Abstract
目的
比较不同类型口腔颅颌面部纤维性结构不良(fibrous dysplasia，FD)的临床病理特点，为临床诊治及预后判断提供依据。
方法
收集2013年1月至2020年12月于北京大学口腔医院确诊为FD或McCune-Albright综合征(McCune-Albright syndrome, MAS)的患者105例，分析其临床资料、影像学和病理学特点，分别归类为单骨型、多骨型、MAS型及口腔颅颌面部特有的口腔颅面型纤维性结构不良(craniofacial fibrous dysplasia，CFD)四型，对各型的临床病理特征、治疗及随访资料等进行分析。
结果
105例患者的男女比为1 ∶1.3，发病年龄0~56岁(中位数为12岁)。本组病例中，单骨型43例(40.95%)，其中上颌骨29例，下颌骨12例，颧骨2例；多骨型32例(30.48%)；MAS型7例(6.67%)；发生在颅上颌部位的FD，经影像学分析确诊CFD型23例(21.90%)。CFD在患者性别、术前血清碱性磷酸酶水平等方面有别于其他类型的FD。病理学上，各型FD的形态特点类似，但多骨型及MAS型患者可能出现以纤维成分增生为主的特征。
结论
口腔颅颌面部FD的临床和病理特点有别于身体其他部位发生的FD病变，CFD的临床和病理特点与发生于颅颌面部的单骨型或多骨型FD也有显著差异，应注意区分，以进一步明确CFD在临床处置及预后等方面的特殊性。
Keywords: 骨纤维发育不良, 面骨, 病理学，临床, 碱性磷酸酶
Abstract
Objective
To compare the clinicopathologic features and prognosis of the different types of fibrous dysplasia (FD) of cranio-maxillofacial region, so as to provide a new reference for clinicians to treat these patients and make prognostic judgement.
Methods
Clinical records, radiographic data and pathological information of 105 patients diagnosed with FD or McCune-Albright syndrome (MAS) at the Department of Oral Pathology, Peking University Hospital of Stomatology from January 2013 to December 2020 were collected. The patients were divided into 4 groups: monostotic FDs, polyostotic FDs, MAS and a specific type called craniofacial fibrous dysplasia (CFD) limited in the craniofacial region. The clinicopathological characteristics, treatment and follow-up data of each type were analyzed.
Results
Of all the 105 patients, 46 were males and 59 were females, with a male-to-female ratio of 1 ∶1.3. The onset age ranged from 0 to 56 years and the median age was 12 years. On the basis of different involvement conditions, 4 types were divided. The most common type was monostotic FDs (43 cases, 40.95%), including maxilla (29 cases), mandibular (12 cases) and zygoma (2 cases). 32 cases (30.48%) were diagnosed with polyostotic FDs, 7 cases (6.67%) were MAS, and 23 cases (21.90%) were CFDs confirmed by computed tomography (CT) analysis. CFD was clearly distinct from other types of FD, such as the patient gender and the serum alkaline phosphatase level in peripheral blood before operative surgery. The pathologic findings of various types FD were quite similar, whilst the predominant fibrous tissue hyperplasia could be observed in polyostotic FDs and MAS types.
Conclusion
The clinicopathologic features of FD in the cranio-maxillofacial region are different from the FD lesions in other parts of the body. The clinicopathological features of CFD are significantly different from those of monostotic and polyostotic FDs in the cranio-maxillofacial region. Therefore, the clinicians should pay attention to distinguish CFD in clinic, imaging and pathology aspects, so as to further clarify its features in clinic management and prognosis.
