대한진단검사의학회지제 27 권제 4 호 2007 Korean J Lab Med 2007;27:248-52 증례 진단혈액학 형질세포와근위신세관세포내 uer rod양봉입체를함유한판코니증후군동반 Ig kappa형경쇄침착질환 1예보고 강지민 1 김진아 2 신석준 3 한경자 1 가톨릭대학교의과대학진단검사의학교실 1, 병원병리학교실 2, 내과학교실 3 Case of Ig kappa Light Chain Deposition Disease and Combined dult Fanconi Syndrome with uer rod-like Intracytoplasmic Inclusions in Plasma Cells and Proximal Renal Tubular Cells Jimin Kahng, M.D. 1, Jeana Kim, M.D. 2, Suk Joon Shin, M.D. 3, and Kyungja Han, M.D. 1 Departments of Laboratory Medicine 1, Hospital Pathology 2, and Internal Medicine 3, The Catholic University of Korea College of Medicine, Seoul, Korea We report a case of Ig kappa light chain deposition disease and combined adult Fanconi syndrome with uer rod-like intracytoplasmic inclusions in plasma cells and proximal renal tubular cells in a 54-yr-old female. Cytochemical stainings revealed a strong acid phosphatase activity of the inclusions and weak periodic acid-schiff positivity, whereas the reactions for peroxidase and -naphthyl acetate esterase were negative. n immunostaining verified Ig-kappa inside the plasma cells. Kidney biopsy revealed ence Jones cast nephropathy with kappa light chain positivity, and Congo red staining was negative. Electron microscopy showed needle-shaped crystals located in tubular epithelial cells. (Korean J Lab Med 2007;27:248-52) Key Words : uer rod-like inclusion, Light chain deposition disease, Fanconi syndrome 서 경쇄침착질환 (Light chain deposition disease, LCDD) 은비아밀로이드성면역글로불린경쇄가조직에침착되는단클론성형질세포질환이며, 주로 kappa형이우세하고특히신장을침범하여신부전을유발한다 [1]. 단클론성감마병증환자의형질세포에서때로핵내또는세포질내봉입체가발견되며, uer rod와유사한형태의세포질내봉입체는 1940년 Steinmann이처음보고한이 접 수 : 2007년 1월 26일 접수번호 : KJLM2013 수정본접수 : 2007년 6월 19일 게재승인일 : 2007년 6월 20일 교신저자 : 강지민 우 420-717 경기도부천시원미구소사동 2 가톨릭대학교성가병원진단검사의학과 전화 : 032-340-2208, Fax: 032-340-2219 E-mail : jmkahng@catholic.ac.kr * 본연구는가톨릭대학교성가병원 2005년도임상의학연구비의일부지원에 의해이루어진것임. 론 래현재까지영문학술지에 7예이상보고되었다 [2-6]. 골수이외의세포에서도이들봉입체가발견되는경우가있고, 특히판코니증후군 (Fanconi syndrome) 이동반된경우에는근위신세관세포 (proximal renal tubular cells) 에서발견된다 [7, 8]. 국내에서도다발성골수종환자의형질세포핵내봉입체 1예 [9] 와세포질내봉입체 1예 [10] 의보고가있었으나, 경쇄침착질환에서보고된바는없다. 저자들은 Ig kappa형경쇄침착질환과연관된판코니증후군환자에서, 형질세포와근위신세관세포의세포질내에서 uer rod양방추형봉입체를관찰하여간단한문헌고찰과함께보고한다. 증례환자는 54세여자로, 1개월간의전신쇠약감을주소로내원하였다. 형간염보균자라는것이외에과거력이나가족력에특이사 248
