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1 Oral Cavity Cancer

2 The 7 th Combined Workshop for Head and Neck Surgery Invitation 항상두경부외과분야에많은관심을주시는선생님들안녕하십니까? 무분별한연수회의남발을막고연수회의수준을높여연수회고유의목적인원활한교육과토론의장을마련하고자세대학이합쳐서실시해온두경부외과합동연수회가어느덧세대학에서각각두번씩의순번이돌아금년에제7회째를맞이하게되었습니다. 금년에는지난 2002년합동연수회에서다루었던구강암을다시한번주제로정하였습니다. 제1회연수회에서다루었던내용을바탕으로이제는세계적인수준에도달한우리나라두경부외과의수준에걸맞는내용을소개하고토론하고자합니다. 어려운연제를맡아서강의해주시는여러교수님들께진심으로감사드리며금년합동연수회에여러선생님들을초대합니다. 특히금년연수회는두경부외과분야의수술에관심을가지는고년차전공의선생님들과두경부외과수술을이제막시작하는전임의선생님들에게도움이되는구체적이고실질적인내용을소개하고토론하고자합니다. 구강암의진단과평가에서원발부위와경부림프절에대한다양한진단방법을통한정확한병기와전이여부를평가하는최신방법들을소개하고이를통하여수술및치료의계획을수립하는데도움을주고자합니다. 또한구강암수술에필요한다양한접근법과최신치료지견그리고구강암수술의실제내용과수술후필요한재활및환자의삶의질에대한내용들을소개하고토론합니다. 특히각단락마다패널토의를도입하여보다실제적인내용을토론할수있는기회를마련하였습니다. 우리나라두경부분야의수준에걸맞는연수회가되도록준비하였습니다. 여러선생님들의많은참여를기대합니다. 감사합니다 년 8 월 두경부외과합동연수회 Course Director 김민식, 노영수, 최은창 1

3 The 7 th Combined Workshop for Head and Neck Surgery Workshop Program 구강암 (Oral Cavity Cancer) 08:00-09:00 Registration Part 1 Analysis & Decision Making for Surgical Plan 좌장 : 노영수 ( 한림의대이비인후과 ) 09:00-09:20 Surgical Anatomy Related to Primary Tumor 조광재 ( 가톨릭의대이비인후과 )/007 09:20-09:40 Radiologic Evaluation of Primary Site & Neck 정소령 ( 가톨릭의대영상의학과 )/019 09:40-10:00 Invasion & Molecular Analysis of Oral Cancer 김세헌 ( 연세의대이비인후과 ) /025 10:00-10:20 PET/CT and Molecular Imaging in Oral Cancer 김재승 ( 울산의대핵의학과 ) /035 10:20-10:40 Question & Discussion 10:40-11:00 Coffee Break Part 2 Surgical Approach & Special Consideration 좌장 : 최은창 ( 연세의대이비인후과 ) 11:00-11:20 Transoral, Visor Flap & Lateral Pharyngotomy Approach 김영모 ( 인하의대이비인후과 ) /043 11:20-11:40 Pull-Through & Mandibulotomy Approach 태경경 ( 한양의대이비인후과 ) /049 11:40-12:00 Lymphangiogenesis in Metastasis & Sentinel Lymph Node Biopsy --- 백정환 ( 성균관의대이비인후과 )/055 12:00-12:20 Laser Surgery of Oral Cavity Cancer 이강대 ( 고신의대이비인후과 ) /063 12:20-12:40 Question & Discussion 12:40-13:30 Lunch Part 3 Surgical Treatment for Oral Cancer 좌장 : 왕수건 ( 부산의대이비인후과 ) 13:30-14:00 Resection of Primary Tumor 노영수 ( 한림의대이비인후과 ) /071 14:00-14:30 Management of Neck : N(0), N(+) & Recurrent Node 최은창 ( 연세의대이비인후과 ) /079 14:30-15:00 Reconstruction & Functional Results of the Oral Cavity 김민식 ( 가톨릭의대이비인후과 ) /083 15:00-15:20 Question & Discussion 15:20-15:40 Coffee Break Part 4 Postoperative Care & Rehabilitation 좌장 : 김민식 ( 가톨릭의대이비인후과 ) 15:40-16:00 Complication & Management of Oral Cancer Surgery 정광윤 ( 고려의대이비인후과 ) /091 16:00-16:20 Swallowing Evaluation & Rehabilitation in Oral Cavity Cancer 박영학 ( 가톨릭의대이비인후과 )/101 16:20-16:40 Speech Evaluation & Rehabilitation 선동일 ( 가톨릭의대이비인후과 )/107 16:40-17:00 Quality of Life in Oral Cancer Patients 주형로 ( 한림의대이비인후과 ) /115 17:00-17:20 Question & Discussion 17:20-17:40 Panel Discussion : Review of Cases 김민식 ( 가톨릭의대이비인후과 ) 3

4 The 7 th Combined Workshop for Head and Neck Surgery Analysis & Decision Making for Surgical Plan Part 1

5 Surgical Anatomy Related to Primary Tumor The 7 th Combined Workshop for Head and Neck Surgery 조광재 가톨릭대학교의과대학이비인후과학교실 가톨릭대학교의과대학졸업 Emory Winship Cancer Institute, Research Fellow 가톨릭대학교의과대학이비인후과학교실부교수 1991년 년 2007-현재 7

6 Part 1 Analysis & Decision Making for Surgical Plan The 7 th Combined Workshop for Head and Neck Surgery Surgical Anatomy Related to Primary Tumor Kwang-Jae Cho, MD Department of Otolaryngology-H&N Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea The Oral Mucosa : oral cavity defined by AJCC - from skin-vermilion junction of the lips to the junction of the hard and soft palate above and the line of circumvallate papillae (linea terminalis) below : eight mucosal areas (subsites) of the oral cavity designated by AJCC 1) mucosal lip 2) buccal mucosa 3) lower alveolar ridge 4) upper alveolar ridge 5) retromolar trigone 6) floor of mouth 7) oral tongue 8) hard palate Arterial Supply to Oral Cavity Regions - arterial supply of the oral cavity region arises from lingual, facial, maxillary, and ascending pharyngeal branches of the external carotid artery 1. Lingual artery - majority of the vascular supply to the oral tongue and tongue base - found deep to the hyoglossus muscle - superficial to the hyoglossus and deep to the mylohyoid muscle hypoglossal nerve, lingual nerve, lingual vein, and Wharton s duct - superficial to the mylohyoid muscle facial artery and submental branch, mylohyoid nerve and artery 9

7 Surgical Anatomy Related to Primary Tumor 2. Facial artery - cross over lateral aspect of the mandible approximately 1 cm anterior to the ascending ramus toward the oral commissure - superior and inferior labial arteries anastomose in the midline vascular ring 3. Maxillary artery - divided into three parts by the lateral pterygoid mandibular, pterygoid, and pterygopalatine 1) Mandibular portion of the maxillary artery : pass through foramina or canal (a) deep auricular artery to EAC (b) anterior tympanic artery to tympanum (c,d) middle (via foramen spinosum) and accessory (via foramen ovale) meningeal artery to cranial cavity (e) inferior alveolar artery to jaw and teeth (via mandibular foramen and canal mental foramen) mylohyoid artery (branches before entry into the foramen) to mylohyoid muscle incisive a. to the canine and the incisors and mental a. to the lower lip and chin 2) Pterygoid portion of the maxillary artery : supply muscles (a) deep temporal artery to the temporalis muscle (b) pterygoid artery to the lateral and medial pterygoid muscles (c) masseteric artery to the masseter muscle (d) buccal artery to the buccinator muscle and buccal mucosa 3) Pterygopalatine portion of the maxillary artery : arise before and within the pterygopalatine fossa 10 The 7 th Combined Workshop for Head and Neck Surgery