Keywords: Fibrous dysplasia of bone; Facial bones; Pathology, clinical; Alkaline phosphatase
纤维性结构不良(fibrous dysplasia，FD)也称骨纤维异常增殖症，是一种非遗传性良性骨病，约占所有良性骨肿瘤的7%，其特点是受累骨组织逐渐被增生的纤维组织所替代，病变中含有数量不等的骨样组织或未成熟的骨小梁，全身骨均可受累，好发于四肢长骨、颅面骨等[1]。FD通常分为单骨型、多骨型和McCune-Albright综合征(McCune-Albright syndrome, MAS)型。以往的口腔颅颌面部FD研究中，由于上颌骨病变常同时累及颧骨、额骨、筛骨等部位，临床症状与上颌骨单骨型病变相似，因而将此类病变归类为单骨型病变[2]。根据2017年《WHO头颈部肿瘤分类》[3]的描述，累及相邻多个颅面骨的FD病变虽曾被认为是单骨型病变，但建议使用颅面型纤维性结构不良(craniofacial fibrous dysplasia，CFD)的命名，目前，口腔颅颌面部FD的亚型分类仍存在分歧[2, 4-6]。
本文回顾性分析北京大学口腔医院2013—2020年确诊的共105例FD或MAS患者的临床病理特征、治疗及随访资料，重点分析CFD型与其他类型FD的差异，以期明确CFD的诊断标准，为临床诊治及预后判断提供依据。
1. 资料与方法
1.1. 研究对象
收集2013年1月至2020年12月于北京大学口腔医院确诊为FD或MAS的患者共105例，纳入标准为：病例资料完整，X线和CT检查有特征性影像，组织病理检查诊断明确为FD。
结合FD的临床特点及CT影像学表现，将患者分类为：(1)单骨型：仅累及单个骨；(2)多骨型：同时累及多处骨的病损，其中发生于颅上颌的累及相邻骨的CFD型除外；(3)MAS型：指满足多骨型病变、内分泌障碍、皮肤或口腔黏膜色素沉着中的两条及以上者，诊断标准符合相关文献描述[7](图 1)；(4)CFD型：仅累及颅上颌多个相邻骨。
图 1.
McCune-Albright综合征1例
A case of McCune-Albright syndrome
A and B, a typical Café-au-lait skin pigmentation on the back of the neck (A), and lower back (B) of a 37-year-old woman with McCune-Albright syndrome which demonstrates jagged "coast of Maine" borders; C-E, CT images demonstrate a ground-glass ill-defined pattern in the cranio-maxillofacial region; F, bilateral clavicle and scapula are involved with chest deformity; G and H, bilateral tibia and femur are involved with bone deformity.
除回顾临床病史外，所有患者的诊断均经口腔病理科及口腔颌面医学影像科医师复查病理及影像资料后确诊。本研究经过北京大学口腔医院生物医学伦理委员会批准(PKUSSIRB-201943019)。
1.2. 临床资料分析
通过查阅患者的病历收集患者的各项临床资料，包括发病年龄、性别、临床表现、病程(末次手术年龄与发病年龄之差)、术前CT影像学资料、术前实验室检查[如术前血清碱性磷酸酶(alkaline phosphatase，ALP)水平等指标]以及手术治疗术式等，对患者末次术后情况进行电话随访(随访105例，失访24例)，随访时间7个月至8年，平均随访时间(4.29±2.10)年。
1.3. 免疫组织化学染色
采用Envision法，抗体Ki-67购自北京中杉金桥生物技术有限公司，以磷酸盐缓冲液替代一抗作为阴性空白对照，同一观察者随机选择5个视野，高倍镜(×400)下计数500~1 000个细胞中的阳性细胞数，细胞核染色为棕黄色或棕褐色判定为阳性细胞，以5个视野的平均阳性细胞百分比表示Ki-67的阳性标记指数。
1.4. 统计学分析
所有数据处理均采用GraphPad Prism 8.0.2统计软件，设定P < 0.05为差异有统计学意义。计量资料服从正态分布者以均数±标准差表示，采用独立样本t检验；服从正态分布但不具备方差齐性者采用校正独立样本t检验；非正态分布数据以中位数(第1四分位数，第3四分位数)[M (P25，P75)]表示，采用Mann-Whitney U检验。计数资料以例数(%)表示，符合卡方检验条件者采用卡方检验，不符合卡方检验条件者采用Fisher确切概率法。若患者某项数据缺失，在进行相关统计时该病例予以剔除。
2. 结果
2.1. 临床资料
患者的临床治疗及随访资料见表 1。
表 1.
