YOSHIDA, ONIZAWA, AND YUSA

J Oral Maxillofac Surg

54:647-651, 1996

647

Squamous Cell Carcinoma Arising in Association With an Orthokera tinized

Odon togenic Kera tocys t Report of a Case

HIROSHI YOSHIDA, DDS, PHD,* KOJIRO ONIZAWA, DDS, PtiD,t AND HIROSHI YUSA, DDS$

Squamous cell carcinoma arising in the epithelial lining of an odontogenic cyst is rare. Although the exact number of documented cases is difficult to deter- mine, Miiller and Waldron’ reported finding 81 cases documented in the world literature in 1991, and since then an additional 5 cases2-6 have been reported in the English literature. The carcinomas have occurred in several types of odontogenic cysts, but more than 50% have developed in inflammatory periapical or residual cysts? Although odontogenic keratocysts are consid- ered to have a more aggressive biologic potential than other types of odontogenic cysts,‘0-‘2 to our knowledge only six cases of carcinoma arising in odontogenic keratocysts have been reported.2.5,“-‘6 Of these six cases, only two developed in an orthokeratinized kera- tocyst? This report presents a third case of squamous cell carcinoma arising in association with an orthokera- tinized odontogenic keratocyst and a review of the literature.

Report of Case

A 39-year-old man was referred to the Division of Oral and Maxillofacial Surgery, University of Tsukuba Hospital, Japan, in April 1993 for treatment of a painful swelling in the right posterior mandible that had been present for 4 months. The patient had initially had root canal treatment

*Professor, Department of Oral and Maxillofacial Surgery, Insti- tute of Clinical Medicine, University of Tsukuba, Ibaraki-ken, Japan.

TAssistant Professor, Department of Oral and Maxillofacial Sur- gery, Institute of Clinical Medicine, University of Tsnkuba, Ibaraki- ken, Japan.

$Cbief Resident, Division of Oral and Maxillofacial Surgery, Uni- versity of Tsukuba Hospital, Ibaraki-ken, Japan.

Address correspondence and reprint requests to Dr Yoshida: be- partment of Oral and Maxillofacial Surgery, Institute of Clinical Medicine, University of Tsukuba, l-l-l Tennoudai Tsnkuba-shi, Ibaraki-ken, 30.5, Japan.

0 1996 American Association of Oral and Maxillofacial Surgeons

0278-2391/96/5405-0021$3.00/O

for the mandibular second molar and administration of anti- biotics by his dentist, but the symptoms persisted. The pa- tient’s medical history showed that he had smoked two packs of cigarettes per day for 1.5 years and used alcohol socially. There was no history of previous malignancy.

Physical examination showed a 4 x 4 X 2-cm extraoral bony expansion in the right posterior mandible that showed no evidence of inflammation and was not adherent to the skin. There was slight paresthesia in the right mental region. No lymphoadenopathy was discernible in the head and neck region.

Oral examination showed that the alveolar ridge posterior to the right mandibular first molar was expanded buccolin- gually and covered with intact, normal-appearing mucosa and that mucosa of the floor of mouth and the buccal region was also intact. The first molar was vital on pulp testing. Radiographs showed a well-demarcated radiolucency ex- tending from the distal of the first molar to the mandibular angle, with involvement of the inferior cortex (Fig 1). Com- puted tomography (CT) scans also showed an extensive, destructive bony lesion in the right posterior mandible, with resorptioh of the lingual cortex (Fig 2).

The second and third molars were removed, and an inci- sional biopsy was performed through the sockets. The lesion was surrounded by a thin capsule in which caseous material was found. Microscopic examination showed a thin orthoke- ratinized epithelial lining of uniform thickness without evi- dence of rete ridges. There was a palisading, cuboidal, hy- perchromatic basal cell layer and a thin, spinous cell layer exhibiting a direct transition from the basal cell layer. The subjacent stroma was partly infiltrated by lymphocytes and plasma cells (Fig 3). Accordingly, a diagnosis of orthokera- tinized odontogenic keratocyst was made.

One week after the biopsy, under general anesthesia, most of the lesion along with overlying mucosa, was enucleated by an intraoral approach. However, in the anterior aspect, the cyst wall was firmly adherent to the surrounding bone and could not be entirely removed. A very thin, smooth, lingual cortex was present with no perforation by the lesion. The neurovascular bundle was depressed inferiorly without adherence to the cyst wall. The defect was packed with a petroleum gauze dressing containing an antibiotic. Histo- logic examination of the specimen showed findings similar to those of the previous biopsy in most parts of the cyst wall. However, there was dysplastic transformation and loss of keratinization in the lining squamous epithelium of the

648 CARCINOMA ARISING IN KERATOCYST

FIGURE 1. Radiograph showing radiolucency extending from the distal of the first molar to the mandibular angle, with involvement in the inferior cortex (arrow).

anterior cyst wall. The subjacent stroma was infiltrated by lymphocytes, plasma cells, and some neutrophils (Fig 4). However, the finding that an orthokeratinized lining epithe- lium led into, or was contiguous with, the dysplastic epithe- lium was not demonstrated in the available microscopic sec- tions. A diagnosis of odontogenic cyst with dysplastic epithelium was made.

