垂體轉(zhuǎn)移性肺非典型類癌

閻曉玲 唐帆 韓竹語 張學(xué)斌 金樹梅

·臨床病理報(bào)告·

垂體轉(zhuǎn)移性肺非典型類癌

閻曉玲 唐帆 韓竹語 張學(xué)斌 金樹梅

目的報(bào)道1例垂體轉(zhuǎn)移性肺非典型類癌患者的臨床資料，總結(jié)此類腫瘤的臨床病理學(xué)特征及診斷與鑒別診斷要點(diǎn)。方法與結(jié)果女性患者，81歲，臨床表現(xiàn)為頭痛，突然失明；頭部MRI提示鞍區(qū)占位性病變。遂行經(jīng)鼻蝶入路鞍區(qū)占位性病變切除術(shù)，術(shù)中可見腫瘤位于鞍內(nèi)，呈灰紅色，直徑約2 cm，質(zhì)地柔軟，血運(yùn)不豐富，無包膜，邊界欠清晰，沿邊緣手術(shù)全切除腫瘤。組織學(xué)形態(tài)觀察，腫瘤組織由形態(tài)較單一、大小較一致的小圓形細(xì)胞構(gòu)成，呈巢片狀彌漫性分布，可見核分裂象和灶性壞死。免疫組織化學(xué)染色，腫瘤細(xì)胞彌漫性表達(dá)突觸素、CD56，部分表達(dá)甲狀腺轉(zhuǎn)錄因子?1、廣譜細(xì)胞角蛋白、P53，不表達(dá)生長(zhǎng)激素、泌乳素、促腎上腺皮質(zhì)激素、卵泡刺激素、促甲狀腺激素、黃體生成素、S?100蛋白、甲狀腺球蛋白、降鈣素，Ki?67抗原標(biāo)記指數(shù)約為33%。結(jié)論垂體轉(zhuǎn)移瘤臨床少見，垂體轉(zhuǎn)移性肺非典型類癌更為罕見，明確診斷依靠臨床病史、組織學(xué)形態(tài)和免疫表型。

肺腫瘤； 類癌瘤； 腫瘤轉(zhuǎn)移； 垂體； 免疫組織化學(xué)； 病理學(xué)

垂體轉(zhuǎn)移瘤臨床罕見［1?3］，近年隨著腫瘤患者生存期的延長(zhǎng)和神經(jīng)影像學(xué)的發(fā)展，病例數(shù)有所增加，發(fā)生率約占全部垂體腫瘤的 1%［2，4?5］，女性乳腺和男性肺部為最常見的腫瘤原發(fā)灶［1?2，6］。本文報(bào)告1例垂體轉(zhuǎn)移性肺非典型類癌患者，通過復(fù)習(xí)相關(guān)文獻(xiàn)，對(duì)其組織形態(tài)學(xué)特點(diǎn)、免疫組織化學(xué)表型、診斷與鑒別診斷、治療及預(yù)后等臨床病理學(xué)特征進(jìn)行總結(jié)。

病歷摘要

圖1 頭部MRI檢查所見 1a 矢狀位T1WI顯示，鞍內(nèi)和鞍上占位性病變，信號(hào)強(qiáng)度不均勻，其內(nèi)可見小片狀低信號(hào)影（箭頭所示） 1b 橫斷面T2WI顯示，鞍上病變呈等信號(hào)，其內(nèi)可見小片狀高信號(hào)影（箭頭所示） 1c 橫斷面增強(qiáng)T1WI顯示，病灶呈明顯不均勻強(qiáng)化（箭頭所示）Figure 1 Head MRI imaging findings Sagittal T1WI showed intrasellar and suprasellar space occupying lesion uneven signal strength.Intralesional findings strip hypointense signal area(arrow indicates,Panel 1a).Axial T2WI showed suprasellar lesion equisignal.There were strip hyperintense signal shadow(arrow indicates,Panel 1b).Axial T1WI enhanced demonstrated a significant enhancement(arrow indicates,Panel 1c).