各型FD患者的临床及随访资料
Clinical characteristics and follow-up data of the different types of FD patients
| Items | MFD (n=43) | PFD (n=32) | MAS (n=7) | CFD (n=23) | Total (n=105) |
| Data are presented as x±s, n (%), or M (P25, P75). FD, fibrous dysplasia; MFD, monostotic fibrous dysplasia; PFD, polyostotic fibrous dysplasia; MAS, McCune-Albright syndrome; CFD, craniofacial fibrous dysplasia; ALP, alkaline phosphatase; NA, not available. | |||||
| Onset age/years | 15.00 (13.00, 30.00) | 9.50 (5.50, 12.75) | 8.57±2.37 | 10.00 (6.00, 14.00) | 12.00 (8.00, 17.00) |
| Onset age group/years | |||||
| ≤10 | 7 (16.28) | 21 (65.63) | 5 (71.43) | 13 (56.52) | 46 (43.81) |
| 11-20 | 23 (53.49) | 7 (21.88) | 2 (28.57) | 7 (30.43) | 39 (37.14) |
| 21-30 | 4 (9.30) | 2 (6.25) | 0 (0) | 2 (8.70) | 8 (7.62) |
| 31-40 | 6 (13.95) | 1 (3.13) | 0 (0) | 1 (4.35) | 8 (7.62) |
| 41-50 | 1 (2.32) | 1 (3.13) | 0 (0) | 0 (0) | 2 (1.90) |
| 51-60 | 2 (4.65) | 0 (0) | 0 (0) | 0 (0) | 2 (1.90) |
| Gender | |||||
| Male | 20 (46.51) | 12 (37.50) | 1 (14.29) | 13 (56.52) | 46 (43.81) |
| Female | 23 (53.49) | 20 (62.50) | 6 (85.71) | 10 (43.48) | 59 (56.19) |
| Clinical sign | |||||
| Facial deformity | 39 (90.70) | 32 (100.00) | 7 (100.00) | 23 (100.00) | 101 (96.19) |
| Pain | 8 (18.60) | 2 (6.25) | 1 (14.29) | 1 (4.35) | 12 (11.43) |
| Treatment | |||||
| Conservative surgery | 41 (95.35) | 30 (93.75) | 6 (85.71) | 21 (91.30) | 98 (93.33) |
| Radical surgery with reconstruction | 2 (4.65) | 2 (6.25) | 1 (14.29) | 2 (8.70) | 7 (6.67) |
| Number of conservative operations | 1.0 (1.0, 1.5) | 2.0 (1.0, 3.0) | 2.0 (1.0, 3.5) | 1.0 (1.0, 1.5) | 1.0 (1.0, 2.0) |
| Course | 8.78±7.86 | 17.09±10.27 | 18.86±9.56 | 10.39±6.77 | 12.34±9.34 |
| Serum ALP concentration | |||||
| Elevation | 5 (11.63) | 22 (68.75) | 6 (85.71) | 11 (47.83) | 44 (41.90) |
| Non-elevation | 36 (83.72) | 10 (31.25) | 1 (14.29) | 11 (47.83) | 58 (55.24) |
| NA | 2 (4.65) | 0 (0) | 0 (0) | 1 (4.35) | 3 (2.86) |
| Follow-up | |||||
| No regrowth | 28 (65.12) | 18 (56.25) | 3 (42.86) | 16 (69.57) | 65 (61.90) |
| Slow regrowth | 3 (6.98) | 3 (9.38) | 1 (14.29) | 1 (4.35) | 8 (7.62) |
| Marked regrowth | 2 (4.65) | 3 (9.38) | 0 (0) | 2 (8.70) | 7 (6.67) |
| Death | 0 (0) | 0 (0) | 1 (14.29) | 0 (0) | 1 (0.95) |
| Loss to follow-up | 10 (23.26) | 8 (25.00) | 2 (28.57) | 4 (17.39) | 24 (22.86) |
本组105例患者中，男性46例，女性59例(男∶女=1 ∶1.3)，发病年龄0~56岁(中位数为12岁)，其中0~20岁(85例，80.95%)为发病高峰(图 2A)。近半数患者术前ALP升高(44例，41.90%)。临床上主要表现为无痛、渐进性的面部不对称膨大畸形。
图 2.