One and a half months after surgery, a rapidly growing,

FIGURE 2. CT scan showing an extensive osteolytic lesion with destruction of the lingual aspect of the posterior mandible.

FIGURE 3. Photomicrograph of the initial biopsy showing a cyst wall lined by thin orthokeratinized epithelium without rete ridge formation, a palisading, hyperchromatic, cuboidal basal cell layer, and a thin spinous cell layer (hematoxylin-eosin stain, original mag- nification X40).

soft, yellowish mass developed in the anterior part of the defect, and pain developed in the mandible, and paresthesia in the mental region persisted (Fig 5). An enlarged right submandibular lymph node was palpated. A biopsy of the mass showed squamous cell carcinoma infiltrated with in- flammatory cells (Fig 6). Scintigraphs showed an abnormal accumulation of gallium in the right mandible, but no other abnormalities were detected by systematic examination, chest and upper aerodigestive tract radiographs, or CT scans of the head and neck. Three weeks after the second biopsy, the patient underwent a hemimandibulectomy extending from the right lateral incisor region to the right condyle, along with a radical neck dissection, and was immediately reconstructed with a microvascular iliac bone graft. The gross specimen consisted of a segment of the right mandible and the cervical soft tissues, and the tumor was filling the bone marrow of the mandible (Fig 7). Histologic examina- tion showed that cancer cells with a conspicuous keratinizing

FIGURE! 4. Photomicrograph of the anterior cyst wall of the enu- cleated specimen showing dysplasia of the lining squamous epithe- lium with loss of keratinization (hematoxylin-eosin stain, original magnification X 100).

YOSHIDA, ONIZAWA, AND YUSA 649

FIGURE 5. Clinical appearance of the mass developing in the anterior part of defect (arrow).

tendency, and forming nests, was infiltrating into the adja- cent bone marrow, and partly destroying the mandibular bone. However, these cells did not penetrate through the cortex. All surgical margins were free of tumor, and the neurovascular bundle was not involved. None of the lymph nodes in the neck dissection specimen were positive for cancer. The patient’s postoperative course was uneventful. Two years, 4 months after definitive surgery, the patient showed no evidence of local recurrence, regional node involvement, or distant metastasis.

Discussion

The presence of a cyst and a contiguous carcinoma in the jaws is open to several interpretations. Ward and Cohen17 pointed out three possible explanations: 1) a preexisting cyst becomes secondarily involved in a car- cinoma of unrelated origin arising either from an adja- cent epithelial structure or as a metastasis from a distant primary tumor; 2) the lesion is a carcinoma from the

FIGURE 6. Photomicrograph of biopsy specimen of the mass, showing squamous cell carcinoma (hematoxylin-eosin stain, original magnification X 100).

FIGURE 7. Radiograph showing the presence of the lingual cortex of the resected specimen (arrow).

outset, a part of which has undergone cystic transforma- tion; or 3) the initial lesion is a cyst, and malignant change has subsequently taken place in the epithelial lining. The only incontrovertible proof that a carcinoma has arisen in an odontogenic cyst is the histologic dem- onstration of a transition of the cells lining the cyst from a benign epithelium to a carcinoma.‘8-20 In the current case, although resorption of the lingual cortex was delin- eated by CT scans, the intact oral mucosa and the pres- ence of the lingual cortex without perforation in the resected mandible ruled out the possibility of invasion by an adjacent primary carcinoma. The lack of evidence of a remote primary tumor on physical and radiologic examinations, and the subsequent clinical course, also ruled out metastasis from a distant primary tumor. Cys- tic transformation of a carcinoma was excluded because both the initial biopsy and most parts of the enucleated specimen showed a benign epithelial lining. The possi- bilities of malignant transformation of the epithelial lin- ing of a cyst or fusion of a cyst and intraosseous carci- noma arising de novo can be considered. Although it is difficult to determine whether the lesions involved transformation or juxtaposition, because a direct transi- tion from a benign epithelial lining to an invasive carci- noma was not histologically demonstrated, the former is suggested based on finding dysplasia in the anterior cyst wall of the enucleated specimen where a mass sub- sequently occurred.

