Original Article J Korean Bone Joint Tumor Soc 2014; 20: 47-53 http://dx.doi.org/10.5292/jkbjts.2014.20.2.47 www.kbjts.or.kr 저등급중심부골육종의진단, 치료및예후 pissn : 1226-4962 eissn : 2233-9841 Diagnosis, Treatment and Prognosis of Low Grade Central Osteosarcoma 송원석 조완형 이광열 공창배 고재수 * 전대근 이수용원자력병원정형외과학교실, * 병리학교실 목적 : 저등급중심부골육종환자의진단, 치료및예후에대하여알아보고자하였다. 대상및방법 : 1994 년부터 2011 년까지저등급중심부골육종으로진단받고본원에서치료받은 16명의환자를대상으로하였다. 결과 : 환자분포는남자가 4명여자가 12명이었으며평균연령은 26세였다. 초기진단은 11명의환자가중심부저등급골육종으로맞게진단되었으나나머지 5명의환자는각각유골골종, 비골화성섬유종, 골모세포종, 동맥류성골낭종, 결합조직형성섬유종등으로오진되었다. 15 명의환자가최종적으로광범위절제술을시행하였으며그중한명은수술전항암치료를시행하였다. 그중 14명의환자가치료후재발없이추시중이며, 한명은기존에앓던신세포암의악화로수술후 21개월후사망하였다. 나머지한명은다발성종양환자로, 부분적으로만광범위절제술을시행하였으며잔존종양에방사선치료만을시행한후 7년째생존중이다. 9명 (56%) 의환자가종양이피질골밖까지파급되어있는소견을보였으며그중한명은구획외로까지의파급을보였다. 결론 : 저등급중심부골육종은진단이어려우나임상적의심과함께조직병리학적, 영상학적인특징을고려하여주의깊은감별이요구된다. 치료에있어서는광범위종양절제술이권장되며, 양성종양으로오진하여병소내절제술만시행한경우라도국소재발이나고등급으로의악성전환가능성이있으므로광범위재절제술을시행할것을권고하는바이다. 색인단어 : 저등급중심부골육종, 진단, 치료 서 론 저등급골육종에는방골성골육종과저등급중심부골육종이있으며전체골육종의 4-5% 를차지한다. 1) 저등급중심부골육종은방골성골육종보다더드물며전체골육종의 1-2% 정도를차지한다. 2) 방골성골육종은방사선학적으로비교적진단이용이하며, 특징적으로원위대퇴후방이나근위상완골, 경골, 비골순으로호발한다. 조직학적으로는화골성근염, 기괴방골성골연골성증식증 (bizarre parosteal osteochondromatous proliferation), 유골골종등과감별하여야한다. 반면저등급중심부골육종은진단이용이하지않다. 영상학적으로도양성종양의양상과비슷하여, 약간의공격적인성향을띠는양성종양으로오인되는경우가있다. 3-6) 70 예를분석한한대규모연구에서는저등급중심부골육종의영상학적특징으로다양한정도의두껍고거친소주골을동반한골융 접수일 2014 년 9 월 16 일심사수정일 2014 년 11 월 26 일게재확정일 2014 년 11 월 28 일교신저자전대근서울시노원구공릉동 215-4, 원자력병원정형외과 TEL 02-970-1242, FAX 02-970-2427 E-mail dgjeon@kcch.re.kr 해소견 (31%), 소주골이얇고불명확하며골융해소견이뚜렷한경우 (30%), 조밀한경화성소견 (24%), 골융해소견과골경화소견이혼합된경우 (14%) 등을보고하였다. 7) 조직학적으로도섬유성골이형성증, 비골화성섬유종, 결합조직형성섬유종 (desmoplastic fibroma) 등다른양성종양과유사한소견을보여이들과의감별이중요하다. 8,9) 저등급중심부골육종의영상학적소견이양성골종양과비슷하기때문에절개생검술없이골소파술만을시행하는경우가종종발생하며, 이경우종양의파급으로이어질수있다. 9-11) 또한절개생검술을적절히시행했다하더라도병리학자에의해제대로진단되지못하는경우도있다. 10-12) 본연구에서는저등급중심부골육종환자 16예를경험하여진단, 치료및예후에관해분석해보고자한다. 대상및방법 1994 년부터 2011 년까지저등급중심부골육종으로진단받은 18 명의환자를선별하였으며, 두명의숙련된병리학자가조직슬라이드를재검하여확인하였다. 조직학적진단의기준으로는피질골과하버시안계로의종양침범및병변주변소주골의포착여부로 대한골관절종양학회지 : 제20 권제2 호 2014 Copyrights 2014 by The Korean Bone and Joint Tumor Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