uer rod 양봉입체를보이는판코니증후군동반 Ig kappa 경쇄침착질환 249 C D E Fig. 1. one marrow plasma cell morphology and special stain. () typical plasma cells with spindle-shaped, uer rod-like intracytoplasmic inclusions (Wright stain, 400/window 1,000). () Strong acid phosphatase activity of the inclusions. Note the lack of staining in surrounding cytoplasm (acid phosphatase, 1,000). (C) Negative in non-specific esterase stain (Non-specific esterase, 1,000). (D) and (E) Immunohistochemical stain showing kappa-positivity (D) and lambda-negativity (E) ( 1,000). 항은없었다. 이학적검사에서경도의간비종대이외에특이소견은없었다. 입원당시일반혈액검사에서혈색소 10.6 g/dl, MCV/MCH/ MCHC 104.4/35.8/34.3 fl, 백혈구 9,800/ L, 혈소판 120,000/ L이었다. 화학검사에서는 UN/Cr 22.7/2.5 mg/dl로증가되었고, 저칼륨혈증 (2.8 meq/l), 고칼슘혈증 (8.1 mg/dl), 저인산혈증 (1.5 mg/dl), 저요산혈증 (0.9 mg/dl), 고염소혈증 (114 meq/l) 을나타내었고, 공복시혈당은 88 mg/dl으로정상이었다. 뇨화학검사에서비중 1.015, ph7.5, 당 (++), 단백 (+/-) 이었으며, 24시간뇨화학검사에서는총량 1,900 ml, 단백 96 mg/dl, Na/K/Cl 61/27.8/60 meq/l이었다. 혈청및뇨 2-microglobulin은각각 3.8 mg/l, 0.2 mg/l이었다. 동맥혈가스분석에서 ph 7.372, PaCO 2 32.9 mmhg, PaO 2 119.5 mmhg, HCO 3 18.7 mmol/l, SaO 2 98.3% 로대사성산증을나타냈다. 혈청단백의전기영동검사와면역전기영동검사, 그리고요단백전기영동검사에서단일클론성단백은관찰되지않았으나, 요단백면역전기영동검사에서 kappa 형의벤스-존스단백뇨 (ence-jones proteinuria) 가관찰되었다. 방사선소견에서흉부단순촬영상특이소견없었고두개골, 대퇴골, 요추-천추, 골반단순촬영상골파괴병변은관찰되지않았다. 복부초음파에서간, 비장, 신장, 췌장에이상소견은없었다. 골수흡인에서전체유핵세포의 4.6% 를차지하는비정형적인형질세포가관찰되었으며, 이들세포질내에는 uer rod와매우흡사한방추형의봉입체가다수포함되어있었다 (Fig. 1). 봉입체들은 acid phosphatase 염색에강양성을나타내었으며 (Fig. 1), -naphthyl acetate esterase 음성이었고 (Fig. 1C), 면역염색결과 Ig-kappa형임을알수있었다 (Fig. 1D, E). 신장생검결과역시 kappa형경쇄에의한벤스- 존스신증이확인되었으며, Congo red 음성이었다 (Fig. 2). 전자현미경하에서근위신세관상피세포내에위치한다수의바늘과같은봉입체들을관찰할수있었다 (Fig. 3). 고찰골수천자검체에서형질세포로추정되는세포의세포질내에 uer rod와흡사한봉입체가관찰되는경우는일차적으로급성골수구성백혈병과감별진단이필요하다는점에서형태학적인의의를갖는다. 세포와봉입체의기원을확인하기위해세포화학및면역염색을시행하고가능한경우전자현미경검경을거치며, 임상정보와방사선소견및생화학검사소견을종합하는일반적인수순 [2, 3, 6] 에따르면, 급성골수구성백혈병의진단배제에이르는데에는큰무리가없다. 이바늘모양의결정체가독특한형태이외에병태생리나예후와관련하여어떤의의를가지고있는지에대해서는정보가그리많지않다. 경쇄침착질환보다보고예가상대적으로많은다발성골수종의예후에있어서, 세포핵의형태변화와는밀접한관련성이있는것으로보고되었으나 [11], 세포질의다양한이상소견은그각각의빈도가낮아서인지예후인자로서통계화한자료가없다. 다만 Gardais 등은단클론성감마병증에서 uer rod와유
250 강지민 김진아 신석준외 1 인 C D Fig. 2. The kidney biopsy revealed ence Jones cast nephropathy with kappa light chain positivity. () H-E stain, 100. () Immunohistochemical stain showing Ig positivity ( 1,000) and (C) kappa positivity ( 1,000). (D) Congo red stain showing negativity ( 100). 사한형태의세포질내봉입체가관찰된다는것은부적절한단백질을세포내에서빠르게분해하였다는것을의미하므로, 종양의신체영향을둔화하여무증상의임상경과를갖게한다고하였다 [12]. 경쇄침착질환은형질세포이형성증에의한파라프로틴혈증중가장드문형태로서, 현재까지 70예미만이보고되었고, 33-79 세 ( 중앙값 56세 ) 의성인에서발병하며, 대개의경우 monoclonal gammopathies of undetermined significance (MGUS) 나골수종과동반된다. 형질세포종양에속하지만종양이크게자라기에앞서, 조직에침착되는면역글로불린분자를생성하기때문에진단당시에는명백한골수종을나타내지않는것이전형적인특징이다. 생리화학적으로변이를일으킨면역글로불린이골수에서생성되어혈류를통해조직에침착되며, 침범한장기기능의저하또는이상을보인다. 진단에는침착을일으킨장기, 특히신장의조직학적소견이필수적이며, Congo red에염색되지않는호산성물질의침착이관찰되고면역염색에의해신사구체또는신세관 기저막가장자리를따라 kappa 경쇄의띠를확인할수있다. 예후는매우나쁘며형질세포의전격적인증식없이도 1, 2년이내에사망한다. 약 15% 에서는 M-단백을나타내지않으며이는조직에강하게결합하는특성을반영한다 [1, 13, 14]. 본증례역시 M-단백을나타내지않았고골수내형질세포는전체유핵세포의 4.6% 에불과했으며골용해소견이없으면서빈혈과신부전을동반하여, MGUS나골수종을동반하지않은경쇄침착질환으로분류된다. 한편, 다발성골수종을포함하는단클론성감마병증사례에서판코니증후군과의관련성은진단례가적은편이다 [8, 10, 12, 15-17]. 판코니증후군은아미노산, 포도당, 인산염, 요산, 나트륨, 칼륨, 중탄산염, 단백등근위신세관이동에전반적인결함이발생하는장애로서, 유전성으로도발생하고후천성인경우는다발성골수종, 아밀로이드증, 중금속독성, 화학요법제등에의해원인물질이신세관에누적되어흡수부전을일으킴으로써발생할수있