患者 女性，81歲，主因間斷性頭痛10余年、視力下降1個(gè)月、失明1周，于2015年5月21日入院。患者10余年前無明顯誘因出現(xiàn)間斷性頭痛，可自行緩解，未予處理；1個(gè)月前因結(jié)腸炎行結(jié)腸鏡檢查后3 d出現(xiàn)雙眼視物模糊，視物成雙，視力進(jìn)行性下降，左眼癥狀較重，無意識(shí)障礙、頭暈、嘔吐，外院診斷與治療（具體不詳）后視力無明顯改善；1周前突然失明，甚至無光感，無意識(shí)障礙、肢體活動(dòng)障礙，外院頭部MRI顯示鞍區(qū)占位性病變。為求進(jìn)一步診斷與治療，至我院就診。患者自發(fā)病以來，精神、飲食尚可，睡眠較差，大小便正常，體重?zé)o明顯減輕。

既往史、個(gè)人史及家族史 患者既往有冠心病病史20余年，藥物控制較佳（具體方案不詳）；高血壓病史3余年，經(jīng)藥物控制（具體方案不詳）為120/70 mm Hg（1 mm Hg=0.133 kPa）左右，已停藥1年；余無特殊。個(gè)人史及家族史均無特殊。

體格檢查 患者體溫36.5℃，脈搏75次/min，呼吸15次/min，血壓 135/86 mm Hg；神志清楚，對(duì)答切題，高級(jí)神經(jīng)功能正常；頭部無畸形；雙側(cè)瞳孔等大、等圓，直徑約3 mm；伸舌居中，無口角歪斜；無頸項(xiàng)強(qiáng)直；余腦神經(jīng)檢查未見異常。四肢肌力5級(jí)、肌張力正常，感覺和共濟(jì)運(yùn)動(dòng)未見明顯異常，腱反射強(qiáng)陽性，病理反射未引出。

輔助檢查 實(shí)驗(yàn)室檢查血常規(guī)和凝血功能試驗(yàn)均于正常值范圍；血清脂質(zhì)：總膽固醇（TC）為5.90 mmol/L（0～5.70 mmol/L），白蛋白為37.60 g/L（40～55 g/L），低密度脂蛋白膽固醇（LDL?C）水平3.48 mmol/L（0～3.12 mmol/L）；垂體激素：泌乳素（PRL）45.97 ng/ml（4.79～23.30 ng/ml），余均于正常值范圍。頭部MRI顯示，鞍內(nèi)和鞍上占位性病變，呈T1WI等或稍低信號(hào)，T2WI等或高信號(hào)，累及左側(cè)海綿竇；增強(qiáng)掃描病灶呈明顯強(qiáng)化，約為2.80 cm×2.40 cm×2.20 cm（圖1）。

診斷與治療經(jīng)過 臨床診斷為垂體占位性病變，考慮垂體瘤可能性大。于2015年5月25日在全身麻醉下行經(jīng)鼻蝶入路鞍區(qū)占位性病變切除術(shù)。術(shù)中可見腫瘤位于鞍內(nèi)，呈灰紅色，直徑約為2 cm，質(zhì)地柔軟，血運(yùn)不豐富，無包膜，邊界欠清晰，沿邊緣手術(shù)全切除腫瘤，行組織病理學(xué)檢查。（1）大體標(biāo)本觀察：手術(shù)切除標(biāo)本呈灰紅色破碎組織一堆，約2.00 cm×1.00 cm×0.50 cm。經(jīng)體積分?jǐn)?shù)為3.70%中性甲醛溶液固定，常規(guī)脫水、石蠟包埋，4μm連續(xù)切片，分別行HE染色和免疫組織化學(xué)染色。（2）HE染色：光學(xué)顯微鏡觀察顯示，垂體正常結(jié)構(gòu)破壞，腫瘤組織由巢片狀分布的小至中等大小細(xì)胞構(gòu)成，形態(tài)較單一、大小較一致，胞核呈圓形或卵圓形，染色質(zhì)呈細(xì)顆粒狀，核仁不明顯，胞質(zhì)較少，核分裂象為5～7個(gè)/10高倍視野（HPF），可見局部小灶性壞死；無包膜，與周圍正常垂體組織界限欠清晰（圖2）。（3）免疫組織化學(xué)染色：采用EnVision二步法進(jìn)行檢測(cè)，檢測(cè)用Ⅰ抗、Ⅱ抗、顯色劑和染色系統(tǒng)參見表1。結(jié)果顯示，腫瘤細(xì)胞胞質(zhì)彌漫性表達(dá)突觸素（Syn，圖3a）、CD56，部分表達(dá)甲狀腺轉(zhuǎn)錄因子?1（TTF?1，圖3b）、廣譜細(xì)胞角蛋白（PCK）、P53，不表達(dá)生長(zhǎng)激素（GH）、PRL、促腎上腺皮質(zhì)激素（ACTH）、卵泡刺激素（FSH）、促甲狀腺激素（TSH）、黃體生成素（LH）、S?100蛋白（S?100）、甲狀腺球蛋白（TG）、降鈣素，Ki?67抗原標(biāo)記指數(shù)約33%（圖3c）。初步病理診斷為：（鞍區(qū)）小藍(lán)圓細(xì)胞惡性腫瘤，考慮轉(zhuǎn)移性神經(jīng)內(nèi)分泌腫瘤。術(shù)后為明確病因建議進(jìn)一步行胸部CT檢查，顯示左肺下葉心緣旁團(tuán)狀軟組織密度影（圖4）。最終病理診斷為（鞍區(qū)）轉(zhuǎn)移性肺非典型類癌。患者自動(dòng)出院后經(jīng)多所醫(yī)院會(huì)診，未再進(jìn)一步治療，3個(gè)月后去世。

