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1 대한내과학회지 : 제 77 권부록 2 호 2009 증례 항면역글로불린 G4 염색양성을보이는 Mikulicz 병 1예와초음파소견 인하대학교의과대학 1 내과학교실, 2 병리학교실, 3 이비인후과학교실 김영욱 1 권성렬 1 주영채 2 임미진 1 김보묵 3 박원 1 case of Mikulicz s disease with positive anti-immunoglobulin G4 staining and unique ultrasonographic findings Young Wook Kim, M.D. 1, Seong Ryul Kwon, M.D. 1, Young Chae Chu, M.D. 2, Mie Jin Lim, M.D. 1, o Mook Kim, M.D. 3, and Won Park, M.D. 1 Departments of 1 Internal Medicine, 2 Pathology and 3 Otolaryngology, Inha University College of Medicine, Incheon, Korea Mikulicz s disease is an immunoglobulin G4-related systemic disease involving enlargement of the lacrimal and salivary glands that differs substantially from Sjögren s syndrome. 45-year-old woman who noticed bilateral swelling in the submandibular region and dry mouth for 6 months was admitted. Ultrasonography of the enlarged glands revealed an irregular, hypoechoic, multilobular mass, and the power Doppler showed that the mass was hypervascular. She had an elevated immunoglobulin G level, positive Schirmer s I test, and positive unstimulated whole salivary flow test, but was negative for antinuclear, anti-ro/ss-, and anti-la/ss- antibodies. The submandibular gland biopsy showed diffuse infiltration of lymphocytes and plasma cells expressing immunoglobulin G4. We report a patient diagnosed with Mikulicz s disease involving the infiltration of plasma cells expressing immunoglobulin G4 and unique ultrasonographic findings. (Korean J Med 77:S484-S488, 2009) Key Words: Mikulicz s disease; Immunoglobulin G4; Ultrasonography 서론 Mikulicz병은특발성으로양측성이고대칭적인눈물샘과침샘의비대를특징으로하는질환이다 1-5). 이질환은조직학적소견이흔히쇼그렌증후군과유사하기때문에쇼그렌증후군의아형으로여겨져왔다 6). 그러나두질환은임상적으로나조직학적으로차이가있기때문에최근에는전혀다 른질환으로여러문헌에소개되고있다 1-4). 임상적으로는지속적인눈물샘및침샘, 특히귀밑샘의비대를보이며건조증상이비교적덜하며당질코르티코이드에좋은반응을보인다. 또한과감마글로불린혈증을보이며흔히자가항체가음성이면서조직학적으로는항면역글로불린 G4 염색에양성소견을보인다 1-4). 이러한임상적, 조직학적특성으로최근외국문헌에서는 Mikulicz병을면역글로불린 G4에연 Received: ccepted: Correspondence to Won Park, M.D., Department of Internal Medicine, Inha University Hospital, ga, Sinheung-dong, Jung-gu, Incheon , Korea parkwon@inha.ac.kr - S 484 -

- Young Wook Kim, et al. Milulicz s disease with positive anti-immunoglobulin G4 and ultrasonographic findings - 관된질환으로소개되고있지만국내에서는아직까지그러한보고가없다.