48 송원석 조완형 이광열외 4 인 서결정하였다. 2,8) 병리학자의재검후두예가제외되었는데, 각각일부만이저등급소견을보인고등급골육종과고등급섬유모세포성골육종이저등급골육종으로오진되었던경우였다. 재검후확진된 16예는나이, 성별, 종양의위치, 단순방사선소견, 종양의크기, 골외로의파급여부, 초기진단및초기치료, 최종진단및최종치료, 절제연, 종양학적예후등을조사하였다. 결과 12명은여자, 4명은남자였으며평균나이는 26세 (7-54) 였다. 13명의환자가치료전본원으로직접의뢰되었으나나머지 3명은타병원에서진단및치료후본원으로전원되었다. 추시기간은평균 81개월 (21-171) 이었다. 종양의위치는대퇴부가 5명, 근위상완골이 3명, 근위경골이 2명, 골반골이 2명, 원위비골, 종골, 견갑골, 원위요골이각각 1명이었다. 초기진단은 16명중 14명의환자가중심부저등급골육종혹은저등급육종으로진단되었으나나머지 2명의환자는각각비골화성섬유종, 동맥류성골낭종등으로오진되었다 (Table 1). 첫진단시전이를보였던환자는없었으며추시중제1 흉추로의전이를보였던한환자는본래앓던신세포암에서유래한것으로판명되어, 결과적으로모든환자에서전이는없었다. 영상학적으로는상기한 Andresen 의기준에따라다음의네그 룹으로분류하여조사하였다 ; 조밀한골경화성소견 (6예 ), 골융해소견과골경화소견이혼합된경우 (5예 ), 다양한정도의두껍고거친소주골을동반한골융해소견 (3예 ), 소주골이얇고불명확하며골융해소견이뚜렷한경우 (2예 ). 종양의크기는자기공명영상검사를이용하여측정하였는데, 종양의길이는평균 7.6 cm (3-17), 종양의부피는평균 74 cc (5.3-200) 이었다. 종양의 Ennecking s criteria 에따른병기는 7예가 stage IA, 9예가 stage IB였다. 한환자는수술전항암화학요법을 2회시행하였는데, 이는이환자의영상학적패턴이공격적이고, 종양의크기가커서 (200 cc) 고등급의악성이의심되었고, 절개생검술을시행한부위가이종양의고등급악성부위를놓쳤을가능성을고려했기때문이었다 (Fig. 1). 그러나종양절제술후시행한전체종양의조직검사상저등급중심부골육종으로확진되어, 이에수술후항암화학요법은시행하지않았다. 이환자 ( 증례 14) 를제외한모든환자가본원에서광범위절제술을시행받았다. 저자들은저등급의악성도를감안하여, 절제연을 2 cm로하되연부조직의절제를최소화하였고, 종양이관절과가까웠던두환자 ( 증례 1, 2) 에서는절제연을 1 cm 이하로하여수술을시행하였다. 15명중세명의환자는종양절제술만을시행받았으며, ( 내골반골절제술 2예, 견갑골절제술 1예 ) 나머지 12명의환자는재건술을시행하였다 ( 종양대치물 5예, 중첩동종골 3예, 동종골혹은재사용자가골과종양대치물복합체 2예, 자가비골이식 1예, 골시멘트보형물 1예 ). 절제술을시 Table 1. Patient Characteristics and Radiologic Feature Case number Age/ Gender Previous diagnosis Previous treatment Location Radiologic Pattern Tumor size (cm)/ Volume (cc) Extra-osseous extension 1 7/F - - Proximal femur Lytic, coarse trabeculation 3 2.1 1.6/5.3-2 11/F - - Proximal humerus Densely sclerotic 3.2 1.7 1.6/4.6-3 19/F - - Proximal humerus Mixed lytic and sclerotic 6.4 4.2 4/56.3 + 4 19/F - - Distal radius Densely sclerotic 7.5 2.9 2.5/28.5 + 5 20/F - - Pelvis, pubis Lytic, coarse trabeculation 8 5 3/62.8 + 6 20/M - - Distal femur Predominantly lytic 8.6 5.6 3.9/98.3 + 7 21/M - - Distal femur Mixed lytic and sclerotic 9.5 6.8 5.9/199.6 + 8 24/F - - Proximal humerus Densely sclerotic 8.7 6 4.9/140 + 9 32/M - - Proximal tibia Mixed lytic and sclerotic 7 6 5/110-10 36/M - - Pelvis, ilium Densely sclerotic 4.6 4.5 2.4/26-11 38/F - - Scapular Densely sclerotic 7.8 6.5 4.5/119.5 + 12 39/F - - Distal fibular Mixed lytic and sclerotic 17 3.5 2.5/77.9 + 13 54/F - - Distal femur Densely sclerotic 6.5 4 2.8/38.1-14 16/F Low-grade sarcoma Radiofrequency Distal femur Lytic, coarse trabeculation 10.3 3.6 3.2/62.1 - Ablation 15 20/F NOF Curettage Calcaneus Mixed lytic and sclerotic 6.3 4.5 3.4/50.5 + 16 38/F ABC on biopsy* Curettage Proximal tibia Predominantly lytic 7 6 5/110 - ABC, aneurismal bone cyst; *Hemangioendothelioma on curettage specimen; NOF, nonossifying fibroma.
