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Primary intraosseous carcinoma of the mandible with probable origin in an odontogenic cyst
Short communications
& case reports
Primary intraosseous carcinoma of the mandible with probable origin in an odontogenic cyst Charles A. Waldron, D.D.S.,*
and Thomas A. Mustoe, M.D.,**
St. Louis, MO.
Primary intraosseous carcinoma of the jaws (PIOC) is an uncommon lesion, but may not be as rare as commonly believed. Since the putative source of the epithelium giving rise to an intraosseous carcinoma is the epithelium involved in odontogenesis, these lesions are often designated as odontogenic carcinomas. These tumors may theoretically arise (1) from the lining of odontogenic cysts, (2) from other epithelial odontogenic tumors, or (3) de novo from presumed odontogenic rests. While not included in most classifications of PIOC, it appears logical to also include intraosseous mucoepidermoid carcinomas as a fourth type of PIOC. A case of primary intraosseous squamous cell carcinoma of the mandible, with evidence of origin in an odontogenic cyst, is presented. The recent literature on carcinomas arising in jaw cysts is reviewed. (ORAL
SURC ORAL MED
ORAL PATHOL
1989;67:716-24)
C
arcinoma arising within bone is a rare lesion and is seen essentially only in the jaw bones. To qualify as a primary intraosseous carcinoma (PIOC), there must be no histologically demonstrable origin from the oral mucosa, overlying skin, or antral or nasal mucosa (in the case of intramaxillary lesions). The possibility that the lesion in question represents a metastasis from a distant (and possibly occult) primary must be ruled out by physical examination, radiologic studies, and the subsequent clinical course. Since the putative source of the epithelium giving rise to a PIOC of the jaws is the epithelium involved in odontogenesis, these lesions are also frequently designated as odontogenic carcinomas.’ In 1982, Elzay2 reviewed the subject of PIOC of the jaws and suggested a modification of the World Health Orga*Professor Oral Pathology, Washington University School of Dental Medicine. **Assistant Professor of Surgery, Division of Plastic Surgery Washington University School of Medicine. 716
nization classification.’ Slootweg and Mi.iller’3 presented a slight modification of Elzay’s classification that has considerable merit. This classification accounts for the various possible origins of a PIOC. Primary intraosseous carcinoma (odontogenic carcinoma) of the jaws (after Slootweg and Mill-
ler3) : Type 1. PIOC ex odontogenic cyst. Type 2A. Malignant ameloblastoma. Type 2B. Ameloblastic carcinoma arising de novo, ex ameloblastoma or ex odontogenic cyst. Type 3. PIOC arising de novo; (a) keratinizing type. (b) Nonkeratinizing type.
Although not included in the classifications proposed by the WHO,’ Elzay,2 or Slootweg and Miiller,3 we believe it is also logical to include intraosseous mucoepidermoid carcinoma as a fourth type of PIOC. Although these tumors are usually considered under the heading of salivary gland tumors and are histologically identical with salivary gland mucoepidermoid carcinoma, there is evidence that a signifi-
Primary intraosseous carcinoma of mandible
Volume 67 Number 6 Table
I. Agel
Year
Author
gender
Location
Type
of cyst
Carcinomas associated with cysts reported since 1974 1977 Martinelli et al.’ 60 M Anterior Residual mandible 1979 Baker et al.’ 22 M Mandibular Lateral premolar periodontal ? 1980 Enriquez et aL9 56 M Mandibular ramus 60 M Anterior 1981 Areen et aLi Odontogenic maxilla keratocyst 1983 Nithianada” 59 M Anterior Residual maxilla 1984 Norris et a1.n 26 M Posterior Dentigerous* mandible 79 F Mandibular Residual 1985 Pearcey” body and ramus 1985 Pearcey” 79 F Left maxilla Residual 1985 Van der Waal14 85 F Posterior Residual mandible 1985 Van der Waal14 45 M Anterior Residual maxilla 1985 Van der Waal14 70 M Left maxilla Residual 1985 Van der Waa14 8 1 F Posterior Odontogenic mandible keratocyst 1985 Van der Waal14 48 M Posterior Dentigerous mandible 1987 Present case 51 M Right ? mandible Intraosseous carcinomas not associated with cysts reported 1985 Lukinmaais 33 M Anterior maxilla XRT
717
= radiation
Initial
TX
Recurrence
Subsequent TX
-
Enucleation
Follow-up
A/W 36 mo -
A/W 30 mo
mo
Resection
A/W 40 mo
2
mo
Maxillectomy plus A/W 18 mo XRT A/W 36 mo
Enucleation
4
mo
Enucleation
S mo
XRT plus chemotherapy XRT
Enucleation plus XRT Enucleation plus hemimandibulectomy Enucleation
18 mo; neck XRT
30
Partial maxillectomy Enucleation
6
Enucleation plus en bloc resections Enucleation
3
En bloc resection En bloc resection
Enucleation plus hemimandibulectomy Hemimandibulectomy since 1982 Excision
A/W 48 mo
mo
Maxillectomy
DOD 9 mo DOC 3 weeks, cardiac arrest A/W 24 mo
-
Chemotherapy
A/W 12 mo A/W 72 mo
mo
-
20 18
DOD 5 mo
mo mo
Excision
-
A/W 24 mo
-
DOC 4 days Not given
therapy.
