Oral Maxillofac Surg (2015) 19:85–89 DOI 10.1007/s10006-014-0465-2
CASE REPORT
Ki-67 and p53 expression in ghost cell odontogenic carcinoma: a case report and literature review G. Del Corso & M. L. Tardio & D. B. Gissi & C. Marchetti & L. Montebugnoli & A. Tarsitano
Received: 3 July 2014 / Accepted: 2 September 2014 / Published online: 14 September 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Ghost cell odontogenic carcinomas are rare neoplasms that arise in the maxillary bones either from a calcifying odontogenic cyst or de novo. They are aggressive locally and can metastasize. We report herein a case of a ghost cell odontogenic carcinoma arising in the mandible of a Caucasian male 86 years of age. We have described the clinical and radiographic features, histological characteristics, immunohistochemistry findings, and surgical treatment. We especially focused on how Ki-67 expression guides the treatment choice. Finally, we reviewed 32 cases described in the literature and compared them with the cases described up until 2014 to help clinicians identify the diagnostic characteristics of and select appropriate treatment modalities for ghost cell odontogenic carcinomas. Keywords Ghost cell carcinoma . Odontogenic carcinoma . Ghost cell tumors
Introduction Ghost cell odontogenic carcinomas (GCOC) are rare malignant odontogenic epithelial tumors with “features of a
G. Del Corso (*) : D. B. Gissi : L. Montebugnoli Department of Biomedical and Neuromotor Sciences, Section of Oral Science, University of Bologna, via S Vitale 59, Bologna, Italy e-mail: [email protected] M. L. Tardio Pathology Unit, Policlinico S. Orsola-Malpighi, Bologna, Italy C. Marchetti : A. Tarsitano Department of Biomedical and Neuromotor Sciences, Section of Maxillo-facial Surgery at Policlinico S. Orsola-Malpighi, University of Bologna, Bologna, Italy
calcifying cystic odontogenic and/or a dentinogenic ghost cell tumor” [1]. This neoplasm was first described in 1985 by Ikemura as a malignant calcifying odontogenic tumor [2]. It usually arises as a swelling on the jaw bone, commonly occurs on the maxilla, and is most prevalent in men (males/females= 4:1), especially Asian males in their 40s [3–5]. GCOC frequently arises from a precedent calcifying odontogenic cyst (COC) left untreated for several years [6]. COCs are divided into two benign forms: a calcifying cyst odontogenic tumor (CCOT), described as a “benign cystic neoplasm of odontogenic origin, characterized by an ameloblastoma-like epithelium with ghost cells that may calcify” [7], and a dentinogenic ghost cell tumor (DGCT), a “locally invasive neoplasm characterized by ameloblastoma-like islands of epithelial cells in a mature connective tissue stroma” [1]. However, some GCOCs arise as novel tumors [8]. Diagnostic criteria have been established for CCOTs, DGCTs, and GCOCs. However, these tumors represent a heterogeneous group due to broad clinical and radiological diversity and variable biological behaviors [9]. Some authors have evaluated the expression of immunohistochemical markers to discriminate benign cysts from tumors [8, 10]. Positivity for Ki-67 and MMP-9 in GCOCs indicates high proliferative activity associated with malignancy in this type of carcinoma [9]. P53 overexpression is seen in more than 70 % of GCOC cells, as described by Motosugi [11]. This marker represents another factor that can discriminate GCOCs from benign COCs. We report a case of mandibular ghost cell odontogenic carcinoma diagnosed in December 2013 at the Department of Oral Sciences of the University of Bologna; after which, the patient underwent surgery at the Maxillo-Facial Unit of the Sant’Orsola Hospital in Bologna, Italy. This case report represents the 33rd case of GCOC described in the literature [2, 4–6, 8, 10–29] and the first reported in Italy. Table 1 summarizes all the case reports and features of
86 Table 1 List of the 32 cases and features of GCOC reported in the literature until 2014
Oral Maxillofac Surg (2015) 19:85–89
Case
Author
Gender/age
Race
Location
Radiographic features
1 2 3 4 5
Ikemura et al. [2] Sun et al. [4] Li et al. [5] Alcalde et al. [6] Roh et al. [8]
F/48 M/30 F/47 F/72 M/55
Asian Asian Asian Asian Asian
Maxilla Maxilla Mandible Maxilla Mandible