49 저등급중심부골육종의진단, 치료및예후 행하지않은나머지한명 ( 증례 3) 의환자는다발성저등급중심부골육종환자로, 타병원에처음방문하여경골근위부의병변만을발견하였으며, 이부위에서두차례조직검사시행후저등급 Figure 1. Plain radiograph of a 21-year-old man showing expansile mixed osteolytic and sclerotic lesion in the distal meta-diaphysis of femur. Radiologic differential diagnosis included osteosarcoma, fibrosarcoma, adamantinoma, and giant osteoblastoma. 중심부골육종으로진단되었다. 이에이부위의병변을절제하고비골이식및골이식을시행하였으며이후재발은없었다. 그러나추시중동측대퇴골두일부, 경부와간부에서도병변이발견되었다. 다만첫방문당시이부위에대한검사를시행하지않아이병변이언제부터존재했었는지는알수가없었다. 이에대퇴골두와경부및간부에골소파술을시행한후전기고주파소작술을시행하였으며, 대퇴간부는이후전기소작으로인한병적골절이발생하여내고정술및골이식을시행하였다. 그러나이후시행한 PET-CT 검사에서동측경골하부관절면부위와동측비구부위에도전이소견이발견되어본원으로의뢰되었다. 본원에서는전이부위에대한근치적절제술은예후상의이득이없을것으로판단하여방사선치료만을시행하였다. 16명중 14명의환자가치료후재발이나전이없이현재까지추시중이다. 나머지두명중한명은기존에앓던신세포암의제 1 흉추로의전이및이후종양의전신파급으로사망하였다. 절제술을시행하지않고방사선치료만을시행한환자 ( 증례 14) 는 7년이지난현재까지종양의파급없이생존중이다 (Table 2). 종양의영상학적파급범위는 9명 (56%) 의환자가피질골밖까지파급된종양소견을보였다. 그중한명은구획외로의파급을보였는데, 본원에서시행한절개생검술의조직검사상결합조직형성섬유종 (desmoplastic fibroma) 으로진단되었다. 그러나영상소견의공격성을감안한임상적판단하에악성종양에준하는광범위절제 Table 2. Surgical Procedure, Immune-Histochemical Analysis, and Clinical Course Case number Chemotherapy Definitive treatment Surgical margin Local recurrence Metastasis Followup (months) Final status 1 - Intercalary resection, Wide - - 56 CDF overlapping allograft 2 - Intercalary resection, Wide - - 57 CDF overlapping allograft 3 - Allograft prosthesis composite Wide - - 35 CDF 4 - Excision, fibula graft Wide - - 171 CDF 5 - Internal pelvectomy Marginal - - 141 CDF 6 - Tumor prosthesis Wide - - 74 CDF 7 + Tumor prosthesis Wide - - 44 CDF 8 - Tumor prosthesis Wide - - 45 CDF 9 - Tumor prosthesis Wide - - 107 CDF 10 - Internal pelvectomy Marginal - - 21 DOC 11 - Scapulectomy Wide - - 122 CDF 12 - Resection, overlapping allograft Wide - - 46 CDF 13 - Tumor prosthesis Wide - - 36 CDF 14 - Radiotherapy - + - 142 AWD 15 - Cement spacer Marginal - - 46 CDF 16 - Pasteurized bone-prosthesis composite Wide - - 162 CDF CDF, continous disease free; AWD, alive with disease; DOC, died of other cause (renal cell carcinoma).