2 - Young Wook Kim, et al. Milulicz s disease with positive anti-immunoglobulin G4 and ultrasonographic findings - 관된질환으로소개되고있지만국내에서는아직까지그러한보고가없다. 또한초음파검사방법은비교적쉽게접근할수있는검사법으로 Mikulicz병과같은경부덩어리의감별에유용하나국내에서는아직 Mikulicz병에서발생된덩어리에대한초음파소견이기술되지않고있다. 이에저자들은국내에서는처음으로드문발생장소인턱밑샘의비대를주소로내원한환자에서항면역글로불린 G4 염색양성을보인 Mikulicz병 1예와함께초음파소견을보고하고자한다. 증례환자 : 45세여자주소 : 경부덩어리, 구강및안구건조증상현병력 : 6개월전부터시작되는양측턱밑샘부위의덩어리로타병원경유하여정밀검사위해본원에내원하였다. 환자는구강및안구건조증상호소하였으나관절통, 피부증상, 기침또는연하곤란등다른증상은없었다. 이학적검사 : 양측경부덩어리의크기는약 3 cm 정도였고, 딱딱하였으며고정되어있었으나압통은없었다. 방사선학적소견 : 타병원에서경부컴퓨터단층촬영을시행하였고, 양측턱밑샘부위의미만성비대가관찰되었고, 림프절은관찰되지않았다. 본원에서시행한경부초음파에서는양측턱밑샘부위의약 cm 크기의경계가뚜렷한원형의덩어리가관찰되었고, 내부는저에코이면서다결절성이었고, power Doppler 검사에서과다혈관상을보였다 ( 그림 1). 검사실소견 : 일반혈액검사에서백혈구 4,200/mm 3, 혈색소 12.3 g/dl, 혈소판 262,000/mm 3 이었고, C-반응단백은 0.05 mg/dl, 적혈구침강속도는 30 mm/hr이었다. 일반화학검사에서총단백 7.9 g/dl, 알부민 4.3 g/dl이었고, 혈청학적검사에서항핵항체, 항 CCP 항체, 류마티스인자는음성이었다. 항 Ro/SS- 항체와항 La/SS- 항체도음성이었다. 면역글로불린 G는 1,953 mg/dl ( 참고치 : 680~1,620) 으로증가되어있었고, 면역글로불린 는 279 mg/dl (84~438), 면역글로불린 M은 99 (57~288) mg/dl으로정상범위였다. 면역글로불린 G1은 9.40 g/l ( 참고치 : 3.65~9.41), 면역글로불린 G2는 g/l ( 참고치 : 1.65~5.45), 면역글로불린 G3는 1.28 g/l ( 참고치 : 0.32~1.16), 면역글로불린 G g/l ( 참고치 : 0.06~1.21) 로면역글로불린 G2와 G3가증가되었다. 자극하지않은상태에서전체침분비량은 15분동안 0.4 cc였고, 침샘신티그래피에서양측귀밑샘과턱밑샘에서흡수는정상이었으나배설은양쪽턱밑샘에서감소되었다. 셔머검사는양쪽아랫눈꺼풀에 25 mm 길이의여과지대를설치한뒤 5분동안관찰하였고, 좌측은 1 mm, 우측은 0 mm이었다. 병리학적소견 : 수술후육안적소견은크기가 cm였고, 절단면은다발성결절형태로비교적균질하였으며노란색을띄었다 ( 그림 2). 병리학적검사에서심한림프구침윤과세엽파괴가관찰되었고, 림프구가상피세포를침윤하는양상을보였다 ( 그림 2-2D). 면역조직화학검사에서림프구는 림프구와 T 림프구가같이침윤되었으며림프구결절을이루는림프구는주로 림프구였다 ( 그림 3, Figure 1. Ultrasonography of the right submandibular gland. () This picture shows cm sized mass that were irregular, hypoechoic, and multilobular appearance with clear border. () The power Doppler shows the presence of highly vascularized mass. - S 485 -

- 대한내과학회지 : 제 77 권부록 2 호 2009 - C D Figure 2. Submandibular gland pathology. () The cut surface showed multinodular grayish-yellow solid homogeneous appearance.

3 - 대한내과학회지 : 제 77 권부록 2 호 C D Figure 2. Submandibular gland pathology. () The cut surface showed multinodular grayish-yellow solid homogeneous appearance. () Intense lymphocytic infiltration associated with germinal center formation and destruction of salivary acini (H & E stining 40). (C) Small epithelial nests are surrounded and infiltrated by lymphocytes (H & E stining 100). (D) t high power view, the epithelial islands have lymphocytic infiltration (H & E stining 400). 3). 또한상피세포가림프구에의해침윤되어상피세포섬을형성하는소견이관찰되었다 ( 그림 3C). 항면역글로불린 G4 면역효소염색에서양성인형질세포가상피세포섬과그주변에서관찰되었다 ( 그림 3D). 치료및경과 : 현재환자는당질코르티코이드를 10 mg으로치료중이며환자의개인적사정및증상호전으로면역글로불린역가, 셔머검사또는침샘신티그래피등의추적검사는시행할수없었으나턱밑샘의덩어리는크기의감소가있고구강건조및안구건조증상이호전중으로외래관찰중이다. 고찰 Mikulicz병은 1888년에 Mikulicz가무증상의침샘과눈물샘의종대를주소로내원한 42세남자농부를보고함으로써처음으로소개되었다 5,7). 1952년 Godwin은양성림프상피병 변 (benign lymphoepithelial lesion: LL) 이라는용어를사용하였으며 8), 1953년 Morgan 과 Castleman 은 Mikulicz병이분리된질환이아니라쇼그렌증후군의한형태라하였으며그이후혈청음성쇼그렌증후군이라고여겨졌다 6). 그러나최근에는 Mikulicz병이쇼그렌증후군과는임상적으로나조직학적으로전혀다른질환이고특히면역글로불린 G4와관련된전신질환으로분류되고있다 1-4). Mikulicz병은 50대에서 60대사이에서호발하고예전에는여성이많다고하였으나최근에는남성에서유병률이증가한다고보고되고있다 1). 임상적으로침샘이붓고통증을유발할수있으나대개무증상의비대를나타내며크기의변화가일어나지않는다 5,7). 건조증상은있을수있으나쇼그렌증후군과비교하여미약하며간혹열을동반한전신증상을나타내는염증을보일수있다. 본증례의경우쇼그렌증후군의건조증상에대한검사를국내에서는처음으로시행하였고, 셔머검사와자극하지않은상태에서전체침 - S 486 -