圖2 光學(xué)顯微鏡觀察所見 HE染色 2a 腫瘤細(xì)胞呈巢片狀彌漫性分布，大小較一致，胞質(zhì)呈嗜酸性 ×200 2b腫瘤細(xì)胞胞核呈圓形，染色質(zhì)細(xì)顆粒狀，核仁不明顯，核分裂象可見 ×400 2c 部分區(qū)域可見壞死 ×200Figure 2 Optical microscopy findings HE staining The tumor was composed of small cells densely growing in sheet?like or nesting growth pattern with eosinophilic cytoplasm(Panel 2a). ×200 Small to intermediate sized round cells nesting arranged,with fine granular chromatin and mitotic figures,nucleolus were not obvious(Panel 2b). ×400 Focal necrosis was seen(Panel 2c).×200

表1 腫瘤免疫組織化學(xué)檢測(cè)各項(xiàng)抗體列表Table 1.Antibodies used for immunohistochemical examination

圖3 光學(xué)顯微鏡觀察所見 免疫組織化學(xué)染色（EnVision二步法） ×200 3a 腫瘤細(xì)胞彌漫性表達(dá)Syn 3b 腫瘤細(xì)胞部分表達(dá)TTF?1 3c Ki?67抗原標(biāo)記指數(shù)約為33%Figure 3 Optical microscopy findings Immunohistochemical staining(EnVision) ×200 The tumor cells were diffusely immunopositive for Syn(Panel 3a)and TTF?1(Panel 3b).Ki?67 labeling index was about 33%(Panel 3c).

討 論

垂體轉(zhuǎn)移瘤臨床罕見［1?3］，近年來隨著腫瘤患者生存期的延長(zhǎng)和影像學(xué)技術(shù)的發(fā)展，病例數(shù)有所增加，其發(fā)生率約占全部垂體腫瘤的 1%［2，4?5］，女性乳腺和男性肺部為最常見的腫瘤原發(fā)灶［1?2，6］，亦可見腮腺腺樣囊性癌［7］、甲狀腺癌［8?9］、肝癌［1，10］、胃腸道腫瘤［1，11］、腎細(xì)胞癌［12］、絨癌［13］、前列腺癌［14］、淋巴瘤［15］、橫紋肌肉瘤［16］和皮膚 Merkel細(xì)胞癌［17］垂體轉(zhuǎn)移的病例。肺非典型類癌屬于神經(jīng)內(nèi)分泌腫瘤，在2015年的世界衛(wèi)生組織（WHO）肺和胸膜腫瘤分類［18?19］中，肺神經(jīng)內(nèi)分泌腫瘤作為上皮組織腫瘤，與鱗狀細(xì)胞癌和腺癌并列，再一次明確非典型類癌的診斷標(biāo)準(zhǔn)：具有類癌組織學(xué)形態(tài)特征，核分裂象2～10個(gè)/2 mm2或壞死（通常為點(diǎn)狀或斑點(diǎn)狀），其生物學(xué)行為和預(yù)后為中級(jí)別。