uer rod 양봉입체를보이는판코니증후군동반 Ig kappa 경쇄침착질환 251 Fig. 3. Ultrastructure of tubular epithelial cells in a case of Ig myeloma kidney. The figure shows needle-shaped crystals located in tubular epithelial cells (TEM) () 2,000 & () 40,000. 다 [18]. 본예의경우, 경쇄의이화작용이주로일어나는근위신세관에비정상적인 kappa 경쇄가침착되어판코니증후군과신부전을유발한것으로생각된다. 경쇄침착질환에서 kappa 경쇄형이 80% 로우세한점은, kappa 경쇄 V 영역 (domain) 30의비정상적인소수성잔기가 cathepsin 에의한단백분해를방해하기때문에결과적으로신세관세포질내에결정체를유발하기때문인것으로추정된다 [19, 20]. 경쇄침착에의한일련의질환군은발생빈도가낮고임상양상과조직학적형태가매우다양하여특성이아직명확히규명되지못한질환들이며, 본증례에서와같이세포질내에경쇄봉입체를갖는경쇄침착질환에서신세관의동일한세포이상이증명된판코니증후군이동반된예는극히드물다. 요약저자들은 54세여자환자에서골수의형질세포세포질과신세관상피세포내에 uer rod와흡사한형태의방추형또는바늘모양의봉입체를갖고있는, Fanconi 증후군을동반한 Ig kappa형경쇄침착질환사례를경험하였다. 세포화학염색에서봉입체들은 acid phosphatase 염색에강양성을나타내었으며, -naphthyl acetate esterase 음성이었고, 면역염색결과 Ig-kappa형임을알수있었다. 신장생검결과역시 kappa형경쇄에의한벤스- 존스신증이확인되었으며, Congo red 음성이었다. 전자현미경하에서근위신세관상피세포내에위치한다수의바늘과같은봉입체들을관찰할수있었다. 참고문헌 1. Jaffe ES, Harris NL, et al. eds. World Health Organization classification of tumours. Pathology and genetics of tumours of haematopoietic and lymphoid tissue. France: IRC Press, Lyon 2001:150-1, 152-4. 2. Castoldi G, Piva N, Tomasi P. Multiple myeloma with uer-rodlike inclusions. Haematologica 1999;84:859-60. 3. Metzgeroth G, ack W, Maywald O, Schatz M, Willer, Hehlmann R, et al. uer rod-like inclusions in multiple myeloma. nn Hematol 2003;82:57-60. 4. Raman S and Van Slyck EJ. Nature of intracytoplasmic crystalline inclusions in myeloma cells (morphologic, cytochemical, ultrastructural, and immunofluorescent studies). m J Clin Pathol 1983;80: 224-8. 5. Casciaro S, Clavio M, occaccio P. Unusual intracellular and extracellular crystal inclusions in light chain multiple myeloma. Haematologica 1999;84:1046-7. 6. VM, Meenu al M, Varma N, Sakhuja V. uer rod-like inclusions in immunoglobulin a multiple myeloma. rch Pathol Lab Med 2005; 129:706-7. 7. Grossniklaus HE, Stulting RD, L Hernault N. Corneal and conjunctival crystals in paraproteinemia. Hum Pathol 1990;21:1181-3. 8. Messiaen T, Deret S, Mougenot, ridoux F, Dequiedt P, Dion JJ, et al. dult Fanconi syndrome secondary to light chain gammopathy. Clinicopathologic heterogeneity and unusual features in 11 patients. Medicine 2000;79:135-54.