50 송원석 조완형 이광열외 4 인 술을시행하였고, 최종조직병리또한저등급중심부골육종으로진단되었다. 고찰 중심부저등급골육종은피질골과의상대적위치에따라방골성골육종과저등급중심부골육종으로구분된다. 두종류의종양모두 30대에호발하고, 무증상기간이길며, 거친소주골을동반하는섬유성간질 (fibrotic stroma) 에비정형방추세포의증식소견이관찰되고, 염색체 12 번이증폭 (amplified) 되는유전적특질을보이며, 재발률, 전이율, 탈분화 (dedifferentiation), 무병생존률이비슷하다는유사점을갖는다. 1,13-15) 반면, 저등급중심부골육종은방골성골육종보다빈도가더드물고, 영상학적으로도양성종양의양상을띠거나, 간혹더공격적인악성종양의모습을보이기도한다 (Fig. 2-4). 때문에저등급중심부골육종은과소진단 (underdiagnosis) 혹은과잉진단 (over-diagnosis) 될가능성이더높다. 이전의연구들은이러한드문중심부저등급골육종의진단에대한난점을보고하였다 (Table 3). 약 30% 의환자가처음방문한병원에서유골골종, 간엽종 (mesenchymoma), 골낭종, 결합조직형성섬유종 (desmoplastic fibroma), 섬유성이형성증, 섬유골성병소 (fibro-osseous lesion), 거대세포종, 악성섬유성조직구증등으로오진된다. 10-12) 게다가골연부종양전문기관에서조차도조직생검후옳은병리학적진단을내는경우가 50-54% 밖에되지않는다. 3,11) 이러한오진으로병소내절제술이나소파술의빈도가 33-56% 까지높게나타난다. 이경우국소재발이잘일어날뿐만아니라, 재발한종양은고등급골육종으로전환될가능성이있기때문에그중 39-56% 가량은수술전항암치료와함께광범위재절 제술을시행하게된다. 11,12) 적절한최종절제술을시행한후에는재발율이약 0-14% 로감소한다고한다. 폐전이의비율은이전연구중 Yoshida 의연구 (43%) 를제외한세연구에서 0-20% 로비교적낮게보고되었는데, 절제연이나항암치료여부가서로차이가있었음에도유사한결과를보였다. 또한 Choong 등은수술만을시행한 20명의환자에서 4명 (20%) 의환자만이전이를보였다고하였다. 3) 즉, 고등급의전형적골육종에서는항암치료가폐전이를유의하게낮추어줄수있지만, 저등급중심부골육종에있어서는항암치료의효과가아직불확실한실정이다. 저자들도이전의연구에서, 재발후공격적인성향을보이는방골성골육종 Figure 3. Plain radiograph of a 20-year-old man showing predominantly lytic lesion in the distal femur. Radiologic differential diagnosis included osteosarcoma, fibrosarcoma, chondrosarcoma, and giant cell tumor with aneurismal bone cystic change. A Figure 2. (A) Plain radiograph of a 19-year-old girl showing mixed osteolytic and sclerotic lesion in the proximal humerus. (B) The typical histologic appearance of low-grade osteosarcoma, permeation of osseous trabeculae by spindle cell stroma (hematoxylin-eosin, 100). B A Figure 4. (A) Plain radiograph of a 54-year-old woman showing sclerotic lesion in the distal femur. (B) Mature bone trabeculae is admixed with permeating spindle cell stroma ( 100). B
51 저등급중심부골육종의진단, 치료및예후 Table 3. Comparison with Previous Studies Author Number of patients Definitive treatment Intralesional operation* (%) Chemotherpy LR Metastasis Final status Current study 16 13/3 3/16 (19%) 1/16 (6%) 0% 0% NED (15), DOC (1), AWD (1) Choong et al 8) 20 12/8 12/20 (60%) - 14% 20% NED (16), DOD (4) Malhas et al 12) 18 11/7 10/18 (56%) 7/18 (39%) 11% 11% NED (16), AWD (1), DOD (1) Yoshida et al 14) 9 3/6 3/9 (33%) 5/9 (56%) 14% 43% NED (4), AWD (2), DOD (1) Dujardin et al 18) 6 NA NA NA NA NA NA Hayashi et al 13) 5 NA 2/5 (40%) NA 0% 0% NED (5) *Either at primary or referral center; LR, local recurrence after definitive treatment; NED, no evidence of disease; DOC, died of other cause; AWD, alive with disease; DOD, died of disease; NA, data not available. 환자에게항암치료를추가한경우를분석하였고, 그결과예후의유의한이득이없었음을확인한바있다. 