8 Kwang-Jae Cho : accompanied by br of the maxillary nerve, pass through bony canals and foramina (a) posterior superior alveolar artery to three molars and two premolars and their respective gingivae (via posterior superior alveolar foramen) (b) infra-orbital artery (via inferior orbital fissure infra-orbital canal and foramen) orbital artery middle and anterior superior alveolar artery to the canine and the incisors facial branches (c) descending palatine artery (via pterygopalatine canal greater and lesser palatine foramina) greater palatine artery to mucosa of the hard palate and ligual gingivae (anastomosed with the nasopalatine artery within the incisive canal) lesser palatine artery to the tonsil and the soft palate (d) spheno-palatine artery (via spheno-palatine foramen) posterior septal and posterior lateral nasal branches to the nasal cavity nasopalatine artery - anastomosed with the greater palatine artery (e) artery of the pterygoid canal (f) pharyngeal branches Innervation of the Oral Cavity Region - The oral cavity receives its sensorimotor innervation via the trigeminal, facial, and hypoglossal nerves 1. Trigeminal nerve - maxillary (V2) and mandibular (V3) division - sensory and motor - sensory (V2, V3) : teeth & gum, lip, palate, ant.2/3 of tongue, FOM, and cheek - motor (V3) : two elevators of mandible, Temporalis & Masseter : two Pterygoid muscles, Medial & Lateral : two Tensors, Palatini & Tympani : two muscles of FOM, Mylohyoid & Digastric (ant.) 11

9 Surgical Anatomy Related to Primary Tumor 2. Facial nerve - motor, secretomotor, and special sensory - motor : muscles of facial expression (Orbicularis oris, Buccinator) : Stylohyoid, post. belly of Digastric - secretomotor (parasympathetic) : palatine ggl. via GSPN&N of pterygoid canal pterygopalatine ggl palatine N : subman & subling ggl. via chorda tympani N lingual N subman ggl lingual N cf) parotid gl. via tympanic br of the CN IX LSPN otic ggl ATN (br of CN V3) - special sensory (taste) : ant. 2/3 of the tongue via chorda tympani N / soft palate via N of pterygoid canal 12 The 7 th Combined Workshop for Head and Neck Surgery

10 Kwang-Jae Cho 3. Hypoglossal nerve - motor - muscles of the tongue : intrinsic and extrinsic m. (except Palatoglossus) - br. from the loop between C1 & C2 : Geniohyoid, Thyrohyoid - ansa cervicalis : Omohyoid, Sternohyoid, Sternothyroid Lymphatic Drainage of the Oral Cavity Subsites of the Oral Cavity 1. Lips - transition from external skin to internal mucous membrane that occurs at the vermilion border - orbicularis oris m.: creates a circumferential ring (sphincter-like function) - blood supply: superior and inferior labial artery (from facial artery) - motor innervation: facial nerve - sensory for the upper lip: infraorbital nerve (CN V2)/lower lip: the mental nerve (CN V3)/the commissure: buccal nerve (CN V3) - lymphatics from the both the upper and lower lips : primarily to the submandibular lymph nodes : midline lower lip lesions may drain to submental lymphatics : upper lip may drain to preauricular, infraparotid, and perifacial lymph nodes 13

11 Surgical Anatomy Related to Primary Tumor 2. Alveolar Ridge - dentoalveolar anatomy : periodontal tissue that support and invest the tooth are composed of the gingival, periodontal ligament, cementum, and alveolar bone : close approximation of mucosa to underlying bone facilitates early bone invasion for malignant tumors in this region (alveolar bone structure) - the mandible - dentate vs edentulous mandible 14 The 7 th Combined Workshop for Head and Neck Surgery

12 Kwang-Jae Cho - intramandibular course of the inferior alveolar nerve in the average adult dentate mandible 3. Oral Tongue - anterior to the linea terminalis - four intrinsic and four extrinsic muscles - extrinsic muscles: genioglossus, hyoglossus, styloglossus, palatoglossus - paired intrinsic muscles: superior & inferior longitudinal, transverse, and vertical - innervation musculature of the tongue exception of palatoglossus m.: hypoglossal nerve palatoglossus m.: pharyngeal branch of the vagus nerve general sensory innervation: lingual nerve special sensory innervation for taste: chorda tympani nerve (CN VII) - blood supply: lingual artery and vein 15

13 Surgical Anatomy Related to Primary Tumor - lymphatic drainage tip drains preferentially to submental nodes lateral tongue drains primarily to the levels I and II base of the tongue drains to the upper cervical lymphatics lack of anastomoses between the anterior tongue lymphatics: lateralized oral tongue lesions tending to drain ipsilaterally base of tongue lesions: crossover and bilateral cervical lymphatic spread 4. Retromolar Trigone - mucosa overlying the ascending ramus of the mandible toward the coronoid process - continuous with the buccal mucosa laterally, anterior tonsillar pillar medially - superior extent: maxillary tuberosity - anterior margin: posterior aspect of the second mandibular molar - sensation: the lesser palatine nerve and branches of the glossopharyngeal nerve - primary lymphatic drainage: the upper cervical-jugulodigastric nodal group - same considerations that were true for alveolar lesions exist for this anatomic site, given the close approximation of mucosa to underlying mandible 16 The 7 th Combined Workshop for Head and Neck Surgery

14 Kwang-Jae Cho 5. Floor of Mouth -boundary 1) oral tongue medially 2) inferior alveolar ridge laterally and anteriorly 3) anterior tonsillar pillar posteriorly - lingual frenulum: divides the region into two oral spaces - mylohyoid and hyoglossus muscles : provide the structural support for contents of the space - branches of the lingual nerve: sensation for FOM - mylohyoid artery (maxillary artery) and nerve (CN V3): mylohyoid muscle - lingual artery (sublingual and deep lingual artery) and vein - lymphatic drainage of the anterior aspect of this space : may cross to contralateral lymphatics submental-submandibular nodes - posterior portion of the space tends to drain to ipsilateral upper cervical L/Ns 6. Buccal Mucosa - from the posterior aspect of the lip to the alveolar ridges medially to the pterygomandibular raphe posteriorly - buccinator muscle: oral competence with orbicularis oris muscle - parotid duct orifice next to the second maxillary molar exit the parotid and pierces the buccinator muscle - sensation is provided by branches of the trigeminal nerve (CN V2 and CN V3) / motor: buccal branch of the facial nerve - lymphatics to submental and submandibular lymph nodes. 17