Carcinomas have been reported to arise in several types of odontogenic cysts, but more than 50% of re- ported cases have developed in inflammatory periapi- cal or residual cysts.7-9 Although Browne and Gough*’ have suggested that keratin metaplasia in the cyst lin- ing is a significant event in the development of carci- noma in odontogenic cysts, keratinization in the epithe- lial lining of a cyst has been demonstrated in just 15% to 18% of reported cases.3S8 In the cases reviewed by

650 CARCINOMA ARISING IN KERATOCYST

Table 1. Reported Cases of Carcinoma Arising in Odontogenic Keratocyst

Author Year Age (YQ Sex Location symptom

Type of Lining

Epithelium Initial

Treatment Subsequent Treatment

Follow-up Duration From

Diagnosis

Areen et al”

Van der Waal et alI4

Siar & Ngli

MacLeod & Soames’h

Foley et al*

1981 60 M

1985 81 F

1987 40 M

1988 57 M

1991 25 M

Anterior maxilla

Entire mandible

Posterior maxilla

Posterior mandible

Posterior mandible

Present case

1992 56 M Entire mandible

1995 39 M Posterior mandible

Swelling

Not stated

Sinus Swelling Pain Swelling

Pain Swelling

Pain Swelling

Numbness Pain Swelling

Not stated Local resection

Not stated

OK

Enucleation

Enucleation

PK

Not stated

Hemimandibulectomy Neck dissection

Enucleation

OK Mandibulectomy Neck dissection

OK Enucleation

Maxillectomy Radiation Chemotherapy

Hemimandibulectomy

NOIE

I9 months AW

72 months AW

Not stated

Not stated

Mandibulectomy Neck dissection Radiation Chemotherapy

NOW

13 months DOD

24 months AW

Hemimandibulectomy 22 months AW Neck dissection

Abbreviations: OK, orthokeratinized; PK, parakeratinized; AW, alive and well; DOD, died of disease

Eversole et al,’ none of the cysts with keratinized lin- ings associated with carcinoma were considered to be odontogenic keratocysts. The presence of keratinized epithelium is not exclusively a property of the odonto- genie keratocyst, because other odontogenic cysts can produce keratin.22 Whether keratinized cysts are odon- togenic keratocysts, or merely represent keratin meta- plasia within other types of odontogenic cysts, should be considered in the differential diagnosis. Pindborg and Hansen,” in 1962, described the following histo- logic characteristics of odontogenic keratocysts: 1) the lining epithelium is usually very thin and uniform in thickness, with little or no evidence of rete ridges; 2) there is a well-defined basal cell layer, the component cells of which are cuboidal or columnar in shape and often arranged in a palisaded fashion; 3) there is a thin spinous cell layer, which often shows a direct transition from the basal cell layer; 4) the cells of the spinous cell layer frequently exhibit intracellular edema; 5) ke- ratinization is predominantly parakeratotic, but it may be orthokeratotic; 6) the keratin layer is often corru- gated; 7) the fibrous cyst wall is generally thin and usually not inflamed. In the current case, histologic examination of the initial biopsy showed findings con- sistent with an odontogenic keratocyst.

Carcinoma arising in association with an odonto- genie keratocyst is rare. To our knowledge, only seven such cases, including the current case, have been re- ported. *sJ~-‘~ The details of these cases are summarized in Table 1. The patients in more than half of the seven cases were older than 40 years of age, and most were men. The mandible was more commonly affected than the maxilla. Swelling and pain were the most common

symptoms. Except for two cases,5*‘6 radiographic ex- amination showed a well-defined, cystic, radiolucent lesion. Adherence of the cyst wall to the bony cavity, which has been reported during surgery in cases of other types of odontogenic cysts associated with carci- noma, 2425 was found only in our case. In most in- stances, the diagnosis of carcinoma was unsuspected and was made only after histologic examination. Al- though an orthokeratinized keratocyst has been clini- cally considered to be less aggressive than a parakera- tinized variant,‘5 three of the seven cases histologically showed an orthokeratinized lining epithelium. After definitive diagnosis, treatment in most cases consisted of radical resection and neck dissection. The prognosis was relatively good if the lesion was treated early, because the tumor appears to have a tendency to grow into the cystic cavity.‘6,24

Histologic examination of the enucleated specimen in the current case showed dysplasia without the appar- ent presence of squamous cell carcinoma in the anterior cyst wall. However, rapid progression into the oral cavity 1 and a half months .after the initial surgery suggested that undetected carcinoma had been present in the residual anterior cyst wall. This case illustrates the importance of adequate examination of all histo- logic sections of cysts and the necessity of careful follow-up after their removal.

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YOSHIDA, ONIZAWA, AND YUSA 651

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