Radiolucent and radiopaque Radiolucent and radiopaque Radiolucent Radiolucent and radiopaque Radiolucent and radiopaque
6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Zhu et al. [10] Motosugi et al. [11] Castle et al. [12] Cheng et al. [13]
M/51 F/17 M/57 M/36 M/35 M/33 M/44 M/42 F/55 M/17 M/20 M/46 M/38 M/59 M/33 M/53 M/24 F/31
Asian Asian White Asian Asian Asian Asian N/A Black N/A N/A White Asian Asian N/A Asian Asian Asian
Maxilla Maxilla Maxilla Mandible Maxilla Maxilla Mandible Maxilla Mandible Maxilla Maxilla Maxilla Maxilla Mandible Mandible Maxilla Maxilla Maxilla
Radiolucent N/A Radiolucent Radiolucent Radiolucent Radiolucent Radiolucent N/A N/A N/A N/A N/A Radiolucent and radiopaque Radiolucent and radiopaque Radiolucent and radiopaque Radiolucent Radiolucent and radiopaque Radiolucent
M/19 M/39 F/13 M/40 M/33 M/39 M/61 M/36 M/86 M/86
Asian Asian Black Black Black Asian N/A Asian Asian White
Mandible Mandible Maxilla Maxilla Maxilla Maxilla Mandible Maxilla Mandible Mandible
Radiolucent and radiopaque Radiolucent N/A Radiolucent and radiopaque N/A N/A Radiolucent and radiopaque Radiolucent and radiopaque Radiolucent Radiolucent
24 25 26 27 28 29 30 31 32 33
Dubiel-Bigaj et al. [14] Ellis et al. [15] Folpe et al. [16] Grodjesk et al. [17] Kamijo et al. [18] Kasahara et al. [19] Kim et al. [20] Li et al. [21] Lu et al. [22]
McCoy et al. [23] Nazaretian et al. [24] Scott et al. [25] Siar et al. [26] Wader et al. [27] Goldenberg et al. [28] Arashiyama et al. [29] Present case
GCOC. We describe the clinical and radiographical features, histological characteristics, immunohistochemistry findings, and the surgical technique. We obtained ethical approval for our study, and we followed the guidelines of the Helsinki Declaration in our investigation.
Case report
dislocated the inferior prosthesis. A panoramic radiograph showed a well-defined radiolucent oval-shaped lesion on the left mandible (Fig. 1). We performed an incisional biopsy under local anesthesia, which confirmed a ghost cell odontogenic carcinoma. Immunostaining of monoclonal anti-Ki67 (Dako, Denmark, clone MIB-1, diluted 1:200) and monoclonal anti-p53 (Dako, clone p53, diluted 1:50) was performed on 2-μm-thick sections serially cut from the selected blocks.
Clinical diagnosis Pathologic findings An 86-year-old Caucasian male with an asymptomatic swelling of the left body of the mandible was seen at the Department of Oral Sciences of the University of Bologna in Bologna, Italy. The patient presented with a gingival swelling that
Diagnosis of a GCOC involves identifying the benign features of a calcifying cystic odontogenic tumor associated with a malignant component consisting of rounded epithelial islands
Oral Maxillofac Surg (2015) 19:85–89
87
Fig. 1 Panoramic radiograph showing an oval-shaped bony lytic radiolucent area without radiographic infiltrative features
in a fibrous stroma (Fig. 2). The neoplastic epithelial cells have rounded hyperchromatic or vesicular nuclei with frequent mitoses. The epithelial cells are surrounded by ghost cells, either isolated or in clusters. We established the cutoff values for p53 and Ki67 overexpression as 20 %, because none of the normal mucosa samples showed a higher value in our previous studies [30]. The immunohistochemical analyses for p53 and Ki-67 revealed a positive reaction against p53 (~60 %) and a less of a reaction against Ki-67 (~10 %) (Fig. 2). Surgical treatment
Fig. 3 Preoperative CT scan showing a lytic lesion involving the left mandibular body
The CT scan demonstrated a lytic area with contrast enhancement, without any evidence of cervical adenopathies (Fig. 3), and confirmed the diagnosis of the panoramic radiograph. The patient was treated surgically under general anesthesia at the Maxillo-Facial Surgery Unit of Sant’Orsola Hospital, University of Bologna, Italy. A partial left mandibulectomy was
performed, preserving the left inferior alveolar nerve and inferior mandibular continuity, and the tumor was excised with clear margins. A titanium plate was fixed on the vestibular surface of the inferior mandibular bone. All specimen margins were negative for tumor cells. No postoperative complications occurred, and no adjuvant radiotherapy was recommended.