各型FD患者的年龄、性别及临床特征
The age, gender and clinical characteristics of the different types of FD patients
A, the differential onset age distribution of four types of FD; B, CFD was more present in men than in women; C, the median onset age of CFD was significantly lower than MFD; D, the proportion of CFD patients with elevated serum ALP before operation was significantly higher than MFD; E, the average course of CFD was significantly shorter than PFD; F, the median number of operations of CFD was significantly less than PFD. * P < 0.05, ** P < 0.01, *** P < 0.001. Abbreviations as in Table 1.
本组105例患者中，单骨型FD为43例(40.95%)，多骨型FD为32例(30.48%)，MAS型为7例(6.67%)例，CFD型为23例(21.90%)。
43例单骨型FD患者(上颌骨29例、下颌骨12例、颧骨2例)的男女比例为1 ∶1.2，发病年龄集中在11~20岁(53.49%，图 2A)，术前血清ALP水平大部分未升高(83.72%)，平均病程(8.78±7.86)年，手术修整1~3次。
32例多骨型FD患者的男女比例为1 ∶1.7，发病年龄集中在0~10岁(65.63%，图 2A)，术前血清ALP水平大部分有升高(68.75%)，平均病程(17.09±10.27)年，手术修整1~5次。
7例MAS型患者中男性1例，女性6例，平均发病年龄为(8.57±2.37)岁，术前血清ALP水平升高者6例(85.71%)，平均病程(18.86±0.72)年，手术修整1~5次。
23例CFD型患者中男性13例，女性10例，各型FD性别比的差异无统计学意义(P>0.05, 图 2B)。CFD患者的发病年龄较早(0~10岁者占56.52%)，约半数患者术前血清ALP水平升高，均与多骨型FD相似(年龄：U=337.50，P>0.05；血清ALP：P>0.05)，但与单骨型FD之间差异有统计学意义(年龄：U=237.50，P < 0.05；血清碱性磷酸酶：P < 0.05，图 2C、D)。另外，CFD的平均病程为(10.61±7.16)年，手术修整1~2次，均与单骨型FD相似(病程：t=0.93，P>0.05；修整次数：U=423.00，P>0.05)，但与多骨型FD之间的差异有统计学意义(病程：t=2.76，P < 0.05；修整次数：U=202.00，P < 0.05，图 2E、F)。
对患者进行电话随访(表 1)，包括33例单骨型FD，24例多骨型FD，5例MAS和19例CFD，另外24例患者失访(22.9%)，平均随访时间(4.29±2.10)年。随访到的患者中，5例行截骨/扩大切除术(单骨型1例，多骨型2例，MAS型1例，CFD型1例)，术后均未见再生长，其余76例患者均行修整术。
2.2. 影像学表现
X线检查在FD的诊断中占有重要地位，按临床上广泛采用的X线影像学分类，剔除仅有影像学报告的4例患者，本组各类型FD的分布及表现如下：硬化型77例(76.24%)，其中单骨型35例，多骨型21例，MAS型3例，CFD型18例，表现为病变区域灰度以磨玻璃样高密度影为主，是FD典型的影像学表现；囊性型3例(2.97%)，包括2例单骨型和1例多骨型，表现为病变区域灰度以囊肿样低密度影为主，但边缘不光滑，边界不清；混合型21例(20.79%)，其中单骨型5例，多骨型9例，MAS型2例，CFD型5例，表现为同时存在透射和阻射两类改变，高低密度影互相间杂，比例相当。
此外，FD病变常常界限不清(96/101，95.05%，图 3A)，骨皮质多受压变薄(80/101，79.21%)，部分骨皮质不连续(21/101，20.79%)。病变的硬化边缘(4/101，3.96%)、牙根吸收(9/101，8.91%)、牙齿移位(15/101，14.85%，图 3A)少见，下颌病变中可见下牙槽神经管移位(35/46，76.09%)。
图 3.