16) Yoshida 의연구에서도 56% 의저등급골육종환자가항암치료를받았지만 43% 의환자가전이를보였다. 12) 저자들은이러한결과들을종합하여볼때저등급에서고등급으로악성도의변이를보인골육종에서는항암치료가예후에별다른도움이되지않을것이라고생각하였다. 하지만정확한관련성은더많은연구가필요하리라사료된다. 중심부저등급골육종에대한방사선치료는이전의연구에서는잘언급되어있지않지만, 본연구에서는근치적광범위절제술을시행하기어려웠던다발성저등급중심부골육종환자에게, 종양의안정화를위하여시행하였다. 이증례의경우 7년추시기간동안더이상의파급없이생존해있다. 그러나이렇게방사선치료가불가피한경우를제외하고는중심부저등급골육종의치료에있어서원칙적으로광범위절제술이권고된다. 결론 저등급중심부골육종은진단이어려우나임상적의심과함께조직병리학적, 영상학적인특징을고려하여주의깊은감별이요구된다. 치료에있어서는광범위종양절제술이권장되며, 양성종양으로오진하여병소내절제술만시행한경우라도국소재발이나고등급으로의악성전환가능성이있으므로광범위재절제술을시행할것을권고하는바이다. 참고문헌 1. Schwab JH, Antonescu CR, Athanasian EA, Boland PJ, Healey JH, Morris CD. A comparison of intramedullary and juxtacortical low-grade osteogenic sarcoma. Clin Orthop Relat Res. 2008;466:1318-22. 2. Kurt AM, Unni KK, McLeod RA, Pritchard DJ. Low-grade intraosseous osteosarcoma. Cancer. 1990;65:1418-28. 3. Choong PF, Pritchard DJ, Rock MG, Sim FH, McLeod RA, Unni KK. Low grade central osteogenic sarcoma. A long-term followup of 20 patients. Clin Orthop Relat Res. 1996;(322): 198-206. 4. Franceschina MJ, Hankin RC, Irwin RB. Low-grade central osteosarcoma resembling fibrous dysplasia. A report of two cases. Am J Orthop (Belle Mead NJ). 1997;26:432-40. 5. Kenan S, Ginat DT, Steiner GC. Dedifferentiated high-grade osteosarcoma originating from low-grade central osteosarcoma of the fibula. Skeletal Radiol. 2007;36:347-51. 6. Muramatsu K, Hashimoto T, Seto S, Gondo T, Ihara K, Taguchi T. Low-grade central osteosarcoma mimicking fibrous dysplasia: a report of two cases. Arch Orthop Trauma Surg. 2008;128:11-5. 7. Andresen KJ, Sundaram M, Unni KK, Sim FH. Imaging features of low-grade central osteosarcoma of the long bones and pelvis. Skeletal Radiol. 2004;33:373-9. 8. Bertoni F, Bacchini P, Fabbri N, et al. Osteosarcoma. Lowgrade intraosseous-type osteosarcoma, histologically resembling parosteal osteosarcoma, fibrous dysplasia, and desmoplastic fibroma. Cancer. 1993;71:338-45. 9. Kumar A, Varshney MK, Khan SA, Rastogi S, Safaya R. Low grade central osteosarcoma--a diagnostic dilemma. Joint Bone Spine. 2008;75:613-5. 10. Hayashi K, Tsuchiya H, Yamamoto N, et al. Diagnosis and treatment of low-grade osteosarcoma: experience with nine cases. Int J Clin Oncol. 2014;19:731-8. 11. Malhas AM, Sumathi VP, James SL, et al. Low-grade central osteosarcoma: a difficult condition to diagnose. Sarcoma. 2012;2012:764796. 12. Yoshida A, Ushiku T, Motoi T, et al. Immunohistochemical analysis of MDM2 and CDK4 distinguishes low-grade osteo-