15 Surgical Anatomy Related to Primary Tumor 7. Hard Palate - margin: maxillary alveolar ridges anteriorly and laterally, soft palate posteriorly - sensation: greater palatine and nasopalatine nerve (CN V2) - greater palatine and nasopalatine a & v - lymphatic drainage: upper cervical lymphatics or lateral retropharyngeal nodes REFERENCES 1) 양훈식. 구강과구인두의해부와생리. 김종선. 이비인후과학두경부외과학. 일조각 ;2002. p ) 김상윤. 구강과구인두의악성종양. 김종선. 이비인후과학두경부외과학. 일조각 ;2002. p ) Agur AMR, Dalley AF. Grant s Atlas of Anatomy, 12 th ed. Philadelphia; Wolters Kluwer/Lippincott Williams&Wilkins; ) Gartner L, Hiatt JL, Werning JW, Lloyd K. Anatomic Considerations. In: Werning JW, editor. Oral cancer, 1 st ed. New York: Thieme;2007. p ) Haribhakti VV. The dentate adult human mandible: an anatomic basis for surgical decision making. Plast Reconstr Surg 1996;97: ) Larson DL, Sanger JR. Management of the mandible in oral cancer. Seminars Surg Oncol 1995;11: ) McCarn KE, Park SS. Lip reconstruction. Facial Plast Surg Clin N Am 2005;13: ) McGregor IA. Anatomical factors in the surgery of oral cancer. Clin Ana 1991;4: ) Pepersack WJ. Tooth vitality after alveolar segmental osteotomy. J Max Fac Surg 1978;1: ) Shah JP. Oral Cavity and Oropharynx. In: Head and Neck Surgery&Oncology. 3 rd ed. St. Louis; Mosby Year Book;2003. p ) Wein RO, Weber RS. Malignant neoplasms of the oral cavity. In: Cummings CW, Flint PW, Harker LA, Haughey BH, Richardson MA, and Schuller DE, editors. Cummings Otolaryngology-Head and Neck Surgery. 4 th ed. St. Louis; Mosby Year Book;2005. p The 7 th Combined Workshop for Head and Neck Surgery

16 Radiologic Evaluation of Primary Site and Neck The 7 th Combined Workshop for Head and Neck Surgery 정소령 가톨릭대학교의과대학영상의학과학교실 가톨릭의과대학졸업가톨릭중앙의료원영상의학과전공의수련후전문의가톨릭중앙의료원영상의학과전임의가톨릭의대성빈센트병원전임강사미국 UCSD로해외연수가톨릭의대강남성모병원조교수 1990년 1997년 년 년 년 2002-현재 19

17 Part 1 Analysis & Decision Making for Surgical Plan The 7 th Combined Workshop for Head and Neck Surgery Radiologic Evaluation of Primary Site and Neck 가톨릭대학교의과대학영상의학과학교실 정소령 구강병변의약 7% 가악성암이고그중 squamous cell carcinoma(scc) 가약 90% 를차지한다. 구강암환자에서영상진단의역할은종양의파급범위 (T stage) 와임파선전이 (N stage) 를진단하는것이며이는치료방침결정혹은치료효과판정에도움을준다. 일반적으로두경부악성종양환자에서영상검사는정확한 T, N staging 을위해 skull base에서 upper mediastinum(level VII lymph node) 까지포함되어야한다. CT와 MRI가구강암영상진단에사용되는데 primary lesion 평가와 bone marrow invasion은 MRI 가, lymph node metastasis 진단에는 CT가우수하다고알려져있다. 본강의록에선구강내침범부위에따른 SCC 소견과주위깊게관찰해야하는사항을중심으로기술하고자한다. 부위별소견 점막모든부위에서 SCC 가발생할수있지만 1) floor of the mouth, 2) the ventrolateral tongue, 3) the soft palate complex(soft palate proper, retromolar trigone, anterior tonsillar pillar) 에주로발생한다. 1. SCC of the floor of the mouth 대부분정중선의 2 cm 이내에발생하며관찰해야할사항은 1) the presence and extent of mandibular involvement, 2) the degree of submucosal extension, 3) the status of regional LN이다. 자유롭게퍼져갈수있는위치인데내측으로는 genioglossus m과 lingual septum 을직접침범하거나 genioglossus와 glossohyoid m사이를통해중앙선을넘어갈수있는데종양과 lingual septum, 종양과 neurovascular bundle 과의관계를잘관찰하여야한다. 외측으로침범하여 mandibular periosteum 을침범할수있고, 아래쪽으로는 mylohyoid m과 hyoglossus m을따라 hyoid bone까지침범할수있다. Mylohyoid m를따라후방 으로확산될수있는데특히 neurovascular bundle 을침범할수있다. 이경우 T4가되며 mandibulectomy 가필요할수있다. 상부로확산되어 oral tongue 를침범할수있다. Submandibular gland duct의출구를막아 duct dilatation 되고염증으로인해악하선이커질수있다. 종양표면적보다침범정도가경부림파절전이와더연관이있다. 2. SCC of the oral tongue 거의모든 Oral tongue SCC는 ventrolateral surface에서발생하며측면에서는중앙과후방 1/3 부위에서발생한다. 특징적으로설근을침범하는데쉽게 intrinsic m를따라심부를침범하고, extrinsic m를따라근육부착부위까지침범하게된다 (hyoid bone, mandible, styloid process, etc). 점막하파급으로 mouth floor, tonsil, mandible, pharyngeal wall 등을침범할수있고, 내측으로설중격침범여부를관찰해야한다. 이는 hemiglossectomy 의 contraindication 이기때문이다. 측부종양은위치에따라 mouth floor, mandible, glossotonsilar sulcus, oropharyngeal tonsil, 심부를침범할수있다. Oral cavity SCC 의약 30~60% 가진단시에림파절전이를관찰할수있으며설근의 SCC 의약 70% 에서진단시에림파절전이를볼수있다 ( 주로양측성 ). 3. SCC of the retromolar trigone 어금니뒤편에침윤성병변으로보이며빠르게주위조직으로파급된다. 내측으로는 the anterior tonsillar pillar, 앞쪽으로는 the buccinator space, 후내측으로는 the parapharyngeal space via the pterygomandibular space, 아래쪽으로는 the floor of the mouth, 위쪽으로는 the nasopharynx 와 maxillary tuberosity로파급된다. Mandible과가까이위치하여초기에 bone invasion 가능성이있어잘관찰하여야한다. 또한 oropharyngeal cancer 의 lateral spread 로인해침범될수도있다. 21