FD的影像学特征
Radiologic characteristics of FD
Single bone was involved in monostotic fibrous dysplasia in A (left mandible) and C (right maxilla), and clear zygomaticomaxillary suture was shown in C and D (white arrow). Multiple bones were involved in B (right mandible and left maxilla). The right maxilla and zygoma were involved crossing the zygomaticomaxillary suture (white arrow) in CFD (D, case 5 in Table 2), while the bone sutures were indistinct in E (case 20 in Table 2). FD, fibrous dysplasia; CFD, craniofacial fibrous dysplasia.
螺旋CT辅助检查可明确FD具体受累骨的情况，是CFD与单骨型FD重要的分类依据。当病变局限在单个骨未跨越骨缝时为单骨型(图 3C)，当颅上颌病变跨越骨缝累及相邻多个骨时为CFD(图 3D)，同时累及多处骨的病损(发生于颅上颌的累及相邻骨的CFD型除外)为多骨型(图 3B)。本组病例经CT检查均明确了病变的具体受累骨。23例CFD患者的临床及随访资料见表 2。此外，62例多骨受累的FD(包括多骨型、MAS、CFD)中，26例病变未跨越中线(41.94%)，36例病变跨越中线累及对侧，包括4例CFD(4/23，17.39%，图 3E)，26例多骨型FD(26/32，81.25%)，6例MAS(6/7，85.71%)。CFD病变跨越中线累及对侧骨的比例均低于多骨型FD和MAS患者(P < 0.05)。
表 2.
CFD患者的临床及随访资料
Clinical characteristics and follow-up data of CFD patients
| No. | Gender | Last treatment | Onset age/ years | Number of the operation | Age at operation/ years | Age at follow-up/ years | Bone involved | Current status |
| *, slow regrowth after the first conservative surgery; & , rapid regrowth after the first extended resection surgery; #, regrowth after three conservative surgeries. CFD, craniofacial fibrous dysplasia. | ||||||||
| 1 | Male | Conservative surgery | 11 | 1 | 19 | 20 | Left zygoma and left sphenoid bone | Loss to follow-up |
| 2 | Female | Conservative surgery | 6 | 1 | 16 | 17 | Left maxilla, left ethmoid bone, left nasal bone, left inferior nasal concha, left temporal bone, left parietal bone, bilateral frontal bone and bilateral sphenoid bone | No regrowth |
| 3 | Female | Conservative surgery | 23 | 1 | 26 | 28 | Left sphenoid bone, left ethmoid bone, left nasal bone, left temporal bone, bilateral frontal bone | No regrowth |
| 4 | Male | Conservative surgery | 11 | 1 | 17 | 20 | Bilateral occipital bone, bilateral frontal bone, right temporal bone, right maxilla, right sphenoid bone, right zygoma, right ethmoid bone | Marked regrowth |
| 5 | Female | Conservative surgery | 10 | 2* | 10, 17 | 20 | Right maxilla, right sphenoid bone, right zygoma, right temporal bone | No regrowth |
| 6 | Female | Extended resection with flap reconstruction | 6 | 2 & | 9, 10 | 13 | Right maxilla, right sphenoid bone | Loss to follow-up |
| 7 | Female | Conservative surgery | 16 | 2* | 16, 31 | 33 | Left maxilla, left sphenoid bone | No regrowth |
| 8 | Female | Conservative surgery | 11 | 1 | 18 | 21 | Left maxilla, left sphenoid bone, left zygoma, left ethmoid bone, left occipital bone, left frontal bone | No regrowth |