Fig. 2 Photomicrographs showing a section stained with hematoxylin and eosin at low magnification (a) and evidence of ghost cells at high magnification (b). Immunohistochemical findings showing low Ki-67 expression (c) and strong p53 expression (d)
88
Discussion GCOC is a rare and malignant neoplasm characterized by high mitotic activity and clusters of ghost epithelial cells. It shows locally aggressive behavior and infiltrative growth. GCOCs occasionally develop from the malignant transformation of a long-term COC; thus, it is important to check for recurrence after therapy [31]. COC represents only 1–2 % of all odontogenic cysts, and its neoplastic transformation ranges from 2–16 % [19, 27]. Three pathogenic mechanisms explaining the histogenesis of an odontogenic carcinoma have been suggested. The first describes a GCOC arising secondary to a benign CCOT. The second mechanism suggests that GCOCs arise from a DGCT, a recurrent malignant neoplasm with the previously mentioned features. The third describes a GCOC arising de novo. The latter mechanism accounted for 12 (40 %) of the reported cases, in that GCOC was not associated with a preceding DGCT or CCOT, as suggested in the present case. The de novo type could potentially represent a secondary onset from an undiagnosed primary lesion [29]. Based on the few articles published in the literature, summarized in Table 1, GCOCs are most prevalent in Asians (only three cases have described in white males and four cases in black individuals). They are more common in males than females (26 vs. 7, respectively), with a predilection for the maxillary bone (12 cases in the mandible and 21 in the maxilla), and occur at a median age of 42 years. These cysts represent an occasional radiographic finding and are usually asymptomatic. The radiographic findings alone are insufficient to confirm the diagnosis; in fact, the lesion appears as a circumscribed radiolucency without radiopaque structures. However, some articles have reported radiopaque foci within the mass [2, 3, 6, 8, 18–20, 22, 24, 27, 28], and the borders tend to be poorly demarcated [13]. In particular, 12 cases appeared radiolucent, and the other 12 showed a mixed radiolucent-radiopaque appearance. In the few cases of GCOC described in the mandible, the malignant neoplasm occurred in the molar region, as in the present case, or in the premolar region [13, 15, 20, 22]. The painful swelling associated with a lymphadenopathy is sometimes caused by local infection. Its biological behavior is not predictable: some cases are asymptomatic, as in our report, while others are associated with pain, swelling, and, in rare cases, extra-bony growth. Clinical and radiological features are not pathognomonic for the diagnosis of GCOC, which must be confirmed histopathologically. The diagnosis requires identification of benign features of a calcifying cystic odontogenic tumor associated with a malignant component consisting of rounded epithelial islands in a fibrous stroma. Pathologists can confirm the morphological diagnosis of GCOC via immunohistochemical analysis of p53. Overexpression of Ki-67 and MMP-9
Oral Maxillofac Surg (2015) 19:85–89
represents a prognostic factor for cell proliferation and tumor invasion [10]. In the present case, expression of p53 was elevated, as in other reports, while the Ki67 value was lower than reported in other similar cases in the literature [10, 11]. The oncological prognosis shows a 5-year survival rate of 73 % [22]. Locoregional and distant metastases are rare. Only two cases have been reported to cause cranial and pulmonary metastases [13, 17]. No evidence supports the efficacy of adjuvant chemo- or radiotherapies, and the recommended treatment is surgical excision with clear microscopic margins. We decided to treat the tumor using a conservative surgical technique without segmental mandibular resection for three reasons: the older age of the patient, the size of the tumor, and the low Ki-67 value. Due to the aggressiveness of GCOCs similar to that of ameloblastomas or low-grade ameloblastic carcinomas [32], long-term follow-up is essential to recognize local recurrences or distant metastases.
