Atypical round or spindle cells were seen,and atypical mitoses＞5/10 high power field(HPF)were found.Microvascular proliferation,perivascular pseudorosettes and localized necrosis were also evident. Immunohistochemically,tumor cells were positive for glial fibrillary acidic protein(GFAP),BRAF V600E,S?100 protein(S?100),CD34,synaptophysin(Syn),non?phosphorylation neurofilament heauy chain SMI?32 and P53,but negative for isocitrate dehydrogenase 1(IDH1),neurofilament protein(NF)and epithelial membrane antigen(EMA).Ki?67 labeling index was about 3%in low grade tumor cells,while Ki?67 labeling index was about 30%in high grade tumor cells.In reticular fibre tissue staining,a lot of reticular fibre tissue were seen. BRAF V600E heterozygous mutation c.1799A＞T was detected by Sanger sequencing.Conclusions Anaplastic PXA in gradeⅢis defined as mitoses＞5/10 HPF in World Health Organization(WHO)classification of tumors of the central neuvous system,2016.Its prognosis is worse than gradeⅡ tumor.The differential diagnosis from glioblastoma(GBM),pilocytic astrocytoma(PA)and ganglioglioma(GG)should be kept in mind,because all of them having some overlaps in clinicopathological presentations,imaging manifestation,immunophenotype features and genetic mutation,but quite different in their biological behavior,treatment and prognosis.

Xanthomatosis; Astrocytoma; Anaplasia; Immunohistochemistry; Pathology

10.3969/j.issn.1672?6731.2017.08.011

100853北京，解放軍總醫(yī)院病理科

王輔林（Email：wfl301@yeah.net）

2017?06?27）