Ghost cell odontogenic carcinoma of the left maxilla

Abstract

We report the case of a 25-year-old man with a maxillary ghost cell odontogenic carcinoma (GCOC). The patient presented to the maxillofacial and head and neck surgery clinic with a growing lump in the left maxilla. Initial workup with CT revealed a cystic lesion in the left upper jaw with associated bone erosion and an enhancing soft-tissue component. Enucleation showed a GCOC associated with a calcifying odontogenic cyst. After the diagnosis was obtained, the patient underwent widening of the first surgical resection. GCOCs are rare odontogenic neoplasms with unspecific clinical and imaging presentation, whose definitive characterisation is based on pathology. Current treatment approaches mainly involve surgical excision, but the prognosis is highly unpredictable due to intertumoral heterogeneity. As tumour recurrences occur in 73% of cases, radical surgery with negative margins is highly recommended. Therefore, it is essential to recognise this entity to offer patients adequate management.

Background

Odontogenic tumours are rare neoplasms that constitute <1% of the oral tumours.¹ They derive from odontogenic cells and its remnants and are mostly benign, although some tumours may present with aggressive growth and recurrence.¹ Odontogenic ghost cell lesions (OGCLs) are characterised by ghost cells’ presence, based on their microscopic features.² They comprise calcifying odontogenic cysts (COCs), dentinogenic ghost cell tumours (DGCTs) and ghost cell odontogenic carcinomas (GCOCs).^{1 3}

GCOCs show a variable growth pattern that ranges from a slow-growing tumour to a highly infiltrative tumour, demanding adequate surgical resection and surveillance given its uncertain prognosis.

Case presentation

A 25-year-old man presented to the head and neck surgery clinic because of a painless gingival swelling for the past 3 months. Clinical examination revealed a hard lump on the anterior left upper quadrant. No gingival ulceration nor teeth mobility were present.

The patient denied other relevant accompanying symptoms, such as nasal obstruction or nose bleeding. A full ear, nose and throat (ENT) examination was unremarkable except for a slight bulge in the left nasal fossa floor with no associated mucosal changes. Laboratory tests were unremarkable, and no relevant personal or family medical history was obtained. Lesion resection was performed following CT.

Investigations

A precontrast-enhanced and postcontrast-enhanced multidetector CT of the maxilla showed an expansile, homogeneous, unilocular mass in the anterior aspect of the left maxilla, measuring 27×28×36 mm in longitudinal, anteroposterior and transverse axes, respectively. The lesion involved the premaxilla and premolar region up to tooth 25, destroying the lateral border of the left incisive foramen and displacing the roots of teeth 22 and 23 (figures 1 and 2). There was additional peripheral bone erosion of the left nasal fossa floor, the anteromedial wall of the left maxillary sinus and the anterior margin of the left maxilla. There was also slight radicular reabsorption of teeth 22 and 23. The tumour had low attenuation coefficients and presented moderate rim enhancement with a solidly enhancing component adjacent to the alveolar process of the maxilla. In the inferior aspect of the mass, there was a 4 mm calcified focus. There were no signs of perineural spread along the course of the palatine nerves or the left maxillary nerve (V2), no cervical lymphadenopathy and no other relevant imaging findings were noted.

Figure 1.

(A, B) Panoramic reconstructions from a maxillary CT depict an expansile osteolytic lesion in the left upper jaw (second quadrant) extending from the incisor to premolar region (teeth 21–25). Note the displacement and subtle erosion of the adjacent roots (dotted arrows) and the presence of small calcified foci that may represent calcified tumour matrix or fragments of the alveolar bone inside the lesion (solid arrow).

Figure 2.

CT: axial plain (A, B, C, D) and axial (E, F), coronal (G) and sagittal (H) postcontrast images in soft-tissue windows and axial bone windows (I, J, K, L) demonstrate a well-defined, expansile, unilocular cystic lesion located at the anterior aspect of the left maxilla causing smooth remodelling of the adjacent bone and large areas of bone dehiscence (arrows in B and C). Also note the bone erosion of the incisor foramen (dotted arrows in J and K), anteromedial wall of the maxillary sinus (arrows in L), hard palate (arrow in H) and floor of the nasal cavity (dotted arrows in G and H) where the lesion comes in close contact with the inferior turbinate. The tumour is homogeneously hypodense on plain CT images and, after contrast administration, shows a thin enhancing rim and a solidly enhancing component on its inferior aspect close to the alveolar process (arrows in E and F).

Tumour enucleation was performed, and the pathology diagnosis revealed a ghost cell calcifying odontogenic carcinoma arising from a COC. The lesion was featured by a papillary-like proliferation of epithelial cells growing from the cyst wall and infiltrating the adjacent connective tissue, containing focal areas of ghost cells (figure 3). Iatrogenic rupture of the cyst wall was noted. There was no evidence of lymphovascular or perineural invasion. The lesion was totally excised with the closest margin of 0.4 mm.

