孫翠云 于士柱

·臨床病理報(bào)告·

脊柱孤立性漿細(xì)胞瘤伴淀粉樣變性

孫翠云 于士柱

目的報(bào)告1例脊柱孤立性漿細(xì)胞瘤伴淀粉樣變性患者的診斷與治療過程，結(jié)合文獻(xiàn)探討其組織病理學(xué)特征。方法與結(jié)果女性患者，46歲，臨床主要表現(xiàn)為雙下肢無力，行走不穩(wěn)伴腳趾麻木感。頭部MRI顯示，T5～7水平脊髓后方硬脊膜外和T6～7水平附件內(nèi)不規(guī)則占位性病變，增強(qiáng)掃描呈不均勻明顯強(qiáng)化，邊界清晰，硬脊膜受壓向前移位。術(shù)中可見T5～7棘突和椎板以及部分T5、T7棘突和椎板被侵蝕，骨皮質(zhì)呈“蟲蝕”樣改變；病變位于椎管內(nèi)硬脊膜外，血供豐富，呈疏松骨樣結(jié)構(gòu)，硬脊膜完整。組織學(xué)形態(tài)觀察，腫瘤細(xì)胞以密集排列的小細(xì)胞為主，可見灶性漿細(xì)胞樣細(xì)胞分化，其間可見片狀粉染物質(zhì)沉積，并多見人工裂紋和散在分布的多核巨細(xì)胞。免疫組織化學(xué)染色，腫瘤細(xì)胞胞質(zhì)CD138、CD38和波形蛋白彌漫性陽性；白細(xì)胞共同抗原散在陽性；免疫球蛋白κ輕鏈和λ輕鏈、CD99、S-100蛋白、廣譜細(xì)胞角蛋白、上皮膜抗原、黑色素瘤相關(guān)抗原HMB45和CD34陰性；Ki-67抗原標(biāo)記指數(shù)約1.25%。特殊染色，粉染物質(zhì)剛果紅染色呈棕紅色。原位雜交顯示免疫球蛋白κ輕鏈DNA含量高于λ輕鏈。最終病理診斷為（脊柱）孤立性漿細(xì)胞瘤伴淀粉樣變性。術(shù)后輔以藥物化療。隨訪18個(gè)月腫瘤無復(fù)發(fā)和轉(zhuǎn)移。結(jié)論脊柱孤立性漿細(xì)胞瘤伴淀粉樣變性臨床罕見，影像學(xué)檢查對診斷有一定提示意義，明確診斷仍依靠特異性組織形態(tài)學(xué)、免疫表型、特殊染色和原位雜交檢測。

漿細(xì)胞瘤；淀粉樣變性；脊柱；免疫組織化學(xué)；原位雜交；病理學(xué)

This study was supported by the National Natural Science Foundation of China(No.81402050, 81502166),Key Projects of Tianjin Application Foundation and Advanced Technology Research Project (No.15JCZDJC34600,15JCYBJC49900),the National Natural Science Foundation of Tianjin(No. 16JCQNJC13400),Foundation of Tianjin Medical University for Young Scientists(No.2015KYZQ11),and Tianjin Medical University General Hospital Youth Incubation Fund(No.ZYYFY2014038, ZYYFY2015032).

孤立性漿細(xì)胞瘤（SP）是漿細(xì)胞單克隆性增生導(dǎo)致的惡性腫瘤，可發(fā)生于骨骼或髓外組織，發(fā)病部位局限，骨髓無異常改變。發(fā)生于脊柱者平均發(fā)病年齡約55歲，男女比例為2∶1，主要累及椎體，臨床主要表現(xiàn)為進(jìn)行性加重的病變椎體周圍疼痛。孤立性漿細(xì)胞瘤伴淀粉樣變性臨床罕見，主要由于免疫球蛋白輕鏈與多糖復(fù)合物沉積于組織器官所致，受累組織器官較廣泛，包括舌、腮腺、皮膚、心臟、胃腸道、周圍神經(jīng)、肝、脾、肺等。明確診斷依靠組織病理學(xué)檢查，剛果紅染色呈棕紅色。本文回顧研究1例脊柱孤立性漿細(xì)胞瘤伴淀粉樣變性患者的診斷與治療過程，結(jié)合相關(guān)文獻(xiàn)對此類疾病的臨床病理學(xué)特征進(jìn)行分析，以期提高疾病的診斷與鑒別診斷能力。