A/W = alive and well. DOD = died of disease. DOC = died of other cause. *Radiographic evidence of cyst only-histologic
information
not available.
cant number of the intraosseous tumors may originate in the epithelial lining of odontogenic cysts.4 Type 4. Intraosseous ma.
mucoepidermoid
carcino-
The following review and discussion will be limited to primary intraosseous squamous cell carcinoma (PIOSC), with presumed origin in dental cysts (Type 1) or apparently arising de novo (Type 3). PIOSC is unquestionably a rare lesion and the total number of reported cases is difficult to determine. Proof that a given lesion actually represents a PIOSC is often difficult and a number of reported cases are open to question. Eversole and coworkers4 conducted a critical review of the literature through 1973 and accepted 36 cases of intraosseous squamous cell carcinomas of the jaws. Due to lack of sufficient documentation, they excluded 33 other reported cases. Earlier reviews of squamous cell carcinomas associated with
odontogenic cysts by Falkmer and coworkers ( 1957)s and Gardner ( 1969)6 included most of the cases accepted by Eversole and his colleagues4 In 1982, Elzay* reviewed the literature on intraosseous carcinomas not associated with odontogenic cysts and accepted 12 cases. A review of the English-language literature since 1973 revealed 13 additional cases that appear to be well-documented examples of PIOSC originating in odontogenic cysts and one case of PIOSC (apparently arising de novo) reported since Elzay’s 1982 review.* The details of these cases are summarized in Table I. CASEREPORT
A 5 I-year-old black man consulted a local public health dental clinic. He reported pain in his jaw of two to three months’ duration. He denied other medical problems or
718
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men was reported as well-differentiated squamous cell carcinoma. Two weeks after the biopsy, the patient was admitted to the hospital and an en bloc resection of the involved mandible, surrounding alveolar mucosa, and the skin through which the previous biopsy had been performed was accomplished. A modified radical neck dissection was also performed with preservation of the sternocleidomastoid muscle. The mandible was reconstructed with a Dacron tray and iliac bone fragments. Postoperatively, the patient did very well and was sitting up in a chair on the second postoperative day. However, at this time he was noted to have become delusional. Discussion with his family revealed that the patient was an alcoholic, although before surgery he had denied alcohol ingestion. Treatment of the delirium tremens was carried out. Approximately 4 hours after the onset of delirium tremens, the patient became quite agitated and subsequently had a respiratory arrest. He was treated aggressively, but his course over the next 48 hours rapidly deteriorated and he died of pneumonia. An autopsy was performed. PATHOLOGY
FINDINGS
The gross specimen consisted of a segment of the right mandible (including the left and right central incisor teeth) and the right lateral incisor, canine,
1. Anterior-posterior and lateral jaw radiographs showing almost total destruction of right mandibular body.
Fig.
weight loss, and stated that he was otherwise in good health. Examination revealed an expansile mass that involved the right mandible and extended from the incisor region to the right angle of the mandible. The alveolar ridge was markedly expanded and was covered with intact, normal-appearing mucosa. Palpation in the right submental region indicated a mass that appeared to be breaking through the bony confines and extending into the soft tissues. The mandibular molar and premolar teeth were mobile and there was indication of a pathologic fracture in the region of the missing right first premolar tooth. The patient’s oral hygiene was poor. Radiographic examination revealed a destructive lesion extending from the angle of the mandible to the incisor area. The mandibular bone was essentially absent (Fig. 1). The patient was referred to the St. Louis Regional Hospital, where an extraoral biopsy was performed by the plastic surgical service. Oral examination at that time revealed no mucosal ulceration or mass. The biopsy speci-
second premolar, and first, second, and third molar teeth. The first premolar was missing and the specimen in this area exhibited mobility that indicated a pathologic fracture. The gingival and alveolar mucosa on the facial aspect of this specimen appeared grossly normal (Fig. 2, A). The lingual, gingival, and alveolar mucosa also appeared normal on gross inspection, except for a 0.6 cm sharply punched out defect on the lingual alveolar mucosa in the mid-root area, lingual to the first and second molar teeth (Fig. 2, B). A soft-tissue mass, representing the neck dissection specimen, was attached to the lower portion of the mandible. A lateral radiograph of the mandibular specimen showed almost total destruction of the mandibular bone (Fig. 3). A series of cross-section cuts were made through the mandible.
A cross section in the second molar area grossly suggested a cavitary defect in the center of the tumor mass. Multiple microscopic sections from the body of the mandible revealed that the bone was almost completely replaced by extensive masses of well-differentiated squamous ceil carcinoma that extended from the central incisor region to the third molar area (Fig. 4, A and B). The tumor had completely destroyed the buccal, lingual, and inferior cortical plates, but did not appear to invade the surrounding
Volume 67 Number 6
Primary
intraosseous carcinoma of mandible
719
3. Radiograph of surgical specimen showing almost total destruction of mandibular bone. A small amount of osseoustissue is present apical to the first molar, and bone is still present at the symphysis of the mandible.
Fig.
2. A, Facial aspect of surgical specimen including segment of skin that was site of biopsy. B, Occlusal view of surgical specimen showing sharply defined defect on lingual alveolar mucosa (large arrow). The tissue separation between the canine and second premolar tooth (small arrow) at the site of the pathologic fracture occurred during manipulation at the time of surgery. Fig.
fibrous tissue, muscle, and adjacent salivary gland tissue (Fig. 5). Sections from the neck dissection specimen showed reactive hyperplasia of several enlarged lymph nodes, with no evidence of carcinoma involving lymph nodes, submandibular gland, or muscle. Multiple sections taken from various locations on the gingival and alveolar mucosa showed normal-appearing mucosa. A cross section of the mandibular specimen, taken from the second molar area, was of particular interest. The apparent cavitary defect noted on gross examination showed a layer of apparently nonneoplastic, stratified squamous epithelium, lining most of the cavity. This epithelial lining was histologically typical of that seen in a benign odontogenic cyst. Numerous foci or basal epithelial dysplasia were present and, in many areas, islands of typical squamous cell carcinoma appeared to originate from
this lining and extend into the underlying tissue (Fig. 6). A soft-tissue section through the margins of the defect noted on the lingual alveolar mucosa (Fig. 2, B) showed an abrupt transition from normal-appearing alveolar mucosa to a depressed area that contained masses of well-differentiated squamous cell carcinoma. The tumor nests were in contact with the normal surface mucosa, but did not appear to be arising from it (Fig. 7). An autopsy was performed shortly after the patient died. The chief pathologic findings were edema and softening of the brain, compatible with hypoxic encepalopathy, massive bronchopneumonia, and acute renal tubular necrosis. There was no evidence of a primary or metastatic neoplasm in the larynx, pharynx, esophagus, lungs, gastrointestinal tract, adrenal glands or kidney. DISCUSSION
We believe that the clinical, radiologic, and pathologic findings-including the autopsy in this casesupport the diagnosis of a primary intraosseous squamous cell carcinoma of the mandible. The presence of the 0.6 cm ulcerated defect on the lingual alveolar mucosa (noted on gross examination of the specimen) is the only-and we consider unhkelyfactor that might cast a slight measure of doubt on this interpretation. The patient was carefully examined by three competent clinicians at the first presentation and seven days later, at the time of the biopsy.