18 Radiologic Evaluation of Primary Site and Neck 4. SCC of the gingival/buccal mucosa Gingival cancer 는초기에 alveolar process 를침범하고 mandible 혹은 maxilla 의골침범을잘한다. Buccal mucosa SCC 는주로 lateral wall 에발생하고 buccinator m를따라 pterygomandibular raphe까지 submucosal spread 하고 bone invasion 하는것이주요파급경로이다. Muscle Invasion MRI 가 CT 보다도움이되는데 muscle 내로침윤하는조영증강되는병변이명확한소견이며 fat-suppression T2 영상에서고신호로보일때가있는데이는초기단계의종양침윤혹은종양에의한염증반응으로추정된다. CT에서 SCC 는주로 delayed enhancement 되는데 vascular phase에서 helical scan을한경우에는조영증강되는종양과주위 muscle 과의경계가불분명할수있다. Bone Invasion Bone erosion은 stage T4로전환된다. CT에서는 cortical destruction 이있는경우쉽게 bone invasion 진단이가능하지만 cortex 변화없이 bone marrow invasion 하는경우가있기때문에종양이 bone 에인접해있는경우 MRI 검사를실시하여침범유무를확인하여야한다. 특히 mandibular foramen 부위에위치한경우 inferior alveolar nerve의 perineural spread 가능성이있기때문에 MRI 검사가필요하다. MRI영상에서 bone invasion 을보기위해서 T1WI, enhanced T1WI with fat suppression이있어야한다. 특히 fat suppression 하지않은조영증강 T1WI 영상만얻는경우에는조영증강되는종양과 fat marrow 가모두고신호강도로보이므로진단이어렵다. T1WI 에서 bone marrow fat이고신호강도로보이기때문에쉽게 bone marrow 침범을진단할수있다. FSE T2WI 에서는 marrow fat 이고신호강도로보여종양과구분이어렵지만, fat suppressed T2WI 에서는침범된 bone marrow 의신호변화를보다정확하게평가할수있다. Nerve Invasion Perineural spread 가발생하면종양의재발이높고예후가나쁘다. 악성종양영상판독시에는 perineural spread 를파악하여적절한수술혹은방사선치료를할수있도록 해야한다. Perineural spread 의 MRI 소견을보면 1) excessive enhancement of cranial nerve branch with widening or destruction of neural foramina/canals, 2) loss of normal T1WI hyperintense fat signal in pterygopalatine fossa(ppf), 3) widening/excessive enhancement in PPF, cavernous sinus, Meckel s cave 등이다. CT 소견으로는 1) widening or destruction of neural foramina/canals, 2) excessive enhancement of neural foramina, 3) loss of normal fat in PPF, 4) enhancement or widening of PPF, cavernous sinus, Meckel s cave등이다. Lymph Node Metastasis 구강암의림프절전이는 anterior oral cavity 종양인경우 level I(submandibular, submental node), posterior oral cavity인경우 level II(jugulodigastric node) 로흔히침범된다. 특히 level II LN는혈관과근육에인접해있어잘구별하기힘들때도있으나, 조영증강양상 ( 혈관 ) 과근육의방향으로구별할수있다. LN metastasis 진단은 MRI 보다 CT가더우수하다고알려져있다. CT 소견으로는 1) 크기 (level I & II는 1.5 cm, 이외의 node는 1 cm 이상 ), 2) 음영 ( 내부저음영및주변부조영증강 ), 3) 모양 ( 구형 ), 4) 림프절수 (3개이상모여있는경우 ), 5) perinodal infiltration 등의소견들이진단에도움된다. CT에서 metastasis 를진단하기어려운경우에는추가로초음파유도하세침흡인검사 (US-FNA) 가필요할수있다. Staging, Grading or Classification Criteria Primary Tumor(T) staging Criteria in Oral Cavity T0:No evidence of primary tumor Tis:Carcinoma in situ T1:Tumor 2 cm in greatest dimension T2:Tumor 2~4 cm T3:Tumor >4 cm T4a:Tumor invading adjacent structures # mandible, maxillary sinus, floor of mouth, skin T4b:Tumor invades masticator space, pterygoid plates, skull base or encases ICA Nodal staging N1:single ipsilateral node 3 cm N2a:single ipsilateral 3~6 cm 22 The 7 th Combined Workshop for Head and Neck Surgery

19 정소령 N2b:multiple ipsilateral 6 cm N2c:bilateral or contralateral 6 cm N3:any nodal mass >6 cm Primary Stage Grouping Criteria in oral cavity 0:Tis N0 M0 I:T1 N0 M0 II:T2 N0 M0 III:T3 N0 M0 or T1-3 N1 M0 IVA:T4a N0-1 M0 or T1-4a N2 M0 IVB:Any T N3 M0 or T4b any N M0 IVc:Any T any N M1 23

20 Invasion and Molecular Analysis of Oral Cancer The 7 th Combined Workshop for Head and Neck Surgery 김세헌 연세대학교의과대학이비인후과학교실 연세대학교의과대학이비인후과학교실강사일본동경대학 Visiting Researcher Memorial Sloan-Kettering Cancer Center Research Fellow Memorial Sloan-Kettering Cancer Center, New York. USA. Visiting investigator 연세대학교의과대학조교수연세대학교의과대학부교수 년 년 년 년 년 2005년-현재 25

21 Part 1 Analysis & Decision Making for Surgical Plan The 7 th Combined Workshop for Head and Neck Surgery Invasion and Molecular Analysis of Oral Cancer 연세대학교의과대학이비인후과학교실 김세헌 구강암에있어종양의침윤정도는매우중요한예후적인자이며, 이과정에관계되는기전및관련물질에대해기술하고자한다. 종양의침윤과전이 (Molecular and Cellular Mechanisms of Invasion and Metastasis) 최근 Hanahan 과 Weinberg 는종양세포가자라고, 침윤을거쳐전이를하게되는핵심적인 6단계를기술하였다. a) 자동증식을위한신호체계의획득 b) 성장억제신호의정지 c) 세포고사로부터의회피 d) 불멸성 e) 신생혈관생성 f) 조직침윤능력의획득이러한생물학적인특성은 Fidler 의모델에서기술된전이과정과연관되어있다. Fidler 등은전이의과정은변형 (transformation), 신생혈관생성 (angiogenesis), 국소적침윤, 분리 (detachment), 색전, 부착 (attachment), 최종적으로원격장소에서의증식 (proliferation) 으로구성된다고보고하였다. 1. 종양침습의기전 (Mechanisms of tumor invasion) Califino 등은 Fidler와 Vogelstein의대장암진행의모델을반영하여두경부편평세포암종의발병기전 (pathogenesis) 에서대립유전자형 (allelotype) 에관한연구를발표하였다. 이개념은두경부편평세포암종의발암과정도중세포의성장, 생존, 세포주기의억제를조절하는주요단백의중요한염색체 loci 에서다수의특이한유전자변이가일어남을증명하였다. 침습형두경부편평세포암종의발생에서, 정확한순서와변이의갯수가중요한데종양형성 (tumorigenesis) 정확한순서보다는변이의총누적 (total accumulation of alteration) 이더중요하다는것이증명되었다. 양성종양과는달리, 악성종양은 Natural host barrier를파괴시키고주위조직에침윤하는성질을가지고있다. 종양의침윤과전이과정은정상세포의부착능력의소실, 기저막과세포외기질의파괴, 종양세포이동 (migration) 을자극, 신생혈관생성을포함하는활성과정이다. 2. 기저막부착 (Attachment to the Basement Membrane) 편평상피아래에있는기저막은, 여러가지모델에서생물학적특성이밝혀졌으며종양세포의침윤에대한자연적방어벽이다. Collagen type IV, Laminin, Collagen type VII, Heparan sulfate proteoglycan등이상피기저막에서발견되었다. 1) Integrins 정상세포와종양세포둘다세포외기질에부착하는능력을가진특이수용체를기저막에가지고있다. Van Waes 등은사람의두경부편평세포암종세포에대한단일클론성항체를길러 A9라는종양표현항원을분리했으며이것이 α6β4 integrin 과동일한것을증명하였다. Integrin 은세포부착분자 (cell adhesion molecules) 군이며, α6β4 integrin 은특이 laminin 에부착하는것으로알려져있다. 정상편평상피세포와두경부편평세포암종검체의면역조직학적연구에서, α6β4 integran 표현이종양에서는좀더광범위하게염색된양상을보였다. α6β4 integrin 의표현은조기재발과전이와관련된다. 2) E-Cadherin E-Cadherin은상피세포의중요한양상인 cell-cell contact 를유지하는역할을하는또다른세포표면 receptor molecule이다. E-Cadherin level은편평상피세포의분화 (differentiation) 과관련되어있다. Poorly differentiated tumors 에서는표현이감소한반면, well-differentiated tumor 27