Conclusion The first Italian case report of GCOC represents an occasional pathological finding. The clinical course of GCOC is difficult to predict, and diagnosis can be difficult because it is usually asymptomatic. However, it is often aggressive and can become fatal. Thus, it is important to recognize and treat this malignant transformation from a benign cyst. The treatment of choice is surgical excision with clear pathological margins. Immunohistochemical findings are useful to discriminate between benign and malignant cysts and also to identify aggressive behavior. Ki-67 and p53 expression values can guide the decision for the preferred surgical treatment, as well as represent a prognostic index. Long-term follow-up is necessary to prevent recurrence and to identify possible rare metastases. Acknowledgments The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see http://www.textcheck.com/certificate/1Azsbg.
References 1. Barnes L, Eveson JW, Reichart P, Sidransky D (2005) Pathology and genetics of head and neck tumours. IARC (International Agency for Research on Cancer) 2. Ikemura K, Horie A, Tashiro H et al (1985) Simultaneous occurrence of a calcifying odontogenic cyst and its malignant transformation. Cancer 56(12):2861–2864 3. Ledesma-Montes C, Gorlin RJ, Shear M et al (2008) International collaborative study on ghost cell odontogenic tumours: calcifying cystic odontogenic tumour, dentinogenic ghost cell tumour and ghost cell odontogenic carcinoma. J Oral Pathol Med 37(5):302–308
Oral Maxillofac Surg (2015) 19:85–89 4. Sun ZJ, Zhao YF, Zhang L et al (2007) Odontogenic ghost cell carcinoma in the maxilla: a case report and literature review. J Oral Maxillofac Surg 65(9):1820–1824 5. Li BH, Cho YA, Kim SM et al (2011) Recurrent odontogenic ghost cell carcinoma (OGCC) at a reconstructed fibular flap: a case report with immunohistochemical findings. Med Oral Patol Oral Cir Bucal 16(5):e651–e656 6. Alcalde RE, Sasaki A, Misaki M et al (1996) Odontogenic ghost cell carcinoma: report of a case and review of the literature. J Oral Maxillofac Surg 54(1):108–111 7. Praetorius F, Ledesma-Montes C (2005) Calcifying cystic odontogenic tumour. In: Barnes L, Eveson JW, Reichart P, Sidransky D (eds) World Health Organization classification of tumours. Pathology and genetics of head and neck tumours. IARC Press, Lyon 8. Roh GS, Jeon BT, Park BW et al (2008) Ghost cell odontogenic carcinoma of the mandible: a case report demonstrating expression of tartrate-resistant acid phosphatase (TRAP) and vitronectin receptor. J Craniomaxillofac Surg 36(7):419–423 9. Gomes da Silva W, Dos Ribeiro B, Santos TC, Cabral MG et al (2014) Clinicopathologic analysis and syndecan-1 and Ki-67 expression in calcifying cystic odontogenic tumors, dentinogenic ghost cell tumor, and ghost cell odontogenic carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 117(5):626–633 10. Zhu ZY, Chu ZG, Chen Y et al (2012) Ghost cell odontogenic carcinoma arising from calcifying cystic odontogenic tumor: a case report. Korean J Pathol 46(5):478–482 11. Motosugi U, Ogawa I, Yoda T et al (2009) Ghost cell odontogenic carcinoma arising in calcifying odontogenic cyst. Ann Diagn Pathol 13(6):394–397 12. Castle JT, Arendt DM (1999) Aggressive (malignant) epithelial odontogenic ghost cell tumor. Ann Diagn Pathol 3(4):243–248 13. Cheng Y, Long X, Li X et al (2004) Clinical and radiological features of odontogenic ghost cell carcinoma: review of the literature and report of four new cases. Dentomaxillofac Radiol 33(3):152–157 14. Dubiel-Bigaj M, Olszewski E, Stachura J (1993) The malignant form of calcifying odontogenic cyst. A case report. Patol Pol 44(1):39–41 15. Ellis GL, Shmookler BM (1986) Aggressive (malignant?) epithelial odontogenic ghost cell tumor. Oral Surg Oral Med Oral Pathol 61(5): 471–478 16. Folpe AL, Tsue T, Rogerson L et al (1998) Odontogenic ghost cell carcinoma: a case report with immunohistochemical and ultrastructural characterization. J Oral Pathol Med 27(4):185–189 17. Grodjesk JE, Dolinsky HB, Schneider LC et al (1987) Odontogenic ghost cell carcinoma. Oral Surg Oral Med Oral Pathol 63(5):576– 581