720
Waldron and Mustoe
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SLR(r
ORar.
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1989
Fig. 4. A, Photomicrograph of cross section of mandible in area of right canine. The gingiva and periodontal ligament around the tooth appear normal, and a small amount of alveolar bone is present. In the deeper portions of the specimen, the bone has been completely replaced by massesof well-differentiated squamous cell carcinoma (Original magnification, X4.) B, Photomicrograph showing typical area of well-differentiated, keratinizing squamous cell carcinoma, which has destroyed most of right side of mandible. The tumor is associated with an intense chronic inflammatory reaction. (Original magnification, x90.)
None of the examiners noted any evidence of mucosal ulceration or any suggestion of a primary mucosal mass. It is likely that this mucosal defect developed sometime during the 2-week interval
between the time of the extraoral biopsy and the mandibulectomy and was caused by penetration of the underlying tumor into the overlying normal mucosa. This is supported by microscopic study at
Volume 67 Number 6
Primary intraosseous carcinoma of mandible
721
5. Photomicrograph at peripheral margin of tumor. The labial cortical bone has been completely destroyed, but the tumor has not penetrated through the surrounding fibrous tissue and has not invaded the nodule of minor salivary gland tissue on the right side of the photograph. (Original magnification, x90.)
Fig.
Fig. 6. Photomicrograph showing benign-appearing epithelial lining of cavity. There are foci of basal dysplasia with areas of squamous cell carcinoma appearing to originate from the lining epithelium. (Original magnification, X90.)
the edge of the defect. In addition, it is most unlikely that a very low-grade squamous cell carcinoma (less than 0.6 cm in diameter) arising on the alveolar mucosa could invade and totally destroy the entire right body of the mandible without manifesting as a large mucosal mass. Whether or not this tumor originated in a pre-existing dental cyst, however, remains a moot point. A cross section of the gross
specimen in the molar area revealed a small central cystic defect that (on microscopic examination) showed a benign-appearing, stratified squamous epithelial lining, with multiple foci of squamous cell carcinoma apparently arising from the basal layer. Cross sections of the mandible extending to the canine area, while not grossly showing a central cystic defect, contained (as seen microscopically)
722
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Fig. 7. Photomicrograph through margin of mucosal defect on lingual alveolar mucosa shown in Fig. 2, B. Normal-appearing alveolar mucosa, which invaginates into the depressed defect, is shown on the left side of the picture. The defect area on the right side of the picture shows well-differentiated squamous cell carcinoma extending to the surface. (Original magnification, X38.)
long strands of benign-appearing, stratified squamous epithelium, suggestive of a proliferating cyst lining intermingled with typical squamous cell carcinoma. It might be argued that this cavity defect only represented cystic degeneration in a squamous cell carcinoma rather than a pre-existing cyst. However, the very benign-appearing epithelial lining throughout a considerable portion of the cavity strongly indicates that a benign cyst was originally present. If a benign cyst was present, its classification also remains speculative. Unfortunately, no detailed dental history was obtained from the patient before his death. The circumstances related to the date and reasons for the loss of the first premolar tooth are unknown. It is possible that this tooth was nonvital and that the cyst may have represented a residual odontogenic cyst. The teeth that were present in the gross specimen contained several relatively shallow amalgam restorations. Most of the teeth were included in microscopic cross sections of the mandible. Although pulpal histology was less than optimal (due to fixation artifact), none of the pulps appeared to be necrotic and there was no evidence that the cyst was of the radicular type. Many authorities in the United States believe that some primordial cysts are not histologically odontogenic keratocysts and this type of cyst may have been present and given rise to the tumor.16 Although primary intraosseous carcinoma of the jaws is unquestionably very uncommon, we suspect it
may not be quite as rare as the literature indicates. One of us (C.A.W.) saw three additional cases (during his 25-year tenure at Emory University) and has reviewed consultation material on at least five more cases. None of these has been reported. Several additional references were found in the German literature, although the individual cases were not documented in great detail. Kreidler and coworkers’7 reported two cases associated with dentigerous cysts in a series of 758 odontogenic cysts seen between 1980 and 1984. Olten and colleagues’* reported five cases of carcinoma, with presumed origin in cysts or follicles of unerupted teeth, seen over a IO-year period at the University Dental Clinic, Freiberg, West Germany. The majority of PIOSCs appear to arise from the epithelial lining of pre-existing odontogenic cysts. Of the 36 cases of intraosseous squamous cell carcinoma accepted by Eversole and coauthors,4 27 (75%) appeared to originate in odontogenic cysts. Our review of the English-language literature subsequent to this article revealed 13 additional cases that demonstrated convincing evidence of origin in the cyst. Although carcinomas have been reported to arise in several types of odontogenic cysts, approximately 55% of reported cases ahve been associated with residual cysts. Many of these patients were elderly and the cysts had presumably been present for many years. Browne and Goughi9 suggested that keratin metaplasia, followed by epithelial hyperpla-
Volume Number
67 6