22 Invasion and Molecular Analysis of Oral Cancer 에서높은 level 로표현된다. 두경부편평세포암종환자에서임상양상과, E-cadherin 표현이종양크기, 병기와관련성은없으나, E-cadherin level 이증가된환자들에서좀더호전적인생존률을보이는것으로나타났다. 낮은 level 의 E- cadherin은두경부편평세포암종에서전이 (metastasis) 로발전하는중요한단계일수있음을보여준다. 3) Catenins 최근에 cadherins 과복합체를이루는 catenins 로불리는 cytoplasmic proteins군이 cell-cell contact 의유지를지지함을확인하였다. 구강암연구에서 catenin level 은종양분화의정도와역의상관관계를보임을나타냈다. Catenin 이침습 (invasion) 과전이 (metastasis) 와관계가있는지에대해지속적으로연구되고있다. 3. 단백질분해와이동 (Proteolysis and Migration) 세포외기질의단백질분해 (Proteolysis) 는종양의침습 (invasion) 에있어중요한단계로여겨진다. 여러종양에서다양한단백분해물질이연구되었고, 조직침습과구역전이 (regional metastasis) 로발전하는데있어, 몇몇특이단백분해효소 (proteolytic emzymes) 가중요한역할을한다는사실이보고되었다. 1) MMPs(Matrix Metalloproteinases) MMPs 는활성을위해 metal ions 이필요하며, 때문에붙여진명칭이다. MMPs 는유방, 대장, 전립선을비롯한많은종양에서침습과전이의중요한매개체이다. Sutinen 등은구강암검체 (oral cancer specimes) 에서 MMP-2 의표현이증가됨을발견하였다. 72-kDa type IV로서알려진이효소의표현은구강종양환자에서경부임파전이와임파, 혈관침습으로진행하는것과관련이있다. Stromelysin-1 으로알려진 MMP-3는두경부편평세포암종의약 50% 에서상향조절 (up-regulation) 되어있음이보고되었다. MMPs 는 laminin, fibronectin, 그리고, type IV collagen 을가수분해 (degradation) 시킨다. 또다른두경부편평세포암종과관련된 MMPs 는 92-kDa type IV collagenase 로알려진 MMP-9 이다. 증가된 MMP-9 activity 는구강암에서종양의침윤도관련이있다. MMP-9 activity 를억제한경우, 설암세포에서종양의침습능력이감소됨이보고되었다. Riedel 등은 MMP-9 staining 이미세혈관농도 (microvessels density) 증가와 VEGF의 up-regulation과관련이됨을보여주었고, 이는 MMP-9 와 VEGF 가두경부편평세포암종의신생혈관형성과정에서상호연관작용이있음 을시사한다. 최근에 MMPs 는 cell 내에서다양한분자들에의해조절되며, 이중가장중요한것이 TIMPs(tissue inhibitors of metalloproteinases) 로불리는 inhibitors group 이다. MMPs 의높은 level과 TIMPs의낮은 level이전이를일으키는데중요한역할을한다는보고가있다. 4. 신생혈관형성 (Acquisition of a Blood Supply- Angiogenesis) 종양의성장, 침윤, 전이에있어신생혈관형성은중요한과정이다. 종양세포들은생존을위해필수영양소와가스교환이요구된다. 적절한혈관화 (vascularization) 없이는 1 mm 3 이상의종양은괴사된다. 대부분종양들은내피세포증식과신생혈관형성을자극함으로서이런장애를극복해나간다. 신생혈관형성 (Angiogenesis or neovascularization) 은다중진행과정 (multistep process) 이며, 자극 (stimulatory) 과억제 (inhibitory) 요인들에의해조절된다. 1) 미세혈관밀도 (Microvessel density) 종양신생혈관형성은 factor VIII, CD31, CD34 같은내피세포표지자로혈관을염색함으로서정량화될수있다. 2) 신생혈관형성조절 (Regulators of Angiogenesis) 신생혈관형성과정에서양성과음성조절자에의해종양내그리고종양주변으로신생혈관형성의정도가결정된다. 3) 신생혈관형성유발인자 (Positive regulators of Angiogenesis) (1) VEGF(Vascular endothelial cell growth factor) VEGF 는다중의 (pleiotropic) 혈관형성효과를갖는다. 내피세포분열촉진인자일뿐아니라, 세포생존 (cell survival), 세포운동 (cell motility), 내피세포조직화 (endothelial cell organization) 와내피세포단일층 (endothelial cell monolayers) 을통한투과능을활성화시킨다. (2) bfgf(basic fibroblast growth factor) bfgf 는내피세포분열촉진물이며, 내피세포이동성과생존률을증진한다. bfgf 는또한세포단백용해제 (tissue proteases) MMP-1 의생산을상향조절 (up-regulation) 한다. (3) PD-ECGF(Platelet-derived endothelial cell growth factor) PD-ECGF 는 in vivo 에서신생혈관능을갖는내피세포분 28 The 7 th Combined Workshop for Head and Neck Surgery

23 김세헌 열촉진인자이다. 구강암및구인두암에서종양세포에높은비율로표현됨을확인되었다. 61) (4) Interleukin-8 IL-8이신생혈관능 (angiogenic activity) 이있는 cytokine임이여러연구에서보고되었다. 두경부편평세포암종에서종양세포내의내피세포에서 IL-8 receptor 가있음이보고되었다. 4) 신생혈관형성의음성조절인자 (Negative Regulators of Angiogenesis) (1) Interferons(IFNs) IFN-a 와 IFN-b 는내피세포증식과이주를억제한다. IFN-b 의표현형감소는 microvessel density 와신생혈관형성과역상관관계를가지며, IL-8, begf, 그리고 MMPs 의표현을하향조절 (down-regulation) 함이보고되었다. (2) Thrombospondines(TSPs) TSPs 는세포증식, 고착 (adhesion), 이주 (migration) 를조절하는 5 secreted glycoproteins 의 multi-gene family 이다. TSP-1 과 TSP-2 는신생혈관형성의억제인자들이다. TSP-1 는내피세포자멸 (apoptosis) 을발생함으로서신생혈관형성을억제한다. (3) Others 최근의연구들에서 Nitric oxide(148) 와 PTEN/MMAC1 gene을신생혈관형성억제자로서관련시키고있다. PTEN 으로알려진 MMAC1 은 10q23.3 에위치한종양억제유전자이며 multiple tumor types 의종양형성 (tumorigenesis) 에서중요한역할을한다. 구강설암의면역조직화학적분석에기초하여, multivariate regression analysis 는 PTEN 표현의결여가 tumor stage 와 nodal status 와비교시 poor outcome 을보이는독립적예측인자임을설명하였다. 5. 자동증식을위한신호체계의획득 (Acquisition of Autonomous Proliferative Signaling) 모든정상세포는증식 (proliferation) 을위해성장신호 (growth signals) 를요구한다. 성장신호들은성장인자 (growth factor) 의세포외기질성분 (extracellular matrix components), 또는 cell-to-cell interactions과같은다양한방법으로제공될수있다. 일반적으로성장신호들은세포표면으로부터핵까지다양한세포내신호 (intracellular signaling pathways) 를통해전달된다. 두경부편평세포암종의발병기전에서성장인자와이들 receptors 의비정상적인발현이그역할을하리라는보고가있다. 1) EGF(Epidermal Growth Factor) 인간성장인자 (Human growth factors) 는특이세포수용체 (specific cellular receptors) 에결합하며증식 (prolifereation) 및분화를자극하는폴리펩티드군 (polypeptides family) 이다. 가장먼저알려진인자중하나로표피성장인자 (EGF ; epidermal growth factor) 를들수있다. EGF 수용체는서로연관된 4개의 transmembrane 수용체로구성되어있다. 포유류에서, EGF 수용체군은 ErB1(EFGR), ErbB2(c-Neu), ErbB3, ErbB4 로구성되어있으며인간 EGF 수용체는흔히 HER family 로언급된다. EGFR 은연구된가장첫번째 ErbB 수용체이다. EGFR signaling 은종양의분화상태와특정장기에따라다양한효과를나타내며, 종양세포분화에서 EGFR signaling 이중요한역할을한다. 그외에세포이동 (modulating tumor cell migration), 혈관형성 (angiogenesis), 성장 (maturation), 침윤 (invasion), 세포고사 (apoptotic response) 등에관여한다. 이러한요소는종양의성장 (progression, growth) 에결정적인역할을하는것으로알려졌다. 또한 EGFR signaling 은악성으로의변화과정및치료에대한반응을볼수있는표현형의변화를알수있는좋은지표가된다. EGF 신호축은두경부편평세포암종의대부분에서상향조절 (up-regulated) 되어있다. 103 명의후두암환자들에대한연구에서정상점막과비교시분화도가나쁜종양에서 EGF-R 표현의증가가특징적으로나타났다. 이연구에서는 EGF-R negative lesion 을가진환자의 2-yr survival 이 82% 인반면, EGF-R positive 환자에서는 58% 를보였다. Multivariate analysis로 EGF-R status 와후두내에서의종양의위치가중요한독립예후인자들임을확인하였다. 최근에는침습 (invasion) 과전이 (metastasis) 에서의 EGF-R 과이 ligands 를연구하고있다. 두경부편평세포암종세포주에서 EGF axis와 MMPs사이의상관관계가보고되었다. 이는 EGF axis 가두경부편평세포암종의침습과전이의조절 (regulation) 에일부역할을함을시사한다. 2) Signal Transducers and Activators of Transcription Proteins(STATs) STATs 는세포표면수용체로부터전사인자 (transcription factors) 로서기능하는핵 (nucleus) 에신호 (signals) 를 29