| 9 | Female | Conservative surgery | 35 | 1 | 35 | 38 | Left maxilla, left sphenoid bone, left zygoma, left ethmoid bone, left occipital bone, left frontal bone | No regrowth |
| 10 | Female | Conservative surgery | 10 | 1 | 25 | 28 | Right maxilla, right ethmoid bone, right zygoma | Loss to follow-up |
| 11 | Male | Conservative surgery | 6 | 1 | 7 | 11 | Right maxilla, right sphenoid bone, right temporal bone | No regrowth |
| 12 | Male | Conservative surgery | 13 | 1 | 43 | 47 | Right maxilla, right zygoma | No regrowth |
| 13 | Male | Conservative surgery | 9 | 1 | 19 | 23 | Left maxilla, left sphenoid bone, left zygoma | Slow regrowth |
| 14 | Male | Conservative surgery | 15 | 1 | 21 | 25 | Right maxilla, right sphenoid bone | No regrowth |
| 15 | Female | Conservative surgery | 9 | 1 | 15 | 18 | Left maxilla, left sphenoid bone, left zygoma | No regrowth |
| 16 | Male | Conservative surgery | 14 | 1 | 21 | 25 | Left maxilla, left sphenoid bone, left temporal bone | No regrowth |
| 17 | Male | Conservative surgery | 4 | 2* | 14, 18 | 22 | Right maxilla, right sphenoid bone, right zygoma | Loss to follow-up |
| 18 | Male | Conservative surgery | 6 | 2* | 12, 23 | 27 | Left maxilla, left sphenoid bone, left temporal bone | Marked regrowth |
| 19 | Male | Conservative surgery | 7 | 2* | 7, 18 | 22 | Right maxilla, right sphenoid bone, right zygoma, right temporal bone, right ethmoid bone | No regrowth |
| 20 | Male | Extended resection with flap reconstruction | 22 | 4# | 22, 25, 40, 47 | 53 | Left zygoma, bilateral maxilla | No regrowth |
| 21 | Male | Conservative surgery | 9 | 1 | 22 | 27 | Left maxilla, left sphenoid bone, left zygoma | No regrowth |
| 22 | Female | Conservative surgery | 8 | 1 | 22 | 28 | Left maxilla, left zygoma | No regrowth |
| 23 | Male | Conservative surgery | 4 | 1 | 19 | 27 | Right maxilla, right sphenoid bone, right zygoma, right temporal bone | No regrowth |
2.3. 病理学表现
FD的典型镜下表现为纤维组织背景下均匀分布形态不一、彼此缺乏连接的幼稚编织骨骨小梁，这些骨小梁无层板结构，纤细呈弓形或分枝状，形成类似O、C、V、W等英文字母的形态，这些骨小梁的周围往往缺乏成排的成骨细胞，病变与周围界限不清(图 4A)，这种典型表现(图 4B)见于所有病例，有部分病例的骨改建表现较为活跃(14例，14.33%)。值得注意的是，有7例患者(6.67%)的病变特点是以丰富的纤维成分为主，骨及骨样物质较少(图 4C)，其中包括5例多骨型FD，1例MAS和1例CFD。我们还将55例患者的石蜡组织进行了Ki-67免疫组织化学染色(包括25例单骨型，16例多骨型，2例MAS型，12例CFD型)。Ki-67阳性标记指数分别为：单骨型2.68%，多骨型2.99%，MAS型2.90%，CFD型2.95%，各型之间差异无统计学意义(P>0.05，图 4D)。
图 4.
FD的病理学特征
Histopathologic characteristics of FD
A, the lesion is ill-defined in continuity with normal bone (HE ×40); B, typical histological features of FD show thin, irregular, and disconnected trabeculae and fibrous tissue replaces the normal bone structures (HE ×40, HE ×400 in the upper right box); C, the predominant of fibrous tissue (HE ×40); D, the low expression of Ki-67 in FD lesions (HE ×400). FD, fibrous dysplasia.