sia and development of epithelial dysplasia of cyst linings, were the significant sequential events in development of carcinoma in dental cysts. They also suggested that cyst linings that reveal keratinization were at greater risk for development of carcinoma. In the cases reviewed by Eversole and coworkers, 15% of the cysts associated with carcinoma showed a keratinized lining, although none of them were considered to be odontogenic keratocysts. While a number of the more recently reported cases contained convincing photomicrographs showing epithelial dysplasia and carcinoma in situ with transition to squamous cell carcinoma, we were not impressed with evidence of hyperkeratotic changes of the benign cystic areas in any of the published photomicrographs or pathologic descriptions. Although odontogenic keratocysts are considered to have a more aggressive biologic potential than other types of odontogenic cysts,20 we are aware of only two reported cases that show convincing origin of a PIOSC in a keratocyst. lo,I4 Pain and swelling are the most common symptoms associated with PIOSC of the jaws and are noted in a majority of cases. Review of published cases indicates that in a substantial number of instances, the clinician had no suspicion that the intrabony lesion represented a malignant condition and the initial treatment of 8 of the 15 more recently reported cases consisted of enucleation of a presumed cyst. In most instances, the diagnosis of carcinoma was apparently quite unsuspected and was made only after pathology examination. Subsequent treatment in most of these cases consisted of en bloc excision or radical resection of the involved bone. The prognosis of PIOSC appears surprisingly good, although long-term follow-up information is notably lacking in most reports. A 53% two-year survival in the 36 cases in one review was noted. In the 15 cases reported since 1974, eight of the patients (53%) were reported to be alive and well from two to six years after the last treatment. Two additional patients were alive and well at 12 and 18 months, respectively. Two patients have died of other causes and only two had died of tumor. Follow-up information on one patient was not given. Local recurrence appears to be a major problem in patients not subjected to primary radical excision. This occurred in eight of the 15 cases and was treated by excision or radiation therapy. None of the recently reported patients was noted to have regional metastasis at the time of initial diagnosis, and metastasis to the regional lymph nodes was reported to have subsequently developed in only one patient. Whether or not carcinomas arising in odontogenic
Primary intraosseous carcinoma of mandible
723
cysts (Type I) have a different prognosis than those arising de novo (Type 3) cannot be determined at this time. We have the distinct impression that the majority of carcinomas associated with cysts are relatively low-grade, keratinizing lesions that may portend better prognosis. By contrast, 8 of the 12 de novo lesions (Type 3) reviewed by Elzay2 were nonkeratinizing (less-differentiated) lesions. The one example of this type published since 1982 was also histologically a nonkeratinizing tumor.” The patients with de novo intraosseous carcinoma reviewed by Elzay2 demonstrated a 40% two-year survival. It is of interest that 66% of these patients had clinical and/or histologic evidence of regional metastasis, either initially or during the course of their disease. By contrast, only one of the 14 more recently reported cases of intraosseous carcinoma associated with cysts demonstrated regional spread.j3 This patient had a poorly differentiated, nonkeratinizing carcinoma, and died nine months later with uncontrolled neck disease. Reporting of additional well-documented examples of PIOC should eventually yield better information on the management and prognosis of these uncommon neoplasms. REFERENCES 1. Pindborg JJ, Kramer IRH. Histologic typing of odontogenic tumors, cysts, and allied lesion. Geneva: World Health Organization, 1971. 2. Elzay RP. Primary intraosseous carcinoma of the jaws. ORAL SURG ORAL MED ORAL PATHOL 1982;54:299-303. 3. Slootweg PJ, Miiller H: Malignant amelobiastoma or ameloblastic carcinoma. ORAL SURG ORAL MED ORAL PATHOL 1984;57:168-76. 4. Eversole LR, Sabes WR, Rovin S. Aggressive growth and neoplastic potential of odontogenic cysts. Cancer 1975; 35:270-82. 5. Falkmer S, Herberts G, Olven S. Carcinoma arising in odontogenic cysts of the jaw: survey and case report. Stand J Dent Res 1957;65:220-31. 6. Gardner AF. The odontogenic cyst as a potential carcinoma: a clinicopathologic appraisal. J Am Dent Assoc 1969;78:74655. I. Martinelli C, Melhado RM, Callestini EA. Squamous cell carcinoma in a residual mandibular cyst. ORAL SURG ORAL MED ORAL PATHOL 1977;44:274-8. 8. Baker RD. Onofrio Ed. Corio RL. Crawford BE. Terrv BC. Squamous’cell carcinoma arising in a lateral periodontai cyst. ORAL
SURG ORAL
MED ORAL
PATHOL
1979;47:495-9.
9. Enriquez RE, Ciola B, Bahn SL: Verrucous carcinoma arising in an odontogenic cyst. ORAL SURG ORAL MED ORAL PATHOL 1980;49:151-6. 10. Areen RG, McClatchey KD, Baker HL. Squamous cell carcinoma developing in an odontogenic keratocyst. Arch Otolaryngol Head Neck Surg 1981;107:568-9. 11. Nithianada S. Squamous cell carcinoma arising in the lining of an adontogenic cyst. Brit J Oral Surg 1983;21:56-62. 12. Norris LU, Baghaei-Rad M, Maloney PL, Simpson G, Guinta J. Bilateral maxillary squamous odontogenic tumors and malignant transformation of a mandibular radiolucent lesion. J Oral Maxillofac Surg 1984;42:827-34. 13. Pearcey RG. Squamous cell carcinoma arising in dental cysts. Clin Radio1 1985;36:387-8.
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14. Van der Waal I, Rauhamaa R, Van der Kwast WAM, Snow GB. Squamous cell carcinoma arising in the lining of odontogenic cysts: report of 5 cases. Int J Oral Surg 1985; 14: I 4052. 15. Lukinmaa PL, Heitanen J, Oikarinen VJ, Calonius PEB, Piirto M. Primary intraosseous carcinoma involving the maxilla. Brit Oral Surg 1985;23:450-5. 16. Brannon RB. The odontogenic keratocyst: A clinicopathologic study of 312 cases. Part I. Clinical features. ORAL SURC ORAL
MED
ORAL
PATHOL
1976;42:54-72.
17. Kreidler J, Haase S, Kemp W: Karzinogenese in kieferzysten. Dts,ch Zahnarzti Z I985;40:548-50. 18. Olten JE, Joos U, Schilli W. Karzinomentstheung auf dem baden des zystenbildenden odontogenen epithels. Dtsch Zahnarztl Z 1985;40:544-7.
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19. Browne RM, Gough NG. Malignant change in the epithelial lining of odontogenic cysts. Cancer 1972;29: I 199-207. 20. Alfors E, Larson A, Sjogren S. The odontogenic kcratocyst-m a benign cystic tumor’! J Oral Maxillofac Surg 1984;42: 10-9.