病歷摘要

患者女性，46歲，主因雙下肢無力、行走不穩(wěn)伴腳趾麻木感20 d余，于2016年6月4日入院。患者20 d前無明顯誘因出現(xiàn)雙下肢無力、行走不穩(wěn)伴腳趾麻木感，未見其他伴隨癥狀。門診行脊椎MRI檢查顯示，T5～7水平硬脊膜外和T6～7水平附件區(qū)占位性病變。門診以“脊柱占位性病變”收入院。患者自發(fā)病以來，精神、飲食佳，睡眠尚可，大小便正常，體重?zé)o明顯變化。

既往史、個(gè)人史及家族史均無特殊。

體格檢查患者體溫36.2℃，心率67次/min，呼吸18次/min，血壓125/80 mm Hg（1 mm Hg= 0.133 k Pa）。神志清楚，語言流利；雙側(cè)瞳孔等大、等圓，直徑約為3 mm，對光反射靈敏，眼球各向活動(dòng)自如；雙上肢肌力5級、左下肢3級、右下肢4級，四肢肌張力均正常；雙上肢腱反射正常，雙下肢強(qiáng)陽性，雙側(cè)Babinski征陽性；雙側(cè)T8水平以下淺感覺減退，雙側(cè)髂前上棘以下音叉振動(dòng)覺減退，四肢共濟(jì)運(yùn)動(dòng)穩(wěn)準(zhǔn)。

輔助檢查實(shí)驗(yàn)室檢查各項(xiàng)指標(biāo)均于正常值范圍。影像學(xué)檢查：脊椎MRI顯示，T5～7水平脊髓后方硬脊膜外團(tuán)塊狀T1WI等信號和T2WI稍低信號影，T6～7水平附件區(qū)T1WI稍短信號和T2WI異常信號影，增強(qiáng)掃描病灶呈不均勻明顯強(qiáng)化，與周圍組織界限清晰，硬脊膜受壓向前移位（圖1）。18F-脫氧葡萄糖（18F-FDG）PET顯示，T6～7骨質(zhì)破壞，葡萄糖代謝異常增高。

診斷與治療經(jīng)過臨床診斷為脊柱占位性病變。遂于全身麻醉下行胸椎占位性病變切除術(shù)。術(shù)中可見T6棘突和椎板以及部分T5、T7棘突和椎板被侵蝕，骨皮質(zhì)呈蟲蝕樣改變，病變位于椎管內(nèi)硬脊膜外，血供豐富，呈骨疏松樣結(jié)構(gòu)，浸潤T6棘突和椎板、部分T5棘突和椎板、T7上部椎板，硬脊膜完整。手術(shù)全切除腫瘤及鄰近骨組織，切除標(biāo)本行組織病理學(xué)檢查。（1）大體標(biāo)本觀察：手術(shù)切除組織包括灰白色破碎組織1塊，大小約為25 mm×20 mm× 10 mm，質(zhì)地中等，血供豐富；灰白色骨組織數(shù)塊，大小約為70 mm×30 mm×15 mm，質(zhì)地較硬。經(jīng)體積分?jǐn)?shù)10%的中性甲醛溶液固定，常規(guī)脫水、石蠟包埋，制備5 μm層厚組織切片，行HE染色和免疫組織化學(xué)染色。（2）HE染色：腫瘤細(xì)胞以密集排列的小細(xì)胞為主，呈灶性漿細(xì)胞樣細(xì)胞分化，其間可見片狀粉染物質(zhì)沉積，并多見人工裂紋和散在分布的多核巨細(xì)胞（圖2）。（3）免疫組織化學(xué)染色：采用ABC三步法，檢測用試劑盒購自丹麥Dako公司；檢測用抗體包括CD138、CD38、波形蛋白（Vim）、白細(xì)胞共同抗原（LCA）、免疫球蛋白κ輕鏈和λ輕鏈、CD99、S-100蛋白（S-100）、廣譜細(xì)胞角蛋白（PCK）、上皮膜抗原（EMA）、黑色素瘤相關(guān)抗原HMB45、CD34和Ki-67抗原購自丹麥Dako公司（均為即用型抗體）。結(jié)果顯示，腫瘤細(xì)胞胞質(zhì)CD138（圖3a）、CD38（圖3b）和Vim（圖3c）呈彌漫性陽性，LCA呈散在陽性，免疫球蛋白κ輕鏈和λ輕鏈、CD99、S-100、 PCK、EMA、HMB45、CD34均呈陰性，Ki-67抗原標(biāo)記指數(shù)約為1.25%（圖3d）。（4）特殊染色：腫瘤細(xì)胞間片狀粉染物質(zhì)剛果紅染色呈棕紅色（圖4）。（5）原位雜交檢測：免疫球蛋白κ輕鏈DNA含量高于λ輕鏈。最終病理診斷為（脊柱）漿細(xì)胞瘤伴淀粉樣變性。患者共住院25 d，出院后于外院輔助術(shù)后藥物化療（具體方案不詳），定期復(fù)查脊椎MRI，未見腫瘤復(fù)發(fā)或轉(zhuǎn)移。