4 - 김영욱외 5 인. 항면역글로불린 G4 염색양성의 Mikulicz 병 - C D Figure 3. () Immunohistochemical stain for CD 20 showed diffuse strong positive in the germinal center ( 100). () Interfollicular lymphocytes were positive for CD3 ( 100). (C) Cytokeratin staining showed lymphoepithelial lesion ( 100). (D) nti-igg4 antibody immunostaining found numerous anti-igg4 positive plasma cells infiltrating in and around acinar and ductal cells ( 100). 분비량검사에서양성소견을보였다. 발생위치는 rmed Forces Institute of Pathology 의자료를분석해보면 83% 는귀밑샘을침범하였고, 11% 는턱밑샘을 6% 는경부나작은침샘을침범한다 9). 국내문헌에서는류등이보고한증례의경우에만턱밑샘에서발생하였고, 그이외의문헌에서는이하선에서발생한경우였다. 영상학적검사소견으로는경부컴퓨터촬영에서대칭적으로양쪽눈물샘이나침샘의비대를보이며림프절의크기는보통 1 cm 이하로관찰된다. 초음파소견으로는저에코의다방성사이막을갖는덩어리로보이며 power Doppler 검사에서과다혈관양상을보인다 1). 초음파검사법은덩어리의형태, 경계와내부에코및균질성을잘관찰할수있는검사법으로질환의감별에유용하지만본증례와같은초음파소견이 Mikulicz 병에특징적인소견인지는더많은증례의보고가필요할것으로생각된다. 혈액학적검사소견에서면역글로불린 G가증가되는고 감마글로불린혈증을보이고하위분류의비율은건강인에서는면역글로불린 G1, 65%; G2, 25%; G3, 6%; G4 4% 정도로면역글로불린 G1이전체면역글로불린 G의대부부분을차지하나 Mikulicz병에서는특징적으로면역글로불린 G4의농도가약 30% 정도까지크게증가한다 1-4). 그러나본증례에서는면역글로불린 G2와 G3의증가만관찰되어추후국내환자들에서의연구가더필요할것으로생각된다. 항면역글로불린 G4 항체는최근에보통천포창 (pemphigus vulgaris), 낙엽천포창 (pemphigus foliaceus) 그리고자가면역췌장염에서도연관성이있다고보고되고있으나병인론에있어서정확하게어떠한역할을하는지는아직까지잘알려져있지않고있어서향후추가적인연구가필요할것으로생각된다 10-12). 혈청학적검사에서는쇼그렌증후군과다르게항핵항체와항 Ro/SS- 항체그리고항 La/SS- 항체가음성을보인다. 조직학적소견으로는면역글로불린 G4 양성을 - S 487 -