89 18. Kamijo R, Miyaoka K, Tachikawa T et al (1999) Odontogenic ghost cell carcinoma: report of a case. J Oral Maxillofac Surg 57(10):1266– 1270 19. Kasahara K, Iizuka T, Kobayashi I et al (2002) A recurrent case of odontogenic ghost cell tumour of the mandible. Int J Oral Maxillofac Surg 31(6):684–687 20. Kim J, Lee EH, Yook JI et al (2000) Odontogenic ghost cell carcinoma: a case report with reference to the relation between apoptosis and ghost cells. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 90(5):630–635 21. Li BB, Gao Y (2009) Ghost cell odontogenic carcinoma transformed from a dentinogenic ghost cell tumor of maxilla after multiple recurrences. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 107(5): 691–695 22. Lu Y, Mock D, Takata T et al (1999) Odontogenic ghost cell carcinoma: report of four new cases and review of the literature. J Oral Pathol Med 28(7):323–329 23. McCoy BP, O'Carroll MK, Hall JM (1992) Carcinoma arising in a dentinogenic ghost cell tumor. Oral Surg Oral Med Oral Pathol 74(3): 371–378 24. Nazaretian SP, Schenberg ME, Simpson I et al (2007) Ghost cell odontogenic carcinoma. Int J Oral Maxillofac Surg 36(5):455–458 25. Scott J, Wood GD (1989) Aggressive calcifying odontogenic cyst—a possible variant of ameloblastoma. Br J Oral Maxillofac Surg 27(1): 53–59 26. Siar CH, Ng KH (1994) Aggressive (malignant?) epithelial odontogenic ghost cell tumour of the maxilla. J Laryngol Otol 108(3):269–271 27. Wader J, Gajbi N (2013) Neoplastic (solid) calcifying ghost cell tumor, intraosseous variant: report of a rare case and review of literature. J Clin Diagn Res 7(9):1999–2000 28. Goldenberg D, Sciubba J, Tufano RP (2004) Odontogenic ghost cell carcinoma. Head Neck 26(4):378–381 29. Arashiyama T, Kodama Y, Kobayashi T et al (2012) Ghost cell odontogenic carcinoma arising in the background of a benign calcifying cystic odontogenic tumor of the mandible. Oral Surg Oral Med Oral Pathol Oral Radiol 114(3):e35–e40 30. Montebugnoli L, Gissi D, Badiali G et al (2011) Ki-67 from clinically and histologically “normal” distant mucosa as prognostic marker in early-stage (T1-T2N0) oral squamous cell carcinoma: a prospective study. J Oral Maxillofac Surg 69(10):2579–2584 31. Kim HJ, Choi SK, Lee CJ et al (2001) Aggressive epithelial odontogenic ghost cell tumor in the mandible: CT and MR imaging findings. AJNR Am J Neuroradiol 22(1):175–179 32. Shafer (2006). Textbook of oral pathology, cysts and tumors of odontogenic origin. 5th edition chap.4: p. 380-400
CASE REPORT
Ki-67 and p53 expression in ghost cell odontogenic carcinoma: a case report and literature review G. Del Corso & M. L. Tardio & D. B. Gissi & C. Marchetti & L. Montebugnoli & A. Tarsitano
Received: 3 July 2014 / Accepted: 2 September 2014 / Published online: 14 September 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Ghost cell odontogenic carcinomas are rare neoplasms that arise in the maxillary bones either from a calcifying odontogenic cyst or de novo. They are aggressive locally and can metastasize. We report herein a case of a ghost cell odontogenic carcinoma arising in the mandible of a Caucasian male 86 years of age. We have described the clinical and radiographic features, histological characteristics, immunohistochemistry findings, and surgical treatment. We especially focused on how Ki-67 expression guides the treatment choice. Finally, we reviewed 32 cases described in the literature and compared them with the cases described up until 2014 to help clinicians identify the diagnostic characteristics of and select appropriate treatment modalities for ghost cell odontogenic carcinomas. Keywords Ghost cell carcinoma . Odontogenic carcinoma . Ghost cell tumors