圖1 脊椎MRI檢查所見1a矢狀位T1WI顯示，T5～7水平脊髓后方硬脊膜外團(tuán)塊狀等信號影，T6～7水平附件內(nèi)等信號影（箭頭所示）1b矢狀位T2WI顯示，T5～7水平脊髓后方硬脊膜外團(tuán)塊狀低信號影，T6～7水平附件內(nèi)稍低信號影（箭頭所示）1c矢狀位增強(qiáng)T1WI顯示，腫瘤呈不均勻明顯強(qiáng)化（箭頭所示），邊界清楚，硬脊膜受壓向前移位1d矢狀位抑脂增強(qiáng)T1WI顯示，腫瘤呈不均勻明顯強(qiáng)化，病變范圍更清晰（箭頭所示）Figure 1 Spinal MRI findings Sagittal T1WI showed iso-intensity signal of an irregular mass behind the spinal cord at T5-7level and within T6-7vertebral body accessory(arrow indicates,Panel 1a).Sagittal T2WI showed low-intensity signal of an irregular mass behind the spinal cord at T5-7level and within T6-7vertebral body accessory(arrow indicates,Panel 1b).Sagittal enhanced T1WI revealed obvious heterogeneous enhancement(arrow indicates).The border was clear and spinal dura mater was compressed to shift forward (Panel 1c).Sagittal enhanced fat-suppressed T1WI revealed irregular enhancement and the lesion was clearer(arrow indicates,Panel 1d).

圖2 光學(xué)顯微鏡觀察所見HE染色2a腫瘤細(xì)胞以密集排列的小細(xì)胞為主，其間可見片狀粉染物質(zhì)沉積× 100 2b粉染物質(zhì)區(qū)域多見人工裂紋和散在分布的多核巨細(xì)胞×200 2c腫瘤細(xì)胞密度增加，有一定異型性，可見灶性漿細(xì)胞樣細(xì)胞分化×400Figure 2 Optical microscopy findings HE staining Tumor cells were composed of intensive small cells.Flake pink staining substance was among them(Panel 2a).× 100 Artificial cracks were common and multinuclear giant tumor cells were scatteredly distributed in the pink staining substance area(Panel 2b).×200 Tumor cells showed increased density and atypia,and plasmacytoid cells were seen in some area(Panel 2c).×400

圖3 光學(xué)顯微鏡觀察所見免疫組織化學(xué)染色（ABC三步法）×400 3a腫瘤細(xì)胞胞質(zhì)彌漫性表達(dá)CD138 3b腫瘤細(xì)胞胞質(zhì)彌漫性表達(dá)CD38 3c腫瘤細(xì)胞胞質(zhì)彌漫性表達(dá)Vim 3d腫瘤細(xì)胞Ki-67抗原標(biāo)記指數(shù)約為1.25%圖4光學(xué)顯微鏡觀察顯示，粉染物質(zhì)呈棕紅色剛果紅染色×200Figure 3 Optical microscopy findings Immunohistochemical staining(ABC)×400 Cytoplasm of tumor cells were diffusely positive for CD138(Panel 3a). Cytoplasm of tumor cells were diffusely positive for CD38 (Panel 3b).Cytoplasm of tumor cells were diffusely positive for Vim(Panel 3c).Ki-67 labeling index of tumor cells was 1.25%(Panel 3d).Figure 4 Optical microscopy showed the pink staining substance was brownish red.Congo red staining×200