Reprint requests to: Dr. Thomas Mustoe Suite 17424 Barnes Hospital St. Louis, MO. 631 IO
& case reports
Primary intraosseous carcinoma of the mandible with probable origin in an odontogenic cyst Charles A. Waldron, D.D.S.,*
and Thomas A. Mustoe, M.D.,**
St. Louis, MO.
Primary intraosseous carcinoma of the jaws (PIOC) is an uncommon lesion, but may not be as rare as commonly believed. Since the putative source of the epithelium giving rise to an intraosseous carcinoma is the epithelium involved in odontogenesis, these lesions are often designated as odontogenic carcinomas. These tumors may theoretically arise (1) from the lining of odontogenic cysts, (2) from other epithelial odontogenic tumors, or (3) de novo from presumed odontogenic rests. While not included in most classifications of PIOC, it appears logical to also include intraosseous mucoepidermoid carcinomas as a fourth type of PIOC. A case of primary intraosseous squamous cell carcinoma of the mandible, with evidence of origin in an odontogenic cyst, is presented. The recent literature on carcinomas arising in jaw cysts is reviewed. (ORAL
SURC ORAL MED
ORAL PATHOL
1989;67:716-24)
C
arcinoma arising within bone is a rare lesion and is seen essentially only in the jaw bones. To qualify as a primary intraosseous carcinoma (PIOC), there must be no histologically demonstrable origin from the oral mucosa, overlying skin, or antral or nasal mucosa (in the case of intramaxillary lesions). The possibility that the lesion in question represents a metastasis from a distant (and possibly occult) primary must be ruled out by physical examination, radiologic studies, and the subsequent clinical course. Since the putative source of the epithelium giving rise to a PIOC of the jaws is the epithelium involved in odontogenesis, these lesions are also frequently designated as odontogenic carcinomas.’ In 1982, Elzay2 reviewed the subject of PIOC of the jaws and suggested a modification of the World Health Orga*Professor Oral Pathology, Washington University School of Dental Medicine. **Assistant Professor of Surgery, Division of Plastic Surgery Washington University School of Medicine. 716
nization classification.’ Slootweg and Mi.iller’3 presented a slight modification of Elzay’s classification that has considerable merit. This classification accounts for the various possible origins of a PIOC. Primary intraosseous carcinoma (odontogenic carcinoma) of the jaws (after Slootweg and Mill-
ler3) : Type 1. PIOC ex odontogenic cyst. Type 2A. Malignant ameloblastoma. Type 2B. Ameloblastic carcinoma arising de novo, ex ameloblastoma or ex odontogenic cyst. Type 3. PIOC arising de novo; (a) keratinizing type. (b) Nonkeratinizing type.
Although not included in the classifications proposed by the WHO,’ Elzay,2 or Slootweg and Miiller,3 we believe it is also logical to include intraosseous mucoepidermoid carcinoma as a fourth type of PIOC. Although these tumors are usually considered under the heading of salivary gland tumors and are histologically identical with salivary gland mucoepidermoid carcinoma, there is evidence that a signifi-
Primary intraosseous carcinoma of mandible
Volume 67 Number 6 Table
I. Agel
Year
Author
gender
Location
Type
of cyst
Carcinomas associated with cysts reported since 1974 1977 Martinelli et al.’ 60 M Anterior Residual mandible 1979 Baker et al.’ 22 M Mandibular Lateral premolar periodontal ? 1980 Enriquez et aL9 56 M Mandibular ramus 60 M Anterior 1981 Areen et aLi Odontogenic maxilla keratocyst 1983 Nithianada” 59 M Anterior Residual maxilla 1984 Norris et a1.n 26 M Posterior Dentigerous* mandible 79 F Mandibular Residual 1985 Pearcey” body and ramus 1985 Pearcey” 79 F Left maxilla Residual 1985 Van der Waal14 85 F Posterior Residual mandible 1985 Van der Waal14 45 M Anterior Residual maxilla 1985 Van der Waal14 70 M Left maxilla Residual 1985 Van der Waa14 8 1 F Posterior Odontogenic mandible keratocyst 1985 Van der Waal14 48 M Posterior Dentigerous mandible 1987 Present case 51 M Right ? mandible Intraosseous carcinomas not associated with cysts reported 1985 Lukinmaais 33 M Anterior maxilla XRT
717
= radiation
Initial
TX
Recurrence
Subsequent TX
-
Enucleation
Follow-up
A/W 36 mo -
A/W 30 mo
mo
Resection
A/W 40 mo
2
mo
Maxillectomy plus A/W 18 mo XRT A/W 36 mo
Enucleation
4
mo
Enucleation
S mo
XRT plus chemotherapy XRT
Enucleation plus XRT Enucleation plus hemimandibulectomy Enucleation
18 mo; neck XRT
30
Partial maxillectomy Enucleation
6
Enucleation plus en bloc resections Enucleation
3
En bloc resection En bloc resection
Enucleation plus hemimandibulectomy Hemimandibulectomy since 1982 Excision
A/W 48 mo
mo
Maxillectomy
DOD 9 mo DOC 3 weeks, cardiac arrest A/W 24 mo
-
Chemotherapy
A/W 12 mo A/W 72 mo
mo
-
20 18
DOD 5 mo
mo mo
Excision
-
A/W 24 mo
-
DOC 4 days Not given
therapy.