252 강지민 김진아 신석준외 1 인 9. Jung JY, Park CJ, Cho HC, Park YS. Intranuclear inclusion in IgGlambda multiple myeloma. Korean J Clin Pathol 1996;16:139-42. ( 정지영, 박찬정, 조현찬, 박영석. 핵내봉입체를보인 IgG-lambda형다발성골수종 1예. 대한임상병리학회지 1996;16:139-42.) 10. Ko G, Park CJ, Cho HC. case of intracytoplasmic crystalline inclusions in multiple myeloma with Fanconi syndrome. Korean J Clin Pathol 1996;16:143-6. ( 고근아, 박찬정, 조현찬. Fanconi 증후군을동반한세포질내결정형봉입체를보인다발성골수종 1예. 대한임상병리학회지 1996;16:143-6.) 11. Greipp PR, Leong T, ennett JM, Gaillard JP, Klein, Stewart J, et al. Plasmablastic morphology--an independent prognostic factor with clinical and laboratory correlates: Eastern Cooperative Oncology Group (ECOG) myeloma trial E9486 report by the ECOG Myeloma Laboratory Group. lood 1998;91:2501-7. 12. Gardais J, Genevieve F, Foussard C, Delisle V, Zandecki M. Is there any significance for intracellular crystals in plasma cells from patients with monoclonal gammopathies? Eur J Haematol 2001;67:119-22. 13. Lin J, Markowitz GS, Valeri M, Kambham N, Sherman WH, ppel G, et al. Renal monoclonal immunoglobulin deposition disease: the disease spectrum. J m Soc Nephrol 2001;12:1482-92. 14. Pozzi C, D mico M, Fogazzi G, Curioni S, Ferrario F, Pasquali S, et al. Light chain deposition disease with renal involvement: clinical characteristics and prognostic factors. m J Kidney Dis 2003; 42:1154-63. 15. Lacy MQ and Gertz M. cquired Fanconi s syndrome associated with monoclonal gammopathies. Hematol Oncol Clin North m 1999;13:1273-80. 16. Lajoie G, Leung R, argman JM. Clinical, biochemical, and pathological features in a patient with plasma cell dyscrasia and Fanconi syndrome. Ultrastruct Pathol 2000;24:221-6. 17. Gu X, arrios R, Cartwright J, Font RL, Truong L, Herrera G. Light chain crystal deposition as a manifestation of plasma cell dyscrasias: the role of immunoelectron microscopy. Hum Pathol 2003;34:270-7. 18. splin JR, Coe FL. Tubular disorders. In: Kasper DL, raunwald E, Fauci S, Hauser SL, Longo DL, Jameson JL, ed. Harrison s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2004: 1694-702. 19. Deret S, Denoroy L, Lamarine M, Vidal R, Mougenot, Frangione, et al. Kappa light chain-associated Fanconi s syndrome molecular analysis of monoclonal immunoglobulin light chains from patients with and without intracellular crystals. Protein Eng 1999;12: 363-9. 20. ucouturier P, auwens M, Khamlichi, Denoroy L, Spinelli S, Touchard G, et al. Monoclonal IgL chain and L chain V domain gragment crystallization in myeloma-associated Fanconi s syndrome. J Immunol 1993;150:3561-8.