討論

孤立性漿細(xì)胞瘤起源于骨骼，好發(fā)于中軸骨，或骨外組織如頭頸部。有25%～70%的孤立性漿細(xì)胞瘤患者血清或尿液中可以檢出免疫球蛋白M（IgM），而在髓外呈低表達(dá)，但可以通過檢測免疫球蛋白游離輕鏈以提高其陽性檢出率。脊柱孤立性漿細(xì)胞瘤的平均發(fā)病年齡約為55歲，男女比例2∶1，多累及椎體，臨床主要表現(xiàn)為逐漸加重的病變椎體周圍疼痛，如果壓迫神經(jīng)，則可出現(xiàn)神經(jīng)受累癥狀與體征［1-4］。因此，對于脊椎及其周圍疼痛，應(yīng)重視早期檢查，特別是脊椎MRI檢查，有助于早期診斷，防止嚴(yán)重的脊柱脊髓損害。

淀粉樣變性系β片層結(jié)構(gòu)的淀粉樣纖維沉積于細(xì)胞外導(dǎo)致的疾病，此類物質(zhì)與碘和硫酸接觸后發(fā)生顏色反應(yīng)與淀粉相似，故命名為淀粉樣變性并沿用至今［5］。淀粉樣變性可發(fā)生于全身多器官和組織，發(fā)病率較低，可以存在單獨(dú)的病理改變，也可以伴惡性淋巴瘤、漿細(xì)胞肉芽腫等全身淀粉樣變性的一部分。淀粉樣變性多繼發(fā)于多發(fā)性骨髓瘤，而其他B細(xì)胞腫瘤如淋巴瘤、白血病等均可并發(fā)淀粉樣變性，此類疾病可發(fā)生異常分泌性免疫球蛋白重鏈或輕鏈沉積，從而導(dǎo)致淀粉樣變性［6］。組織活檢時(shí)淀粉樣變性組織有一定硬度。大體標(biāo)本觀察，腫瘤組織大小不等，呈均勻致密排列，半透明，無包膜。組織學(xué)形態(tài)觀察，粉染物質(zhì)呈無細(xì)胞，同質(zhì)，均勻，紅色，片狀、團(tuán)塊狀或網(wǎng)格狀彌漫性分布于細(xì)胞外基質(zhì)（ECM）。特異性診斷依據(jù)組織活檢術(shù)以及粉染物質(zhì)免疫組織化學(xué)染色和特殊染色。其中，特殊染色粉染物質(zhì)剛果紅染色呈棕紅色，是診斷淀粉樣變性經(jīng)典的特異性標(biāo)記［5］。

脊柱孤立性漿細(xì)胞瘤伴淀粉樣變性的明確診斷仍依靠組織病理學(xué)檢查，結(jié)合組織學(xué)形態(tài)和免疫表型不難作出診斷。鑒別診斷包括：（1）骨肉瘤。腫瘤細(xì)胞和腫瘤性成骨可資鑒別。（2）脊柱轉(zhuǎn)移瘤。根據(jù)組織學(xué)形態(tài)、免疫表型和PET-CT顯像可以排除診斷。（3）大細(xì)胞淋巴瘤。組織學(xué)形態(tài)和免疫表型可資鑒別。

孤立性漿細(xì)胞瘤患者中位生存期為7.50～12.00年，發(fā)生于脊柱者的生存期尚未見文獻(xiàn)報(bào)道。何妙俠等［7］報(bào)告13例脊柱孤立性漿細(xì)胞瘤患者，認(rèn)為其預(yù)后影響因素包括年齡、腫瘤部位和大小、腫瘤細(xì)胞分化程度、手術(shù)時(shí)機(jī)、局部手術(shù)范圍是否徹底和病灶處理方法等，長期隨訪觀察尤為重要。但此方面的隨訪資料目前較少見諸文獻(xiàn)報(bào)道，尚待大樣本的臨床研究進(jìn)行長期觀察總結(jié)。