A/W = alive and well. DOD = died of disease. DOC = died of other cause. *Radiographic evidence of cyst only-histologic
information
not available.
cant number of the intraosseous tumors may originate in the epithelial lining of odontogenic cysts.4 Type 4. Intraosseous ma.
mucoepidermoid
carcino-
The following review and discussion will be limited to primary intraosseous squamous cell carcinoma (PIOSC), with presumed origin in dental cysts (Type 1) or apparently arising de novo (Type 3). PIOSC is unquestionably a rare lesion and the total number of reported cases is difficult to determine. Proof that a given lesion actually represents a PIOSC is often difficult and a number of reported cases are open to question. Eversole and coworkers4 conducted a critical review of the literature through 1973 and accepted 36 cases of intraosseous squamous cell carcinomas of the jaws. Due to lack of sufficient documentation, they excluded 33 other reported cases. Earlier reviews of squamous cell carcinomas associated with
odontogenic cysts by Falkmer and coworkers ( 1957)s and Gardner ( 1969)6 included most of the cases accepted by Eversole and his colleagues4 In 1982, Elzay* reviewed the literature on intraosseous carcinomas not associated with odontogenic cysts and accepted 12 cases. A review of the English-language literature since 1973 revealed 13 additional cases that appear to be well-documented examples of PIOSC originating in odontogenic cysts and one case of PIOSC (apparently arising de novo) reported since Elzay’s 1982 review.* The details of these cases are summarized in Table I. CASEREPORT
A 5 I-year-old black man consulted a local public health dental clinic. He reported pain in his jaw of two to three months’ duration. He denied other medical problems or
718
Waldron and Mustoe
ORAl-
SURG
ORAL
Meu ORAL PATHOL .June1989
men was reported as well-differentiated squamous cell carcinoma. Two weeks after the biopsy, the patient was admitted to the hospital and an en bloc resection of the involved mandible, surrounding alveolar mucosa, and the skin through which the previous biopsy had been performed was accomplished. A modified radical neck dissection was also performed with preservation of the sternocleidomastoid muscle. The mandible was reconstructed with a Dacron tray and iliac bone fragments. Postoperatively, the patient did very well and was sitting up in a chair on the second postoperative day. However, at this time he was noted to have become delusional. Discussion with his family revealed that the patient was an alcoholic, although before surgery he had denied alcohol ingestion. Treatment of the delirium tremens was carried out. Approximately 4 hours after the onset of delirium tremens, the patient became quite agitated and subsequently had a respiratory arrest. He was treated aggressively, but his course over the next 48 hours rapidly deteriorated and he died of pneumonia. An autopsy was performed. PATHOLOGY
FINDINGS
The gross specimen consisted of a segment of the right mandible (including the left and right central incisor teeth) and the right lateral incisor, canine,
1. Anterior-posterior and lateral jaw radiographs showing almost total destruction of right mandibular body.
Fig.
weight loss, and stated that he was otherwise in good health. Examination revealed an expansile mass that involved the right mandible and extended from the incisor region to the right angle of the mandible. The alveolar ridge was markedly expanded and was covered with intact, normal-appearing mucosa. Palpation in the right submental region indicated a mass that appeared to be breaking through the bony confines and extending into the soft tissues. The mandibular molar and premolar teeth were mobile and there was indication of a pathologic fracture in the region of the missing right first premolar tooth. The patient’s oral hygiene was poor. Radiographic examination revealed a destructive lesion extending from the angle of the mandible to the incisor area. The mandibular bone was essentially absent (Fig. 1). The patient was referred to the St. Louis Regional Hospital, where an extraoral biopsy was performed by the plastic surgical service. Oral examination at that time revealed no mucosal ulceration or mass. The biopsy speci-
second premolar, and first, second, and third molar teeth. The first premolar was missing and the specimen in this area exhibited mobility that indicated a pathologic fracture. The gingival and alveolar mucosa on the facial aspect of this specimen appeared grossly normal (Fig. 2, A). The lingual, gingival, and alveolar mucosa also appeared normal on gross inspection, except for a 0.6 cm sharply punched out defect on the lingual alveolar mucosa in the mid-root area, lingual to the first and second molar teeth (Fig. 2, B). A soft-tissue mass, representing the neck dissection specimen, was attached to the lower portion of the mandible. A lateral radiograph of the mandibular specimen showed almost total destruction of the mandibular bone (Fig. 3). A series of cross-section cuts were made through the mandible.
A cross section in the second molar area grossly suggested a cavitary defect in the center of the tumor mass. Multiple microscopic sections from the body of the mandible revealed that the bone was almost completely replaced by extensive masses of well-differentiated squamous ceil carcinoma that extended from the central incisor region to the third molar area (Fig. 4, A and B). The tumor had completely destroyed the buccal, lingual, and inferior cortical plates, but did not appear to invade the surrounding
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3. Radiograph of surgical specimen showing almost total destruction of mandibular bone. A small amount of osseoustissue is present apical to the first molar, and bone is still present at the symphysis of the mandible.
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2. A, Facial aspect of surgical specimen including segment of skin that was site of biopsy. B, Occlusal view of surgical specimen showing sharply defined defect on lingual alveolar mucosa (large arrow). The tissue separation between the canine and second premolar tooth (small arrow) at the site of the pathologic fracture occurred during manipulation at the time of surgery. Fig.
fibrous tissue, muscle, and adjacent salivary gland tissue (Fig. 5). Sections from the neck dissection specimen showed reactive hyperplasia of several enlarged lymph nodes, with no evidence of carcinoma involving lymph nodes, submandibular gland, or muscle. Multiple sections taken from various locations on the gingival and alveolar mucosa showed normal-appearing mucosa. A cross section of the mandibular specimen, taken from the second molar area, was of particular interest. The apparent cavitary defect noted on gross examination showed a layer of apparently nonneoplastic, stratified squamous epithelium, lining most of the cavity. This epithelial lining was histologically typical of that seen in a benign odontogenic cyst. Numerous foci or basal epithelial dysplasia were present and, in many areas, islands of typical squamous cell carcinoma appeared to originate from
this lining and extend into the underlying tissue (Fig. 6). A soft-tissue section through the margins of the defect noted on the lingual alveolar mucosa (Fig. 2, B) showed an abrupt transition from normal-appearing alveolar mucosa to a depressed area that contained masses of well-differentiated squamous cell carcinoma. The tumor nests were in contact with the normal surface mucosa, but did not appear to be arising from it (Fig. 7). An autopsy was performed shortly after the patient died. The chief pathologic findings were edema and softening of the brain, compatible with hypoxic encepalopathy, massive bronchopneumonia, and acute renal tubular necrosis. There was no evidence of a primary or metastatic neoplasm in the larynx, pharynx, esophagus, lungs, gastrointestinal tract, adrenal glands or kidney. DISCUSSION
We believe that the clinical, radiologic, and pathologic findings-including the autopsy in this casesupport the diagnosis of a primary intraosseous squamous cell carcinoma of the mandible. The presence of the 0.6 cm ulcerated defect on the lingual alveolar mucosa (noted on gross examination of the specimen) is the only-and we consider unhkelyfactor that might cast a slight measure of doubt on this interpretation. The patient was carefully examined by three competent clinicians at the first presentation and seven days later, at the time of the biopsy.