Introduction Ghost cell odontogenic carcinomas (GCOC) are rare malignant odontogenic epithelial tumors with “features of a
G. Del Corso (*) : D. B. Gissi : L. Montebugnoli Department of Biomedical and Neuromotor Sciences, Section of Oral Science, University of Bologna, via S Vitale 59, Bologna, Italy e-mail: [email protected] M. L. Tardio Pathology Unit, Policlinico S. Orsola-Malpighi, Bologna, Italy C. Marchetti : A. Tarsitano Department of Biomedical and Neuromotor Sciences, Section of Maxillo-facial Surgery at Policlinico S. Orsola-Malpighi, University of Bologna, Bologna, Italy
calcifying cystic odontogenic and/or a dentinogenic ghost cell tumor” [1]. This neoplasm was first described in 1985 by Ikemura as a malignant calcifying odontogenic tumor [2]. It usually arises as a swelling on the jaw bone, commonly occurs on the maxilla, and is most prevalent in men (males/females= 4:1), especially Asian males in their 40s [3–5]. GCOC frequently arises from a precedent calcifying odontogenic cyst (COC) left untreated for several years [6]. COCs are divided into two benign forms: a calcifying cyst odontogenic tumor (CCOT), described as a “benign cystic neoplasm of odontogenic origin, characterized by an ameloblastoma-like epithelium with ghost cells that may calcify” [7], and a dentinogenic ghost cell tumor (DGCT), a “locally invasive neoplasm characterized by ameloblastoma-like islands of epithelial cells in a mature connective tissue stroma” [1]. However, some GCOCs arise as novel tumors [8]. Diagnostic criteria have been established for CCOTs, DGCTs, and GCOCs. However, these tumors represent a heterogeneous group due to broad clinical and radiological diversity and variable biological behaviors [9]. Some authors have evaluated the expression of immunohistochemical markers to discriminate benign cysts from tumors [8, 10]. Positivity for Ki-67 and MMP-9 in GCOCs indicates high proliferative activity associated with malignancy in this type of carcinoma [9]. P53 overexpression is seen in more than 70 % of GCOC cells, as described by Motosugi [11]. This marker represents another factor that can discriminate GCOCs from benign COCs. We report a case of mandibular ghost cell odontogenic carcinoma diagnosed in December 2013 at the Department of Oral Sciences of the University of Bologna; after which, the patient underwent surgery at the Maxillo-Facial Unit of the Sant’Orsola Hospital in Bologna, Italy. This case report represents the 33rd case of GCOC described in the literature [2, 4–6, 8, 10–29] and the first reported in Italy. Table 1 summarizes all the case reports and features of
86 Table 1 List of the 32 cases and features of GCOC reported in the literature until 2014
Oral Maxillofac Surg (2015) 19:85–89
Case
Author
Gender/age
Race
Location
Radiographic features
1 2 3 4 5
Ikemura et al. [2] Sun et al. [4] Li et al. [5] Alcalde et al. [6] Roh et al. [8]
F/48 M/30 F/47 F/72 M/55
Asian Asian Asian Asian Asian
Maxilla Maxilla Mandible Maxilla Mandible
Radiolucent and radiopaque Radiolucent and radiopaque Radiolucent Radiolucent and radiopaque Radiolucent and radiopaque
6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Zhu et al. [10] Motosugi et al. [11] Castle et al. [12] Cheng et al. [13]
M/51 F/17 M/57 M/36 M/35 M/33 M/44 M/42 F/55 M/17 M/20 M/46 M/38 M/59 M/33 M/53 M/24 F/31
Asian Asian White Asian Asian Asian Asian N/A Black N/A N/A White Asian Asian N/A Asian Asian Asian