5 - The Korean Journal of Medicine: Vol. 77, Suppl. 2, 보이는형질세포의침윤이관찰되며쇼그렌증후군과는다르게세포자멸사를보이지않는다. 치료를보면쇼그렌증후군에서는스테로이드반응이불충분하다고알려져있으나 Mikulicz병에서는스테로이드를투여시고감마글로불린혈증의개선및면역글로불린 G4 역가의감소를보이고덩어리의크기감소와눈물샘및침샘분비의빠른호전을나타낸다. 지속적인효과를위해서는저용량의당질코르티코이드유지요법과함께필요시 azathioprine 과같은면역억제제의병합요법이필요하다 1-3). 우리증례의경우당질코르티코이드의사용이한달밖에지나지않아관찰이필요하나그반응이부족하다면향후 azathioprine 등의추가요법이필요할수도있다. Mikulicz 병에서장기적인예후는잘알려져있지않으나쇼그렌증후군과같이림프종의발생이증가할것으로보인다 5). 요 Mikulicz병은쇼그렌증후군과는임상적과조직학적으로구별되는면역글로불린 G4와관련된전신질환으로감별을위해서는면역글로불린 G4의상승과항면역글로불린 G4 염색양성여부를확인해야한다. 또한경부초음파검사는쉽게접근할수있고추후다른질환의병발여부및치료에대한덩어리크기감소등을추적할수있기때문에초기및추적검사방법으로가장유용하다고할수있겠다. 이에저자들은국내에서는처음으로항면역글로불린 G4 양성소견을보이는 Mikulicz병을보고하면서특징적인턱밑샘초음파의소견을소개하고자한다. 중심단어 : Mikulicz 병 ; 면역글로불린 G4; 초음파소견 약 REFERENCES 1) Yamamoto M, Takahashi H, Ohara M, Suzuki C, Naishiro Y, Yamamoto H, Shinomura Y, Imai K. new conceptualization for Mikulicz s disease as an IgG4-related plasmacytic disease. Mod Rheumatol 16: , ) Miyake K, Moriyama M, izawa K, Nagano S, Inoue Y, Sadanaga, Nakashima H, Nakamura S. Peripheral CD4+ T cells showing a Th2 phenotype in a patient with Mikulicz s disease associated with lymphadenopathy and pleural effusion. Mod Rheumatol 18:86-90, ) Yamamoto M, Harada S, Ohara M, Suzuki C, Naishiro Y, Yamamoto H, Takahashi H, Imai K. Clinical and pathological differences between Mikulicz s disease and Sjögren s syndrome. Rheumatology 44: , ) Shimoyama K, Ogawa N, Sawaki T, Karasawa H, Masaki Y, Kawabata H, Fukushima T, Wano Y, Hirose Y, Umehara H. case of Mikulicz disease complicated with interstitial nephritis successfully treated by high-dose corticosteroid. Mod Rheumatol 16: , ) 류재영, 최호영, 신철, 이등호. Mikulicz 증후군을보이는 MLT 림프종 1 예. 대한이비인후과학회지 47: , ) hattacharyya N, Frankenthaler R, Gomolin HI, Kadin ME, Lauretano M. Clinical and pathologic characterization of mucosa-associated lymphoid tissue lymphoma of the head and neck. nn Otol Rhinol Laryngol 107: , ) Meyer D, Yanoff M, Hanno H. Differential diagnosis in Mikulicz s syndrome, Mikulicz s disease, and similar disease entities. m J Ophthalmol 71: , ) Chaudhry P, Cutler LS, Yamane GM, Satchidanand S, Labay G, Sunderraj M. Light and ultrastructual features of lymphoepithelial lesions of the salivary glands in Mikulicz s disease. J Pathol 148: , ) ernier JL, haskar SN. Lymphoepitheial lesions of salivary glands: histogenesis and classification based on 186 cases. Cancer 11: , ) Parlowsky T, Welzel J, magai M, Zillikens D, Wygold T. Neonatal pemphigus vulgaris: IgG4 autoantibodies to desmoglein 3 induce skin blisters in newborns. J m cad Dermatol 48: , ) Warren SJ, rteaga L, Rivitti E, oki V, Hans-Filho G, Qaqish F, Lin MS, Giudice GJ, Diaz L. The role of subclass switching in the pathogenesis of endemic pemphigus foliaceus. J Invest Dermatol 120: , ) Hamano H, Kawa S, Horiuchi, Unno H, Furuya N, kamatsu T, Fukushima M, Nikaido T, Nakayama K, Usuda N, Kiyosawa K. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 344: , S 488 -

Jkbcs016(92-97).hwp

Jkbcs016(92-97).hwp Expression of bcl-2 and Apoptosis and Its Relationship to Clinicopathological Prognostic Factors in Breast Cancer - A Study with Long Term Follow-up correlated with the survival rate.(journal of Korean