Figure 3.

Pathology slices of the surgical specimen stained with H&E (A) low magnification (20×), shows to advantage the empty pre-existing calcifying odontogenic cyst, lined with squamous epithelium with no atypia (asterixis) and in the upper left region of the slide the hypercellular, malignant component of the tumour (black arrows). Also note the iatrogenic rupture of the cyst wall (dotted arrow). (B) On higher magnification (100×) the benign odontogenic cyst is seen in the upper part of the slide and a proliferation of malignant epithelial cells forming sheets and pseudopapillae are seen below immersed in a hyalinised stroma. The cells are uniform, basaloid with round hyperchromatic nuclei and frequent mitoses. (C) Higher magnification (400×) shows clusters of cells with abrupt keratinisation and empty central nuclear spaces (ghost cells) in the inset.

Differential diagnosis

Cystic lesions of the jaws are mostly benign, with a wide range of differential diagnoses. Clinical and imaging features are usually unspecific and, similarly to other bone lesions, radiology–pathology correlation offers the best definitive diagnosis. This is crucial to define further patient’s management which may range from simple enucleation, complete resection with long-term follow-up or major jaw resection in the case of a locally aggressive or malignant lesion. Clinically, rapid growth, pain, gingival ulceration and nerve dysfunction portray an aggressive behaviour. Radiographically, teeth loosening, root resorption, the presence of solidly enhancing components, aggressive patterns of bone destruction and invasion of adjacent structures also typify a rapidly growing lesion.¹ Additional imaging features, helpful in limiting the list of differentials, include cyst morphology (unilocular or multilocular), presence of mineralised components (calcifications, cement, chondroid or osteoid matrix) and relationship with adjacent teeth.

In our case, smooth expansion and remodelling of adjacent bone suggested a slow-growing lesion. In contrast, displacement and resorption of adjacent teeth roots and bone destruction elements (erosion of the incisor canal and hard palate) associated with a short clinical course of 3 months before presentation indicated an aggressive behaviour. Together, these imaging features suggested an aggressive transformation of a benign slow-growing lesion. As these findings were not initially recognised, the patient underwent tumour enucleation at a different institution and required more extensive surgery to widen the surgical margins.

Cystic lesions of the jaws with solidly enhancing components include ameloblastoma, odontogenic keratocyst (OKC), odontogenic myxoma, squamous odontogenic tumour (SOT), adenomatoid odontogenic tumour (AOT), aneurysmal bone cyst (ABC) and giant cell tumour (GCT).^{1 4}

Both OKC and ameloblastoma have an incidence peak between the second and fourth decades and are more common in the mandible. OKCs tend to be unilocular, grow along the mandibular rami axis, and show well-corticated scalloped margins producing little bone expansion. Contrast enhancement is variable, from linear and peripheral to solid papillary intracystic projections.^{1 4–7} Ameloblastomas span a wide range of biologic aggressiveness. They are most often benign, but malignant transformation with locally aggressive and metastatic behaviour can occur. They tend to present as a painless, slow-growing jaw swelling, more commonly in the molar region (81%). On imaging, an expansile, multiloculated, mixed solid and cystic appearance with well-corticated borders is typical. However, in the maxilla, they can be unilocular and show contrast-enhancing soft-tissue components projecting into the cystic cavity.1 4–6 8

Odontogenic myxomas (OMs) and SOTs are rare, benign odontogenic lesions with an incidence peak between the second and third decades presenting with painless jaw swelling. OMs are expansile, can be locally invasive, unilocular or multilocular and, when present, internal septations may be thin to coarse and straight to curvilinear. The presence of variable contrast-enhancing soft-tissue components makes them indistinguishable from ameloblastoma.^{1 4 9} SOTs are periodontal lesions that present as a unilocular radiolucency typically between the roots of adjacent teeth, equally prevalent in the maxilla and the mandible. AOTs are more prevalent in the maxilla and affect mainly adolescents and young adults with 90% of cases found before 30 years of age. Commonly associated with unerupted canines they are radiologically indistinguishable from a dentigerous cyst.¹⁰ Both SOTs and AOTs can show internal calcifications, enucleation is the treatment of choice and recurrences are exceedingly rare.¹

ABCs primarily affect the mandible of children and adolescents, with 80% of cases diagnosed before age 20, and up to a third are secondary to an underlying lesion. This lesion’s hallmarks include the clinical presentation as a painful jaw swelling, absence of an epithelial lining on pathology, and the presence of fluid-fluid levels on imaging, best depicted on MRI.¹ ABCs are composed of blood-filled spaces, separated by connective tissue, containing bone trabeculae, osteoid and osteoclast giant cells.¹ On imaging, they are expansile, unilocular or multilocular lesions with sclerotic margins and ill-defined internal septa. Unilocular variants can be quite expansile and lead to cortical thinning and dehiscence.⁵

Giant cell reparative granuloma or central GCT affects the anterior segment of the jaws in 70% of cases. Radiological hallmarks include the multilocular bubbly appearance with thin internal septa and the presence of a spontaneously hyperdense soft tissue component reflecting the presence of blood and hemosiderin-laden giant cells.¹¹ Brown tumours, secondary to hyperparathyroidism, should be ruled out.^{4 11} Histiocytosis (in children) and plasmacytoma/multiple myeloma (in adults) should also be considered in the differential of an osteolytic lesion of the jaws with a spontaneously hyperdense, contrast-enhancing soft tissue mass.