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Solitary plasmacytoma of spine with amyloidosis

SUN Cui-yun,YU Shi-zhu
Tianjin Medical University General Hospital;Tianjin Neurological Institute;Tianjin Key Laboratory of Injury, Variation and Regeneration of Nervous System;Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System,Ministry of Education,Tianjin 300052,China
< class="emphasis_italic">Corresponding author:YU Shi

YU Shi-zhu(Email:tjyushizhu@yahoo.com)

ObjectiveTo report the diagnosis and treatment of one case of solitary plasmacytoma of spine with amyloidosis and investigate the clinicopathological features combined with literatures.Methods and ResultsThe patient was a 46-year-old woman.She suffered from weakness of both lower limbs,unsteady gait and numbness of toes for 20 d.MRI examination revealed an irregular mass behind the spinal cord at T5-7level and T6-7vertebral body accessory.The enhanced MRI showed obvious heterogeneous enhancement.The border was clear and spinal dura mater was compressed to shift forward. During operation,T5-7processus spinosus and vertebral laminae were eroded,and the cortex of bone showed "moth-eaten"erosion.The intraspinal and extradural lesion had rich blood supply,loose bone structure and intact spinal dura mater.Histologically,tumor cells were composed of intensive small cells,and focal plasmacytoid cells were seen.Flake pink staining substance was among them.Artificial cracks were common and multinuclear giant tumor cells were scatteredly distributed.Immunohistochemical analysis showed the cytoplasm of tumor cells were diffusely positive for CD138,CD38 and vimentin(Vim),scatteredly positive for leukocyte common antigen(LCA),and negative for immune globulin κ light chain (IgGκ)and λ light chain(IgGλ),CD99,S-100 protein(S-100),pan cytokeratin(PCK),epithelial membrane antigen(EMA),HMB45 and CD34.The Ki-67 labeling index was 1.25%.Congo red staining showed the pink staining substance was brownish red.Hybridization in situ examination showed the DNA content of Ig Gκ was more than that of Ig Gλ.The final pathological diagnosis was solitary plasmacytoma of spine with amyloidosis.The patient was treated with postoperative chemotherapy,and there was no recurrence or metastasis during 18-month follow-up period.ConclusionsSolitary plasmacytoma of spine with amyloidosis is a rare tumor.The imaging features can offer a few diagnostic cues.However,a clear diagnosis depends on specific histomorphology,immunophenotyping,special staining and hybridization in situ examination.

Plasmacytoma;Amyloidosis;Spine;Immunohistochemistry;In situ hybridization;Pathology

2016-12-09）

10.3969/j.issn.1672-6731.2017.01.010

國家自然科學(xué)基金資助項(xiàng)目（項(xiàng)目編號：81402050）；國家自然科學(xué)基金資助項(xiàng)目（項(xiàng)目編號：81502166）；天津市應(yīng)用基礎(chǔ)及前沿技術(shù)研究計(jì)劃項(xiàng)目（項(xiàng)目編號：15JCZDJC34600）；天津市應(yīng)用基礎(chǔ)及前沿技術(shù)研究計(jì)劃項(xiàng)目（項(xiàng)目編號：15JCYBJC49900）；天津市自然科學(xué)基金青年科學(xué)基金資助項(xiàng)目（項(xiàng)目編號：16JCQNJC13400）；天津醫(yī)科大學(xué)青年科學(xué)基金資助項(xiàng)目（項(xiàng)目編號：2015KYZQ11）；天津醫(yī)科大學(xué)總醫(yī)院青年孵育基金資助項(xiàng)目（項(xiàng)目編號：ZYYFY2014038）；天津醫(yī)科大學(xué)總醫(yī)院青年孵育基金資助項(xiàng)目（項(xiàng)目編號：ZYYFY2015032）

300052天津醫(yī)科大學(xué)總醫(yī)院天津市神經(jīng)病學(xué)研究所天津市神經(jīng)損傷變異與再生重點(diǎn)實(shí)驗(yàn)室教育部中樞創(chuàng)傷修復(fù)與再生重點(diǎn)實(shí)驗(yàn)室

于士柱（Email：tjyushizhu@yahoo.com）