24 Invasion and Molecular Analysis of Oral Cancer 전달하는세포질단백군 (cytoplasmic proteins family) 이다. 두경부편평세포암종에서 STAT proteins, 특히 STAT3 는 EGF/TGF mediated cell growth 에서중요한역할을한다. STAT3 활성은세포고사 (apoptosis) 를감소시킨다. 3) Nuclear Factor Kappa B(NF-kB) NF-kB 는면역과염증반응을유발하는유전자를조절하는전사인자이다. 정상세포에서 NF-kB 는세포질내에다량으로남아있으며, 적절한자극을받기전까지는비활성상태로남아있는다. 자극에대한반응으로, inhibitor proteins (IkBs) 이 proteolysis된다. 이 IkBs의가수분해로 NF-kB 가유리된다. 최근에는, NF-kB 가암발달과진행의 multiple hallmarks 의획득 (acquisition) 과관련된다고보고있다. NFkB는증가된세포증식 (cyclin D1), 세포고사의회피 (apoptosis evasion)(c-iap-2, SIAP), 침습 (MMP-9) 그리고신생혈관형성 (interleukin-8) 관련유전자들의매개체로증가된전사를통해, 여러과정에서종양진행을증진시킴이확인되었다. 4) Hepatocyte Growth Factor Axis HGF/SF(Hepatocyte growth factor/scatter factor) 는각각다른세포들에서다양한생물학적기능을가진다. Dong 등은 proangiogenic cytokines인 IL-8과 VEGF 의상향조절을통해두경부편평세포암종에서 HGF 가신생혈관생성과관련된역할을함을보여주었다. 6. 성장억제신호의정지 (Inhibition of Growth Inhibitory Signals) 정상세포에서성장과분화는철저히통제된다. 비록정상성장인자를통한지속적인세포증식의자극이종양발달에필수이지만, 이자체만으로정상세포의발암성전환 (oncogenic transformation) 을유발하기에는불충분하다. 성장관련요소들의복잡한상호작용이세포주기를통해세포진행을조절하게된다. 세포주기를통한 DNA 복제와세포분열 (cell division) 은몇가지 phases 로구성된다 -G1(growth phase 1), S(DNA synthesis), G2(growth phase 2), & M(mitosis). 세포주기조절의핵심은 cyclins 와이들조절인자들 (regulators), cyclin-dependent kinases(cdks) 와 cyclindependent kinase inhibitors(cdkis) 로불리는물질군 (molecules group) 이다. Cyclins, CDKs, CDKIs 에영향을주거나조절하는분자들은잠재적으로발암유발인자들이며, 세포성장에서중요하게역할을한다. 1) Retinoblastoma Gene(Rb) 망막모세포종유전자 Rb gene과 prb(its protein product) 은세포주기로의관문 (gateway) 으로명명된다. 정상상태에서는 prb는전사요소 (transcription factor) 인 E2F와결합되어있음으로써세포주기를진행시키는것을억제한다. 그러나다양한 cyclin/cdk 복합체들은인산화 (phosphorylation) 과정을통하여비활성 prb 를인산화시키고, 이로인해 prb 가활성화되면 prb 는 E2F를방출하고이는 G1 phase 에서 S phase 로세포회로를진행시키며, DNA 합성이시작되도록한다. 세포주기억제에중요한역할을하기때문에두경부평편세포암종을포함하여다양한종양형에서 Rb에대해활발히연구되고있다. 2) P53 Gene 종양억제유전자인 p53 은인간암에서가장흔히변이되는 locus 이다. 염색체 17 short arm 에위치한 p53 은 393- amino acid protein 이며, 체내모든조직내에서표현된다. p53 의생물학적역할은방사선 (radiation), 화학발암물 (chemical carcinogens) 또는다른기전들로인한 DNA damage 로부터세포를보호하는것이다. p53 은세포주기억제 (arrest) 를통해 DNA 복구를유발하거나, 세포고사 (programmed cell death(apoptosis)) 를유발한다. p53 의변이는 DNA damage 에대한세포고사를막으며, 방사선치료나항암치료인자에의한종양세포저항을일으킬수있다. Anderson Cancer Center 연구에서, 정상상피세포에서 19%, 과증식 (hyperplastic) lesion 에서 29%, 이형성 (dysplastic) lesion 에서 45%, 침습형암에서 58% 가 p53 과표현형을보였으며, 이는두경부종양이진행함에따라점차적으로 p53 abnormalities 가서서히증가함을보여주었다. HPV protein E6, E7은 p53 에결합하고기능을비활성화시킨다. 3) INK4(Inhibitors of DCK4) Gene Family 종양염색체 9p21-22 의연구에서 16 protein 으로 encode 된유전자가세포주기에서억제인자로중요한역할을함이보고되었다. Reed 등은, p16 활성이종양의 83% 에서소실되었음을보고하였다. 구강의전암성병변과악성병변에서 p16 유전자의 coding gene이잦은변성 (alteration) 을보인다는보고가있다. 4) Cyclin D1 암진행에서세포주기조절인자중 cyclin D1은가장많은영향을주는요소이다. Cyclin D1 증폭은두경부평편세포암종에서많게는 64% 30 The 7 th Combined Workshop for Head and Neck Surgery