3. 讨论
FD是一种累及单一或多处骨骼的良性骨病变，其发生与编码Gsα的基因突变有关。颅面骨和股骨是FD最常见的病变部位，但其也可发生于任何部位的骨骼，单骨型FD受累骨的常见部位由高到低依次为股骨、颅骨、胫骨、肋骨，多骨型FD依次为股骨、骨盆、胫骨[8]。发生在颅颌面部以外的病变一般早期症状不明显，但发生于颅颌面部的病变，由于其解剖结构的特殊性，即使是很小的病变，也可引起严重的颌面部畸形和不对称，影响美观和功能。目前，颌面部FD的临床特点和分类仍存在争议，本研究收集并分析了口腔颅颌面部不同类型FD的相关临床资料，以期为口腔颅颌面部FD的临床处置及预后判断提供参考。
FD是口腔颅颌面部常见的纤维-骨性病变之一，不同类型口腔颅颌面部FD患者的临床特征存在显著差异。Sweeney等[5]报道的70例颌面部FD患者中，女∶男=2.18 ∶1.00，本组患者中，女∶男=1.28 ∶1.00，与Cheng等[6]报道的266例FD患者的性别比例(女∶男=1.40 ∶1.00)接近。上述结果的差异可能与种族、病例数不同相关。本研究中，CFD患者中男性多于女性(男∶女=1.3 ∶1.0)，其余的FD类型均为女性多于男性，CFD的发现年龄集中在0~10岁，更接近多骨型FD患者。血清ALP水平在一定程度上反映了成骨活性，Ma等[9]发现年轻及累及多骨的颌面部FD患者的术前ALP水平显著高于成人及单骨型颌面部FD患者。本研究中，术前ALP升高的CFD患者比例接近多骨型FD，这一点支持CFD病变接近多骨型FD，而CFD患者的病程、手术次数与单骨型FD相似，这可能是因为CFD病变较为集中且多块邻近病变骨的修整手术一般同次进行。
由于CFD病变较为集中(多数未跨越中线累及对侧)，症状接近单骨型，临床医生常视其为单骨型FD，但综合分析口腔颅颌面部FD患者的临床特征发现，在发病年龄及术前血清ALP水平升高的患者比例上，CFD患者均接近多骨型FD患者，另外，CFD患者中男性稍多，与单骨型和多骨型FD不同，因此CFD应被视为不同于单骨和多骨型FD的特殊类型。
以往研究常把FD的CT表现分为三组：囊性型(11%~22%)、混合型(40%~55%)、硬化型(34%~38%)[10]。本组患者的术前CT表现以硬化型为主，典型的影像学表现为病变骨呈磨玻璃样改变，边界不清，与周围正常骨区移行，骨皮质常常受压变薄。病变常同时累及其邻近的颅面诸骨，牙槽骨轻度受累，下颌管上移，硬骨板破坏消失，牙周韧带间隙变窄而显示不清，牙移位、牙根吸收和硬化边缘少见，与以往文献报道相似[11-12]。以往文献报道，多骨型FD有明显的同侧发病倾向[7]，本组CFD病变跨越中线累及对侧骨的比例(4/23, 17.39%)均低于多骨型FD(26/32，81.25%)和MAS患者(6/7，85.71%)，表明CFD型患者的病变范围比多骨型FD和MAS患者更局限，这在一定程度上也说明CFD型虽然累及多骨，但与多骨型FD仍有区别，应被认为是一种不同于多骨型的特殊类型。
鉴于以上分析，以及参考以往文献报道[3, 13-14]，我们认为对于CFD的诊断有重要参考价值的指征有：(1)主要指征：①发生在颅上颌的病变，②经CT确认病变跨越骨缝累及颅上颌多个相邻骨，③排除全身其他部位的病变，④排除综合征相关病变；(2)辅助指征：①发病年龄小于20岁，尤其是10岁前发病的男性患者，②术前血清ALP水平升高，③病变常局限于中线一侧。