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Original Article pissn : 1226-4962 eissn : 2233-9841 J Korean Bone Joint Tumor Soc 2014; 20:47-53 http://dx.doi.org/10.5292/jkbjts.2014.20.2.47 www.kbjts.or.kr Diagnosis, Treatment and Prognosis of Low Grade Central Osteosarcoma Won Seok Song, Wan Hyeong Cho, Kwang-Youl Lee, Chang-Bae Kong, Jae-Soo Koh*, Dae-Geun Jeon, and Soo-Yong Lee Departments of Orthopedic Surgery and *Pathology, Korea Cancer Center Hospital, Seoul, Korea Purpose: We analyzed the diagnosis and the treatment outcomes of patients with central low grade osteosarcoma. Materials and Methods: We retrospectively reviewed 16 patients with central low grade osteosarcoma were treated at out institution between 1994 and 2011. Results: There were 4 men and 12 women with mean age of 26 years. Eleven patients were correctly diagnosed but 5 patients were misdiagnosed as osteoid osteoma, non ossifying fibroma, aneurysmal bone cyst, desmoplastic fibroma. 15 patients finally received wide margin en bloc excision and one of them treated under neoadjuvant chemotherapy. Final survival status was continuous disease free in 14 and 1 patient died of renal cell cancer. Remaining 1 with multifocal lesions is alive with disease for 7 years only treated radiation therapy on residual tumors. Nine (56%) of 16 tumors showed extra-osseous extension of tumor (56%) and 1 of them showed extra-compartmental tumors. Conclusion: The diagnosis of central low grade osteosarcoma is challenging, however, considering of the clinical suspicion, the typical findings of radiologic and pathologic features, proper diagnosis is needed. This tumor should be treated with wide excision, even after an intralesional excision, to avoid local recurrence or transformation to higher histologic grade. Key words: central low grade osteosarcoma, diagnosis, treatment Received September 16, 2014 Revised November 26, 2014 Accepted November 28, 2014 Correspondence to: Dae-Geun Jeon Department of Orthopedic Surgery, Korea Cancer Center Hospital, 215-4, Gongneung-dong, Nowon-gu, Seoul 139-706, Korea TEL: +82-2-970-1242 FAX: +82-2-970-2427 E-mail: dgjeon@kcch.re.kr The Journal of the Korean Bone and Joint Tumor Society Vol. 20, No. 2 (December 2014) Copyrights 2014 by The Korean Bone and Joint Tumor Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.