25 김세헌 에서확인되었다. Bova 등은 148 명의설암환자를대상으로 cyclin D1의표현에대해분석하였고, 68% 에서과표현됨을확인하였다. 이현상은통계학적으로유의하게, 낮은 disease free & overall survival과관련있었다. 또다른연구에서는 cyclin D1의높은표현이임파선전이와관련이있음을확인하였다. 후두의편평세포암연구에서, cyclin D1 의증폭은신생물의 37% 에서확인되었고, 이는국소침습, locoregional recurrence 그리고병리학병기와관련이있었다. Cyclin D1 mrna 과표현 (overexpression) 과유전자증폭 (gene amplification) 간의높은연관성은두경부평편세포암종의발병기전 (pathogenesis) 에서이단백질이중요한역할을함을의미한다. 또한하인두암연구에서, cyclin D1 유전자증폭 (gene amplification) 과단백질과표현형 (protein overexpression) 은예후와연관될뿐아니라적절한치료요법을확인하는데유용하였다. cyclin D1-negative tumor가 multimodal 치료에좋은반응을보였다. HNSCC 에서 cyclin D1 단백의과표현형은재발 (recurrence) 에대한독립적인예후인자임이보고되었다. 5) P21 Family p21 family 는 p21, p27, p57로구성된다. p21은확인된첫번째 CDK inhibitors 중하나이다. 서로다른연구들에서발견되어 WAF1, CIP1, SDI1, mda-6 로다양한이름을가지고있다. p27, p57 은역시 KIPI1 과 KIP2 로알려져있다. 이 family 는 CDKs 에다양한억제 (inhibitory) 영향을가지고있다고알려져있다. 최근의연구에서, 구강편평세포암에낮은 p27 level 을갖는환자에서 higher stage disease 를가졌으며, 낮은 overall survival 을보였다. 7. 세포고사로부터의회피 (Evasion of Apoptosis) 예정된사포의사멸 (Programmed cell death) 은세포항상성에있어매우중요한단계이다. 세포고사의생화학적과정은막용해 (membrane dissolution), 핵붕괴 (nuclear breakdown), 세포질골격붕괴 (cytosolic skeletons-breakdown), 염색체가수분해 (chromosomal degradation), 그리고핵의분쇄 (fragmentation) 같은, 생리적자극에의해유도되는정밀한연속적단계이다. 세포고사는 3가지과정으로요약된다. 첫번째과정은시작또는신호단계이다. 일반적으로, 세포외또는세포내신호는세포자멸 machinery 를유발한다. 두번째과정은세포고사의실질적과정인데이시기에궁극적세포파괴인자인 caspases의방출을이끌도록여러작용물질들 (multiple effector molecules) 이신호 (signal) 로작용한다. 세번째과 정은형태학적변화 (morphologic changes) 를포함한다. 이러한복잡한과정은성공적시작 (initiation) 과이과정의완성을위해여러조절물질과작용물질들 (multiple regulatory & effector molecules) 이필요하다. 따라서세포고사와관련된단백물질들의변이는세포생존증가와종양형성 (tumorigenesis) 의중요한역할을할수있다. 세포고사는세포외적 (extracellular) 또는세포내적 (intracelluar) 경로에의해시작될수있다. 세포외적세포고사의억제인자들은 Fas, tumor necrosis factor receptor, TRAMP, TRAIL-R1, TRAIL-R2, DR-6 같은세포표면수용체들 (cell surface receptors) 에결합하는 ligands들이다. 이들은 death receptors 로불려진다. 세포내적물질들도세포고사를유발할수있다. 현재까지가장많이연구된물질은 p53 유전자이다. 이것은 DNA 손상에대한세포고사를유도하는등다양한기능을갖는다. Bax/Bcl-2ratio, cyclin D1 level과세포고사사이의관계도의미있는연관이있다. 세포고사의세포내효과인자 (cellular effectors) 는 proteases인 caspase family 이다. 이 family 는적어도 13개단백질을포함하고, 임상적으로 3개의 groups 으로나뉜다 : a) nonapoptotic caspases-caspases 1,4,5,11,12,13 으로세포자멸에서역할이없는것으로나타남 ; b) initiator caspases-caspase 8,9,10 으로 caspase cascade의시작및증폭을담당, c) effector caspases-caspase 2,3,6,7 로세포고사의궁극적인효과인자 (effectors) 이다. 세포고사유발로인해항암효과를나타내는항암제중일부는 caspases의상향조절에의해그효과가나타난다. 예로, 5-FU는 caspases 1,3,8의상향조절을보인다. Cisplatin 은 caspases 3,8,9 의상향조절을보인다. 다양한조절분자들이세포고사경로에서그역할을한다. 이중가장많이연구된분자는 mitochondria 에서 cytochrome C유리를조절하는 Bcl-2 family 이다. 이 family 는 proapoptotic molecules(i.e., Bax, Bak, Bid) 와 antiapoptitic molecules(i.e., Bcl-2, Bcl-XL, Bfl-1) 로구성된다. 두경부평편세포암종에서 Bcl-2 과표현형과 Bax 표현의소실은 poor prognosis 와연관된다. NK-kB 에의한세포고사억제는 c-flip, TRAF1, TRAF2, c-iap1, c-iap2, A1/Vfl-1, Bcl-XL, IEX-1, xiap를포함하는 multiple apoptosis inhibitory proteins expression의전사조절인자 (transcriptional modulation) 를통해이뤄진다. NF-kB 의활성은 p53 dependent 세포고사의감소를보인다. 8. 불멸성 (Immortalization) 종양이 immortalization 을획득하는기전은현재로서명 31