在疾病的不同时期，FD的镜下表现因纤维基质和骨及骨样物质的比例不同而呈现出不同的特点，病变早期表现为纤维组织背景下均匀分布形态不一、彼此缺乏连接的幼稚骨小梁，无层板结构，纤细呈弓形或分枝状[15]；随后，不成熟的编织骨骨小梁增厚，有时可见特征性的垂直于骨表面的胶原纤维束，相当于Sharpey纤维，可见类骨质，由于广泛的骨重建过程，层板骨中可见间歇线和反折线；时间较长的病变可见骨小梁“成熟”为层板骨并相互平行排列，这是口腔颅面部FD的特有表现，长骨FD均由编织骨骨小梁构成，未见层板骨骨小梁的报道[13, 16]。值得注意的是，本组病例中多骨型及MAS型患者的病变组织在镜下可观察到的特征是以丰富的纤维成分为主，骨及骨样物质较少。Riminucci等[17]曾将13例FD患者的组织学特征分为字母样FD、佩吉特(Pagetoid)样FD、细胞丰富型FD等组织学类型，但目前FD的组织学分类尚未统一。此外，其他文献还报道了比较少见的病理表现，如伴随黏液变、巨细胞反应、动脉瘤性骨囊肿、颌骨FD牙骨质小体样表现等[18-19]。
Ki-67是细胞增殖的标志物之一，本研究中Ki-67的阳性比例普遍较低(图 4D)，过低的阳性率在区别各类FD的细胞增殖活性上存在明显的局限性。以往研究比较了Ki-67在FD、骨化纤维瘤及其他纤维-骨性病变中的表达水平，发现并无显著差异[20]。FD和骨化纤维瘤是纤维-骨性病变中需要重点鉴别的两种疾病，两者最重要的区别是骨化纤维瘤的边界清楚和/或有包膜，而FD病变组织与周围骨相融合，没有明确边界。FD的骨小梁周边无成排的成骨细胞围绕，这也是两者的区别之一，但是少部分FD的骨小梁周围也可见成骨细胞围绕，因此仅凭组织学表现难以直接诊断FD，仍需依靠临床、影像及病理三者相结合。此外，GNAS基因突变检测是FD与骨化纤维瘤重要的辅助鉴别手段[21]。
FD的治疗以往几乎都要依赖于手术，手术的目的在于尽可能纠正外形和恢复功能，但颅颌面部FD的手术适应证存在争议，目前通常有三种基本处置策略：①观察，②保守手术，③扩大手术切除并重建。本组患者中，98例行保守手术治疗，7例行扩大手术切除并重建，其中2例行扩大切除的CFD患者(病例6和病例20，表 2)均为巨大病变，均有快速增长病史，因此，对此类患者不能笼统地视为单骨型病变，应慎重选择治疗方式，密切随诊。FD患者的预后良好，肉瘤变罕见，单骨型FD的肉瘤变发生率约为0.5%，MAS患者约为4%[22]。本组2例恶变的患者中包括1例单骨型下颌病变和1例MAS患者，单骨型患者失访，MAS患者术后2年电话随访，病变无再生长。
综上所述，口腔颅颌面部FD临床病理表现多样，包括单骨型、多骨型、MAS型、CFD型，由于解剖结构的特殊性，CFD的临床和病理特点有别于身体其他部位发生的FD病变，应更明确地加以区分。CFD为口腔颅面部所特有，并且CFD与发生于上颌的单骨或多骨型FD有显著差异，在临床、影像及病理学上应注意区分，以进一步明确该型FD在临床处置及预后等方面的特殊性。
Funding Statement
中国医学科学院口腔颌面部肿瘤精准病理诊断创新单元(2019RU034)和北京大学口腔医学院教育教学研究项目(YS030120)
Supported by the Research Unit of Precision Pathologic Diagnosis in Tumors of the Oral and Maxillofacial Regions, Chinese Academy of Medical Sciences (2019RU034) and the Education and Teaching Research Project Fund of Peking University School of Stomatology (YS030120)
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