Maxilla Maxilla Maxilla Mandible Maxilla Maxilla Mandible Maxilla Mandible Maxilla Maxilla Maxilla Maxilla Mandible Mandible Maxilla Maxilla Maxilla
Radiolucent N/A Radiolucent Radiolucent Radiolucent Radiolucent Radiolucent N/A N/A N/A N/A N/A Radiolucent and radiopaque Radiolucent and radiopaque Radiolucent and radiopaque Radiolucent Radiolucent and radiopaque Radiolucent
M/19 M/39 F/13 M/40 M/33 M/39 M/61 M/36 M/86 M/86
Asian Asian Black Black Black Asian N/A Asian Asian White
Mandible Mandible Maxilla Maxilla Maxilla Maxilla Mandible Maxilla Mandible Mandible
Radiolucent and radiopaque Radiolucent N/A Radiolucent and radiopaque N/A N/A Radiolucent and radiopaque Radiolucent and radiopaque Radiolucent Radiolucent
24 25 26 27 28 29 30 31 32 33
Dubiel-Bigaj et al. [14] Ellis et al. [15] Folpe et al. [16] Grodjesk et al. [17] Kamijo et al. [18] Kasahara et al. [19] Kim et al. [20] Li et al. [21] Lu et al. [22]
McCoy et al. [23] Nazaretian et al. [24] Scott et al. [25] Siar et al. [26] Wader et al. [27] Goldenberg et al. [28] Arashiyama et al. [29] Present case
GCOC. We describe the clinical and radiographical features, histological characteristics, immunohistochemistry findings, and the surgical technique. We obtained ethical approval for our study, and we followed the guidelines of the Helsinki Declaration in our investigation.
Case report
dislocated the inferior prosthesis. A panoramic radiograph showed a well-defined radiolucent oval-shaped lesion on the left mandible (Fig. 1). We performed an incisional biopsy under local anesthesia, which confirmed a ghost cell odontogenic carcinoma. Immunostaining of monoclonal anti-Ki67 (Dako, Denmark, clone MIB-1, diluted 1:200) and monoclonal anti-p53 (Dako, clone p53, diluted 1:50) was performed on 2-μm-thick sections serially cut from the selected blocks.
Clinical diagnosis Pathologic findings An 86-year-old Caucasian male with an asymptomatic swelling of the left body of the mandible was seen at the Department of Oral Sciences of the University of Bologna in Bologna, Italy. The patient presented with a gingival swelling that
Diagnosis of a GCOC involves identifying the benign features of a calcifying cystic odontogenic tumor associated with a malignant component consisting of rounded epithelial islands
Oral Maxillofac Surg (2015) 19:85–89
87
Fig. 1 Panoramic radiograph showing an oval-shaped bony lytic radiolucent area without radiographic infiltrative features
in a fibrous stroma (Fig. 2). The neoplastic epithelial cells have rounded hyperchromatic or vesicular nuclei with frequent mitoses. The epithelial cells are surrounded by ghost cells, either isolated or in clusters. We established the cutoff values for p53 and Ki67 overexpression as 20 %, because none of the normal mucosa samples showed a higher value in our previous studies [30]. The immunohistochemical analyses for p53 and Ki-67 revealed a positive reaction against p53 (~60 %) and a less of a reaction against Ki-67 (~10 %) (Fig. 2). Surgical treatment
Fig. 3 Preoperative CT scan showing a lytic lesion involving the left mandibular body
The CT scan demonstrated a lytic area with contrast enhancement, without any evidence of cervical adenopathies (Fig. 3), and confirmed the diagnosis of the panoramic radiograph. The patient was treated surgically under general anesthesia at the Maxillo-Facial Surgery Unit of Sant’Orsola Hospital, University of Bologna, Italy. A partial left mandibulectomy was
performed, preserving the left inferior alveolar nerve and inferior mandibular continuity, and the tumor was excised with clear margins. A titanium plate was fixed on the vestibular surface of the inferior mandibular bone. All specimen margins were negative for tumor cells. No postoperative complications occurred, and no adjuvant radiotherapy was recommended.