26 Invasion and Molecular Analysis of Oral Cancer 확하지않다. Telemeres 는염색체의끝에 protective caps 처럼역할하고염색체의파괴를막는다. 각각의복제주기 (replicative cycle) 에서 telomeric DNA의작은양이소실된다. 그러므로시간이지날수록 telomeres 는점점짧아진다. Telomeric DNA 가충분히소실되면, chromosomal ends는더이상보호되지않으며, chromosome의 fusion 과 karyotypic abnormalities 를유발하여결국세포사멸을일으킨다. 거의대부분의종양세포는 telomeric length 를유지하기위한기전들을획득한다. 가장잘알려진이기전은 telomeres 의길이를연장시키는 enzyme telomerase 의표현 (expression) 이다. 두경부평편세포암종에서 telomerase 활성에대한연구에의하면, 16개의두경부평편세포암종세포주와 29개의두경부평편세포암종조직을이용한연구에서, 정상세포에서는 telomerase 가전혀발견되지않은반면침습형암의 90% 에서확인되었다. Telomerase 활성은종양분화와치료반응의정도와관계가있으며, 진행된암 (T4 HNSCC) 에서 higher telomerase level 을가짐이보고되었다. 9. Lymphangiogenesis 두경부편평세포암종에서경부림프절전이는 tumor aggressiveness 의중요한 index 이며, 불량한예후와관련이있다. 일부종양들이 lymphangiogenesis 로인해새로운 lymphatic capillaries형성을유도한다는보고가있다. 신생혈관생성성장인자인 VEGF-C 는 in vivo 에서 lymphatic vascular endothelium 의성장을자극한다. 수용체인 Flt-4 는정상조직에서 lymphatic endotheila에서우세하게표현된다. VEGF-C 는악성흑색종만큼, 유방, 대장, 위, 폐그리고갑상선암들과같은다양한인간종양들에서표현되며, VEFG- C의표현 (expression) 이림프절전이와관련이있다는보고가있다. 10. Lymphatic endothelium : New markers Lymphatic endothelium-specific markers 로는다음과같은것이있다. (a) podoplasnin, (b) Prox-1; early lymphatic developement에서역할, (c) LYVE-1 ; extracellular matrix/lymphatic fluid glycosaminoglycan 인 hyaluronan에대한 lymphatic endothelial receptor REFERENCES 1) Hanahan D, Weinberg RA. The hallmarks of the cancer. Cell 2000; 100: ) Fidler JI. Critical factors in the biology of human cancer metastasis: twenty eighth G.H.A Clowes memorial award lecture. Cancer Metastasis Res 1990;50: ) Fidler IJ, Kumar R, Bielenberg DR, et al. Molecular determinants of angiogenesis in cancer metastasis. Cancer J Sci Am 1998;4(suppl 1):S ) Fidler IJ. Rationale and methods for the use of nude mice to stud the biology and therapy of human cancer metastasis. Cancer Metastasis Rev 1986;5: ) Califao K, van der Riet P, Westra W, et al. Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res 1996;56: ) Fearon ER, Vogeltein B. A genetic model for colorectal tumorigenesis. Cell 1990;61: ) Fidler IJ. Metastasis. In: DeVita VT, Hellman S, Rosenerg SA, et al, eds. Cancer: principles and practice of oncology/vol 1. Philadelphia: Lippincott Wolians & Winkins; ) Ridley A. Molecular switches in metastasis. Nature 2000;406: ) Weiss L. Metastasis of cancer: a conceptual history from antiquity to the 1990s. Cancer Metastasis Rev 2000;19:I-SI, ) Sakr WA, Zarbo RJ, Jacobs JR, et al. Distribution of basement membrane in squamous cell cacinoma of the head and neck. Hum Pathol 1987;18: ) Wetzels Rh, van der Velden LA, Schaafsma HE, et al. Immunohistochemical localization of basemen membrane type VII collagen and lamininin neoplasms of the head and neck. Histopathology 1992;21: ) Carter RL, Burman JF, Barr L, et al. Immunohistochemical localization of basemen membrane type IV collagen in invasive and metastatic squamous carcinomas of the head and neck. J Pathol 1985;147: ) Wissr R, van der Beek JM, Havenith MG, et al. Immunohistochemical detection of basemen membrane antigens in the instopathological evaluation of laryngeal dysplasia and neoplasia. Histopathology 1986;10: ) van Waes C, Koxarsky KF, Warren AB, et al. The A9 antigen associated with aggresive human squamous carcinoma is structurally and functionally similar to the newly defined integrin alpha 6 beta 4. Cancer Res 1991;51: ) Carey TE, Nari Ts, Chern C, et al. Blood group antigens and integrins as biomarkers in head and neck cancer: is aberrant trosine phosphorylation the cause of altered alph6 beta4 integrin expression? J Cell Biochem Suppl 1993; ) Wolf GT, Jones J, Speight P. Integrins and oral cancer. Oral Oncol 1997;33: ) Wolf GT, Carey TE. Tumor antigen phenotype, biologic staging, and pognosisun head and neck squamous carcinoma. J natl Canceer Inst Monogr 1992;13: ) Wu H, Otan R, Menter D, et al. Expression of E-cadherin is associated with squamous differentiation in squamous cell carcinomas. Anticancer Res 2000;20: ) Schipper H, Unger A, Jahnke K. E-caderin as a fuctional marker of the differentiatio and invasioness of squamous cell carcinoma of the head and neck. Clin Otolarngol 1994;19: ) Gottardi DJ, Mbine BM. Adhesion signaling: how bea-caenin interacts with its partners. Curr Biol 2001;11:R ) Lo Muzio L, Staibano S, Pannone G, et al. Beta-and gamma-catenin expression in oral squamous cell carcinomas. Anticancer Res 1999; 19: ) Liotta LA, Rao CN. Tumor invasion and metastasis. Monogr Pathol 1986; ) Uao J, Xiong S, Klos K, et al. Multiple signaling pathway involved in activation of matirix metalloproteinase 9 (MMP-9) by heregulin beta-1 in human breast cancer cells. Oncogene 2001;20: ) Liabakk NB, Talbot I, Smith RA, et al. Matrix metalloproteinase 2 (MMP-2) and matirix metalloproteinase 9 (MMP-9) type IV colla- 32 The 7 th Combined Workshop for Head and Neck Surgery

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29 PET/CT and Molecular Imaging in Oral Cancer The 7 th Combined Workshop for Head and Neck Surgery 김재승 울산대학교의과대학핵의학과학교실서울아산병원 서울의대졸업, 이후서울대학교대학원의학석, 박사학위취득서울대학교병원인턴및진단방사선과전공의수련, 진단방사선과전문의자격획득서울아산병원핵의학과전임의및핵의학과전문의자격획득미국 NIMH Molecular Imaging Branch 방문연구원울산의대서울아산병원핵의학과부교수재직 1989년 년 년 년 2000-현재 35

30 Part 1 Analysis & Decision Making for Surgical Plan The 7 th Combined Workshop for Head and Neck Surgery PET/CT and Molecular Imaging in Oral Cancer 울산대학교의과대학서울아산병원핵의학과학교실 김재승 서론 두경부암은전체암중 6번째로흔한암으로이중약 30% 는구강에서발생한다. 구강암의 95% 를차지하는편평상피세포암은높은당대사활동 (glycolytic activity) 을보이는종양으로포도당유사체인 F-18 FDG( 이하 FDG) 의섭취가높아 1980년대말부터두경부암의진단과치료에 FDG PET 의이용이점차증대되고있다. 본강의에서는구강암중다수를차지하는편평상피세포암을중심으로구강암의진단과치료에서 FDG PET/CT 의역할과두경부암의진단에새로이시도되고있는분자영상검사법을소개하고자한다. 본론 1. 정상두경부의 FDG PET/CT 소견구강을포함하는두경부는인체의다른부위보다그해부학적구조가복잡하여 CT나 MRI 와같은방사선학적단층영상에서그해석이쉽지않다. 두경부의 FDG PET/CT 영상에서도악성종양에의한비정상적섭취외에정상구조물의섭취증가와정상변이혹은양성종양등에서의섭취증가가흔히발견되므로이에대한해석에주의를요한다. 두경부의정상구조물중 FDG 섭취가흔히보이는구조들과양성병변들은 Table 1과같다. 2. 병기결정구강암환자에서경부림프절전이의발견은치료방침결정과예후에가장중요한요소중하나이다. 구강암에서경부림프절전이의빈도는진단시약 50% 정도로알려져있고원격전이는약 10% 에서발견된다. 치료전경부림프절의전이유무를정확히진단하기위해서일반적으로임상소견과 CT, MRI 및초음파등비침습적인방법및생검에의한조직학적진단이이용되어왔다. 그러나경부림프절전이를진단하는데있어임상소견이나 CT/MRI 등의방사선학검사방법은종양의발견및전이를진단하는데있어예민도면에서제한점이있다. 경부림프절전이에대한 FDG PET 의진단적정확도는병리학적으로진단된림프절을어떤단위, 즉환자나경부측 (neck side), 림프절그룹 (cervical lymph node level) 그리고개개의림프절 (individual lymph node) 단위로평가하느냐에따라다양하게보고되고있으나 75~100% 의예민도와 89~100% 의특이도를보이고또한동시에시행한 CT나 MRI(53~ 84% 의예민도와 71~95% 의특이도 ) 보다유의하게높은예민도를보인다. 이처럼구강암환자에서 FDG PET/CT 가 CT나 MRI 에비해전이된림프절에대한예민도가높은이유로는 PET이 1 cm 이하의작은전이림프절을발견할수있고경부 CT나 MRI에서흔히보일수있는의치나보철물등에의한인공물의영향을덜받으며병변과배후조직 Table 1. Normal structures and benign condition which can show increased FDG uptake in the head and neck Normal structure Extraocular muscle Tonsil (pharyngeal, palatine, lingual) Palate (hard and soft) Surface of tongue Slaivary gland (parotid, submandibular, sublingual) Hypopharynx Glottis (vocalis muscle, posterior cricoarythenoid muscle) Thyroid gland Skeletal Muscle (sternoclavicular, pterygoid, temporalis) Bone marrow of cervical vertebra Esophagus Adipose tissue (Brown fat) Benign disease Dental problem Inflammation (sinusitis, tonsilitis, thyroiditis, sialadenitis, etc) Reactive hyperplasia of cervical lymph node Benign tumor (Warthin s tumor, thyroid adenoma, hibernoma) Spur change of cervical vertebra Postradiation change Postbiopsy change Tracheostomy change 37