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Fig. 4. A, Photomicrograph of cross section of mandible in area of right canine. The gingiva and periodontal ligament around the tooth appear normal, and a small amount of alveolar bone is present. In the deeper portions of the specimen, the bone has been completely replaced by massesof well-differentiated squamous cell carcinoma (Original magnification, X4.) B, Photomicrograph showing typical area of well-differentiated, keratinizing squamous cell carcinoma, which has destroyed most of right side of mandible. The tumor is associated with an intense chronic inflammatory reaction. (Original magnification, x90.)
None of the examiners noted any evidence of mucosal ulceration or any suggestion of a primary mucosal mass. It is likely that this mucosal defect developed sometime during the 2-week interval
between the time of the extraoral biopsy and the mandibulectomy and was caused by penetration of the underlying tumor into the overlying normal mucosa. This is supported by microscopic study at
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5. Photomicrograph at peripheral margin of tumor. The labial cortical bone has been completely destroyed, but the tumor has not penetrated through the surrounding fibrous tissue and has not invaded the nodule of minor salivary gland tissue on the right side of the photograph. (Original magnification, x90.)
Fig.
Fig. 6. Photomicrograph showing benign-appearing epithelial lining of cavity. There are foci of basal dysplasia with areas of squamous cell carcinoma appearing to originate from the lining epithelium. (Original magnification, X90.)
the edge of the defect. In addition, it is most unlikely that a very low-grade squamous cell carcinoma (less than 0.6 cm in diameter) arising on the alveolar mucosa could invade and totally destroy the entire right body of the mandible without manifesting as a large mucosal mass. Whether or not this tumor originated in a pre-existing dental cyst, however, remains a moot point. A cross section of the gross
specimen in the molar area revealed a small central cystic defect that (on microscopic examination) showed a benign-appearing, stratified squamous epithelial lining, with multiple foci of squamous cell carcinoma apparently arising from the basal layer. Cross sections of the mandible extending to the canine area, while not grossly showing a central cystic defect, contained (as seen microscopically)
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Fig. 7. Photomicrograph through margin of mucosal defect on lingual alveolar mucosa shown in Fig. 2, B. Normal-appearing alveolar mucosa, which invaginates into the depressed defect, is shown on the left side of the picture. The defect area on the right side of the picture shows well-differentiated squamous cell carcinoma extending to the surface. (Original magnification, X38.)
long strands of benign-appearing, stratified squamous epithelium, suggestive of a proliferating cyst lining intermingled with typical squamous cell carcinoma. It might be argued that this cavity defect only represented cystic degeneration in a squamous cell carcinoma rather than a pre-existing cyst. However, the very benign-appearing epithelial lining throughout a considerable portion of the cavity strongly indicates that a benign cyst was originally present. If a benign cyst was present, its classification also remains speculative. Unfortunately, no detailed dental history was obtained from the patient before his death. The circumstances related to the date and reasons for the loss of the first premolar tooth are unknown. It is possible that this tooth was nonvital and that the cyst may have represented a residual odontogenic cyst. The teeth that were present in the gross specimen contained several relatively shallow amalgam restorations. Most of the teeth were included in microscopic cross sections of the mandible. Although pulpal histology was less than optimal (due to fixation artifact), none of the pulps appeared to be necrotic and there was no evidence that the cyst was of the radicular type. Many authorities in the United States believe that some primordial cysts are not histologically odontogenic keratocysts and this type of cyst may have been present and given rise to the tumor.16 Although primary intraosseous carcinoma of the jaws is unquestionably very uncommon, we suspect it
may not be quite as rare as the literature indicates. One of us (C.A.W.) saw three additional cases (during his 25-year tenure at Emory University) and has reviewed consultation material on at least five more cases. None of these has been reported. Several additional references were found in the German literature, although the individual cases were not documented in great detail. Kreidler and coworkers’7 reported two cases associated with dentigerous cysts in a series of 758 odontogenic cysts seen between 1980 and 1984. Olten and colleagues’* reported five cases of carcinoma, with presumed origin in cysts or follicles of unerupted teeth, seen over a IO-year period at the University Dental Clinic, Freiberg, West Germany. The majority of PIOSCs appear to arise from the epithelial lining of pre-existing odontogenic cysts. Of the 36 cases of intraosseous squamous cell carcinoma accepted by Eversole and coauthors,4 27 (75%) appeared to originate in odontogenic cysts. Our review of the English-language literature subsequent to this article revealed 13 additional cases that demonstrated convincing evidence of origin in the cyst. Although carcinomas have been reported to arise in several types of odontogenic cysts, approximately 55% of reported cases ahve been associated with residual cysts. Many of these patients were elderly and the cysts had presumably been present for many years. Browne and Goughi9 suggested that keratin metaplasia, followed by epithelial hyperpla-