肺類癌占所有原發(fā)性肺腫瘤的2%，典型類癌與非典型類癌的發(fā)病比例約為9∶1，平均發(fā)病年齡50～60歲，盡管有文獻(xiàn)報(bào)道非典型類癌以男性為主，但大多數(shù)學(xué)者認(rèn)為女性常見［19］。非典型類癌主要表現(xiàn)為周圍型，更具侵襲性，有40%～50%患者存在淋巴結(jié)轉(zhuǎn)移，約20%出現(xiàn)遠(yuǎn)處轉(zhuǎn)移，5和10年生存率分別為60%和35%［19］，而發(fā)生垂體轉(zhuǎn)移的病例僅為個(gè)案報(bào)道［20?23］。近50%的支氣管肺類癌為體格檢查時(shí)偶然發(fā)現(xiàn)，最常見癥狀是咳嗽和咯血，是與支氣管堵塞有關(guān)的典型癥狀。類癌綜合征少見，僅見發(fā)生廣泛轉(zhuǎn)移時(shí)。如果不考慮原發(fā)腫瘤，發(fā)生垂體轉(zhuǎn)移的患者通常為無癥狀，偶爾因垂體受累引起的癥狀與體征考慮垂體疾病而就診，而70%的癥狀性患者可出現(xiàn)尿崩癥［24］，23%出現(xiàn)垂體激素降低［22］，6.30%出現(xiàn)高泌乳素血癥，其他表現(xiàn)還包括視野缺損［21］、腦神經(jīng)麻痹和頭痛，偶可見原發(fā)性神經(jīng)內(nèi)分泌腫瘤（肺和胰腺）垂體轉(zhuǎn)移后分泌ACTH和生長(zhǎng)激素釋放激素（GHRH）致Cushing綜合征和肢端肥大癥［25?26］。本文患者為老年女性，以視力下降、突然失明的垂體占位征象入院，血清泌乳素水平升高，可能是垂體柄受壓所致。也有個(gè)案報(bào)道，泌乳素＞250 ng/ml影響臨床診斷與治療［26］，臨床應(yīng)予以注意。術(shù)后為進(jìn)一步明確診斷，胸部CT顯示呈周圍型肺非典型類癌。

圖4 胸部CT顯示，左肺下葉心緣旁團(tuán)塊狀軟組織密度影，邊緣毛糙（箭頭所示）Figure 4 Axial chest CT scan suggested a soft tissue density masses on the left lower lobe beside the heart,with roughen edges(arrow indicates).

典型神經(jīng)內(nèi)分泌腫瘤（類癌和小細(xì)胞癌）具有獨(dú)特的組織學(xué)形態(tài)特點(diǎn)，但垂體轉(zhuǎn)移性肺非典型類癌目前僅見個(gè)案報(bào)道。免疫組織化學(xué)染色，胞核部分表達(dá)TTF?1。研究顯示，TTF?1常表達(dá)于肺典型和非典型類癌，而不表達(dá)于其他器官類癌［23］，Penman等［27］認(rèn)為，表達(dá)于結(jié)腸癌和直腸癌腫瘤細(xì)胞胞核的TTF?1克隆號(hào)為SPT24，而克隆號(hào)為8G7G1的TTF?1呈陰性，這也是采用TTF?1這一生物學(xué)標(biāo)志物進(jìn)行鑒別診斷時(shí)應(yīng)注意的。

當(dāng)腫瘤細(xì)胞數(shù)目較少、分化較差、病史不典型時(shí)，易出現(xiàn)診斷困難或誤診，應(yīng)注意與以下疾病相鑒別：（1）垂體腺瘤。最常發(fā)生于蝶鞍的腫瘤，發(fā)病年齡隨腺瘤類型的不同而各異。MRI表現(xiàn)為均質(zhì)性，T1WI呈低信號(hào)。腫瘤細(xì)胞豐富，呈彌漫性生長(zhǎng)，胞核呈圓形、染色質(zhì)纖細(xì)，胞質(zhì)中等，核分裂象不常見；腫瘤細(xì)胞胞質(zhì)表達(dá)Syn、嗜鉻素A（CgA）和相應(yīng)垂體激素，Ki?67抗原標(biāo)記指數(shù)通常＜3%。（2）垂體增生。可由多種生理性或病理性原因?qū)е拢跋駥W(xué)表現(xiàn)為鞍區(qū)球形占位效應(yīng)，一般以中線為主，界限清晰，垂體上緣膨隆，高度增加。傳統(tǒng)認(rèn)為，CT所示垂體增高＞10 mm伴或不伴鞍底侵犯和垂體柄偏移是診斷垂體腺瘤的標(biāo)準(zhǔn)，故彌漫性垂體增生與垂體腺瘤難以鑒別；MRI顯示垂體信號(hào)不均勻，垂體柄偏斜。增生細(xì)胞因類型不同而形態(tài)各異，組織學(xué)形態(tài)可見結(jié)節(jié)性和彌漫性增生，結(jié)節(jié)性增生表現(xiàn)為腺泡擴(kuò)張，而細(xì)胞相對(duì)單一，對(duì)周圍組織無擠壓，界限清晰；彌漫性增生表現(xiàn)為垂體細(xì)胞數(shù)目增加，但無腺泡結(jié)構(gòu)改變，有時(shí)需行細(xì)胞計(jì)數(shù)以明確診斷。核分裂象罕見。Ki?67抗原標(biāo)記指數(shù)均較低。網(wǎng)織纖維染色可見正常腺泡結(jié)構(gòu)，有助于區(qū)分正常垂體組織、增生垂體組織與垂體腺瘤。（3）副節(jié)瘤。副節(jié)瘤常發(fā)生于特定解剖部位，易與類癌的器官樣結(jié)構(gòu)相混淆，但可見S?100陽性的包繞小葉的支柱細(xì)胞，主細(xì)胞細(xì)胞角蛋白（CK）呈陰性，而類癌細(xì)胞CK呈陽性。（4）其他轉(zhuǎn)移性腫瘤。組織學(xué)形態(tài)、免疫組織化學(xué)染色和臨床病史有助于鑒別診斷。