Fig. 2 Photomicrographs showing a section stained with hematoxylin and eosin at low magnification (a) and evidence of ghost cells at high magnification (b). Immunohistochemical findings showing low Ki-67 expression (c) and strong p53 expression (d)
88
Discussion GCOC is a rare and malignant neoplasm characterized by high mitotic activity and clusters of ghost epithelial cells. It shows locally aggressive behavior and infiltrative growth. GCOCs occasionally develop from the malignant transformation of a long-term COC; thus, it is important to check for recurrence after therapy [31]. COC represents only 1–2 % of all odontogenic cysts, and its neoplastic transformation ranges from 2–16 % [19, 27]. Three pathogenic mechanisms explaining the histogenesis of an odontogenic carcinoma have been suggested. The first describes a GCOC arising secondary to a benign CCOT. The second mechanism suggests that GCOCs arise from a DGCT, a recurrent malignant neoplasm with the previously mentioned features. The third describes a GCOC arising de novo. The latter mechanism accounted for 12 (40 %) of the reported cases, in that GCOC was not associated with a preceding DGCT or CCOT, as suggested in the present case. The de novo type could potentially represent a secondary onset from an undiagnosed primary lesion [29]. Based on the few articles published in the literature, summarized in Table 1, GCOCs are most prevalent in Asians (only three cases have described in white males and four cases in black individuals). They are more common in males than females (26 vs. 7, respectively), with a predilection for the maxillary bone (12 cases in the mandible and 21 in the maxilla), and occur at a median age of 42 years. These cysts represent an occasional radiographic finding and are usually asymptomatic. The radiographic findings alone are insufficient to confirm the diagnosis; in fact, the lesion appears as a circumscribed radiolucency without radiopaque structures. However, some articles have reported radiopaque foci within the mass [2, 3, 6, 8, 18–20, 22, 24, 27, 28], and the borders tend to be poorly demarcated [13]. In particular, 12 cases appeared radiolucent, and the other 12 showed a mixed radiolucent-radiopaque appearance. In the few cases of GCOC described in the mandible, the malignant neoplasm occurred in the molar region, as in the present case, or in the premolar region [13, 15, 20, 22]. The painful swelling associated with a lymphadenopathy is sometimes caused by local infection. Its biological behavior is not predictable: some cases are asymptomatic, as in our report, while others are associated with pain, swelling, and, in rare cases, extra-bony growth. Clinical and radiological features are not pathognomonic for the diagnosis of GCOC, which must be confirmed histopathologically. The diagnosis requires identification of benign features of a calcifying cystic odontogenic tumor associated with a malignant component consisting of rounded epithelial islands in a fibrous stroma. Pathologists can confirm the morphological diagnosis of GCOC via immunohistochemical analysis of p53. Overexpression of Ki-67 and MMP-9
Oral Maxillofac Surg (2015) 19:85–89
represents a prognostic factor for cell proliferation and tumor invasion [10]. In the present case, expression of p53 was elevated, as in other reports, while the Ki67 value was lower than reported in other similar cases in the literature [10, 11]. The oncological prognosis shows a 5-year survival rate of 73 % [22]. Locoregional and distant metastases are rare. Only two cases have been reported to cause cranial and pulmonary metastases [13, 17]. No evidence supports the efficacy of adjuvant chemo- or radiotherapies, and the recommended treatment is surgical excision with clear microscopic margins. We decided to treat the tumor using a conservative surgical technique without segmental mandibular resection for three reasons: the older age of the patient, the size of the tumor, and the low Ki-67 value. Due to the aggressiveness of GCOCs similar to that of ameloblastomas or low-grade ameloblastic carcinomas [32], long-term follow-up is essential to recognize local recurrences or distant metastases.
Conclusion The first Italian case report of GCOC represents an occasional pathological finding. The clinical course of GCOC is difficult to predict, and diagnosis can be difficult because it is usually asymptomatic. However, it is often aggressive and can become fatal. Thus, it is important to recognize and treat this malignant transformation from a benign cyst. The treatment of choice is surgical excision with clear pathological margins. Immunohistochemical findings are useful to discriminate between benign and malignant cysts and also to identify aggressive behavior. Ki-67 and p53 expression values can guide the decision for the preferred surgical treatment, as well as represent a prognostic index. Long-term follow-up is necessary to prevent recurrence and to identify possible rare metastases. Acknowledgments The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see http://www.textcheck.com/certificate/1Azsbg.
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