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sia and development of epithelial dysplasia of cyst linings, were the significant sequential events in development of carcinoma in dental cysts. They also suggested that cyst linings that reveal keratinization were at greater risk for development of carcinoma. In the cases reviewed by Eversole and coworkers, 15% of the cysts associated with carcinoma showed a keratinized lining, although none of them were considered to be odontogenic keratocysts. While a number of the more recently reported cases contained convincing photomicrographs showing epithelial dysplasia and carcinoma in situ with transition to squamous cell carcinoma, we were not impressed with evidence of hyperkeratotic changes of the benign cystic areas in any of the published photomicrographs or pathologic descriptions. Although odontogenic keratocysts are considered to have a more aggressive biologic potential than other types of odontogenic cysts,20 we are aware of only two reported cases that show convincing origin of a PIOSC in a keratocyst. lo,I4 Pain and swelling are the most common symptoms associated with PIOSC of the jaws and are noted in a majority of cases. Review of published cases indicates that in a substantial number of instances, the clinician had no suspicion that the intrabony lesion represented a malignant condition and the initial treatment of 8 of the 15 more recently reported cases consisted of enucleation of a presumed cyst. In most instances, the diagnosis of carcinoma was apparently quite unsuspected and was made only after pathology examination. Subsequent treatment in most of these cases consisted of en bloc excision or radical resection of the involved bone. The prognosis of PIOSC appears surprisingly good, although long-term follow-up information is notably lacking in most reports. A 53% two-year survival in the 36 cases in one review was noted. In the 15 cases reported since 1974, eight of the patients (53%) were reported to be alive and well from two to six years after the last treatment. Two additional patients were alive and well at 12 and 18 months, respectively. Two patients have died of other causes and only two had died of tumor. Follow-up information on one patient was not given. Local recurrence appears to be a major problem in patients not subjected to primary radical excision. This occurred in eight of the 15 cases and was treated by excision or radiation therapy. None of the recently reported patients was noted to have regional metastasis at the time of initial diagnosis, and metastasis to the regional lymph nodes was reported to have subsequently developed in only one patient. Whether or not carcinomas arising in odontogenic
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cysts (Type I) have a different prognosis than those arising de novo (Type 3) cannot be determined at this time. We have the distinct impression that the majority of carcinomas associated with cysts are relatively low-grade, keratinizing lesions that may portend better prognosis. By contrast, 8 of the 12 de novo lesions (Type 3) reviewed by Elzay2 were nonkeratinizing (less-differentiated) lesions. The one example of this type published since 1982 was also histologically a nonkeratinizing tumor.” The patients with de novo intraosseous carcinoma reviewed by Elzay2 demonstrated a 40% two-year survival. It is of interest that 66% of these patients had clinical and/or histologic evidence of regional metastasis, either initially or during the course of their disease. By contrast, only one of the 14 more recently reported cases of intraosseous carcinoma associated with cysts demonstrated regional spread.j3 This patient had a poorly differentiated, nonkeratinizing carcinoma, and died nine months later with uncontrolled neck disease. Reporting of additional well-documented examples of PIOC should eventually yield better information on the management and prognosis of these uncommon neoplasms. REFERENCES 1. Pindborg JJ, Kramer IRH. Histologic typing of odontogenic tumors, cysts, and allied lesion. Geneva: World Health Organization, 1971. 2. Elzay RP. Primary intraosseous carcinoma of the jaws. ORAL SURG ORAL MED ORAL PATHOL 1982;54:299-303. 3. Slootweg PJ, Miiller H: Malignant amelobiastoma or ameloblastic carcinoma. ORAL SURG ORAL MED ORAL PATHOL 1984;57:168-76. 4. Eversole LR, Sabes WR, Rovin S. Aggressive growth and neoplastic potential of odontogenic cysts. Cancer 1975; 35:270-82. 5. Falkmer S, Herberts G, Olven S. Carcinoma arising in odontogenic cysts of the jaw: survey and case report. Stand J Dent Res 1957;65:220-31. 6. Gardner AF. The odontogenic cyst as a potential carcinoma: a clinicopathologic appraisal. J Am Dent Assoc 1969;78:74655. I. Martinelli C, Melhado RM, Callestini EA. Squamous cell carcinoma in a residual mandibular cyst. ORAL SURG ORAL MED ORAL PATHOL 1977;44:274-8. 8. Baker RD. Onofrio Ed. Corio RL. Crawford BE. Terrv BC. Squamous’cell carcinoma arising in a lateral periodontai cyst. ORAL
SURG ORAL
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1979;47:495-9.
9. Enriquez RE, Ciola B, Bahn SL: Verrucous carcinoma arising in an odontogenic cyst. ORAL SURG ORAL MED ORAL PATHOL 1980;49:151-6. 10. Areen RG, McClatchey KD, Baker HL. Squamous cell carcinoma developing in an odontogenic keratocyst. Arch Otolaryngol Head Neck Surg 1981;107:568-9. 11. Nithianada S. Squamous cell carcinoma arising in the lining of an adontogenic cyst. Brit J Oral Surg 1983;21:56-62. 12. Norris LU, Baghaei-Rad M, Maloney PL, Simpson G, Guinta J. Bilateral maxillary squamous odontogenic tumors and malignant transformation of a mandibular radiolucent lesion. J Oral Maxillofac Surg 1984;42:827-34. 13. Pearcey RG. Squamous cell carcinoma arising in dental cysts. Clin Radio1 1985;36:387-8.
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14. Van der Waal I, Rauhamaa R, Van der Kwast WAM, Snow GB. Squamous cell carcinoma arising in the lining of odontogenic cysts: report of 5 cases. Int J Oral Surg 1985; 14: I 4052. 15. Lukinmaa PL, Heitanen J, Oikarinen VJ, Calonius PEB, Piirto M. Primary intraosseous carcinoma involving the maxilla. Brit Oral Surg 1985;23:450-5. 16. Brannon RB. The odontogenic keratocyst: A clinicopathologic study of 312 cases. Part I. Clinical features. ORAL SURC ORAL
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17. Kreidler J, Haase S, Kemp W: Karzinogenese in kieferzysten. Dts,ch Zahnarzti Z I985;40:548-50. 18. Olten JE, Joos U, Schilli W. Karzinomentstheung auf dem baden des zystenbildenden odontogenen epithels. Dtsch Zahnarztl Z 1985;40:544-7.
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19. Browne RM, Gough NG. Malignant change in the epithelial lining of odontogenic cysts. Cancer 1972;29: I 199-207. 20. Alfors E, Larson A, Sjogren S. The odontogenic kcratocyst-m a benign cystic tumor’! J Oral Maxillofac Surg 1984;42: 10-9.
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