垂體轉(zhuǎn)移瘤的診斷與治療主要是原發(fā)灶的診斷與治療以及對(duì)癥治療，雖然可以選擇放射治療或藥物化療，但對(duì)于癥狀性患者，如本文患者有頭痛、失明表現(xiàn)，外科手術(shù)以緩解癥狀是必須的。研究顯示，是否外科手術(shù)解除垂體占位效應(yīng)無明顯差異［1］，生存期根據(jù)原發(fā)腫瘤的侵襲性和分期通常為6個(gè)月至 1 年［26，28?29］。

垂體轉(zhuǎn)移瘤臨床罕見，迄今文獻(xiàn)報(bào)道的垂體轉(zhuǎn)移性肺非典型類癌病例僅為個(gè)案報(bào)道，應(yīng)注意診斷與鑒別診斷。由于組織學(xué)形態(tài)和生物學(xué)行為均存在異質(zhì)性，對(duì)其治療與預(yù)后尚待進(jìn)一步研究。本文患者自動(dòng)出院后經(jīng)多所醫(yī)院會(huì)診，但未進(jìn)一步治療，3個(gè)月后死亡。

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Atypical lung carcinoid metastasis to the pituitary gland

YAN Xiao?ling,TANG Fan,HAN Zhu?yu,ZHANG Xue?bin,JIN Shu?mei
Department of Pathology,Tianjin Huanhu Hospital,Tianjin 300350,China
Corresponding author:YAN Xiao?ling(Email:ll934065@126.com)

ObjectiveTo study clinicopathological features,diagnosis and differential diagnosis of atypical lung carcinoid metastasis to the pituitary gland based on clinical data of one patient.Methods and ResultsA 81?year?old female presented headache and sudden blindness,and head MRI showed that there was a lesion at the saddle area.The tumor was detected at intrasellar and in grayish red during surgery.The diameter of tumor was 2 cm.The tumor was soft with no envelop at and well?defined margins,and insufficiency in blood supply.The tumor was removed completely along its edge.Under optical microscopy,the tumor was consisted of small round cells of the same size.Tumor cells were distributed around blood vessels in a nest manner or diffuse manner with brisk mitotic activity and focal necrosis. By using immunohistochemical staining,the tumor cells were diffusely positive for synaptophysin(Syn),CD56 and thyoid transcription factor?1(TTF?1),focal positive for cytokeratin(CK)and P53,and negative for growth hormone(GH),prolactin(PRL),adrenocorticotropic hormone(ACTH),follicle stimulating hormone(FSH),thyroid stimulating hormone(TSH),luteinizing hormone(LH),S?100 protein(S?100),thyroglobulin(TG)and calcitonin.Ki?67 labeling index was about 33%.ConclusionsPituitary metastasis is a rare tumor,and only a few cases of atypical lung carcinoid metastasis to the pituitary gland have been reported.Definite diagnosis could be made by history,typical histopathological characteristics and immunohistochemical expressions.

Lung neoplasms; Carcinoid tumor; Neoplasm metastasis; Pituitary gland;Immunohistochemistry;Pathology

10.3969/j.issn.1672?6731.2017.09.010

300350天津市環(huán)湖醫(yī)院病理科

閻曉玲（Email：ll934065@126.com）

2017?06?22）