All the above-mentioned lesions can lead to cortical bone dehiscence, extension into adjacent soft tissues and erosion and displacement of adjacent teeth roots. In our case, a small mineralised component was seen at the inferior aspect of the lesion, which could represent a bone fragment detached from the alveolar bone or mineralised matrix. The latter suggests a different set of odontogenic lesions, including calcifying or cemento-ossifying tumours. The differential diagnosis with chondroid and/or osteoid producing tumours (chondroblastoma, chondrosarcoma, osteoblastoma, ossifying fibroma and osteosarcoma) requires the accurate recognition of chondroid and osteoid matrix, which is not always easy.

Calcifying odontogenic tumours of the jaws are rare and include the calcifying epithelial odontogenic tumour (CEOT) and the COC. The 2017 WHO classification categorised the former under benign odontogenic tumours of epithelial origin and the later as a mixed odontogenic tumour.¹ The CEOT, formerly known as Pindborg tumour, has its highest prevalence between the third and fifth decades and is much more common in the posterior mandible. The hallmark of this benign slow-growing tumour is the presence of focal areas of calcification, providing a mixed lytic-sclerotic pattern. On pathology, it is composed of sheets of epithelioid cells and amorphous, amyloid-like material which stains positive with Congo red and harbours dystrophic calcifications. Treatment is by conservative surgical resection and recurrences are rare.⁴

The COC is the most benign lesion of the spectrum of ghost cell odontogenic tumours which also include the DGCT and the GCOC. It is considered a developmental cyst, comprises less than 1% of odontogenic cysts and is most often located in the anterior jaws at the incisor-cuspid area. On imaging, they present as a well-defined unilocular radiolucency, 50% show calcification and one-third associates with an unerupted tooth. Root displacement and resorption can occur. COCs are lined by ameloblastoma-like epithelium and can contain dysplastic dentin. Their pathological hallmark is the presence of focal ghost cells which may calcify. These lesions can be treated by enucleation as they rarely recur.^{4 5}

Although benign, DGCTs tend to have more aggressive behaviour and, therefore, wide local excision is recommended, particularly for those with ill-defined borders. Although the recurrence rate remains low, malignant transformation has been documented.³ Radiographically, these tumours tend to show more significant contrast-enhancing soft-tissue components than COCs but are otherwise indistinguishable. Pathology shows proliferation of sheets and islands of ameloblastoma-like odontogenic epithelium, the presence of dentine or osteo-dentine-like material and ghost cells in the basal layer extending into the adjacent connective tissue, with variable amounts of calcification.¹

In the most aggressive end of the spectrum is the GCOC, characterised by rapid growth and ill-defined borders featuring an infiltrating growth. Pathology discloses an admixture of malignant epithelial cells featured by pleomorphism, hyperchromatism, mitosis and necrosis, ghost cell keratinisation and dentinoid formation. These malignant tumours may arise de novo or result from the malignant transformation of a COC or a DGCT.¹ In our case, imaging and pathology were both consistent with malignant transformation of a COC. The former showing bone expansion and smooth bone remodelling together with areas of bone destruction and root resorption and the later, depicting a papillary-like proliferation of malignant epithelial cells invading the adjacent connective tissue, growing from the wall of a COC and containing ghost cells.

Treatment

Based on the features of tumour aggressiveness and the pathology diagnosis of a malignancy resected with an insufficient margin (<1 mm), the multidisciplinary head and neck surgery team decided to widen the surgical margins, which the patient accepted. A partially maxillectomy was performed at our institution with resection of the alveolar process of the incisor region, the inferior turbinate and a fragment of the palate showing no evidence of residual tumour on pathology. No further treatment was offered at this time.

Outcome and follow-up

Unfortunately, after the second surgery, the patient developed an oroantral fistula in the left upper quadrant (figure 4) fixed by a vestibule-palatine flap during a third reconstructive intervention. Since the first surgical procedure, the patient reports haemifacial pain and is currently medicated with carbamazepine and gabapentin for neuropathic pain with some symptom relief. Imaging follow-up with CT and MRI 2 years after the first surgery showed no local relapse or cervical lymphadenopathy.

Figure 4.

Follow-up CT: coronal image in bone window shows the postsurgical oroantral fistula (arrow), with regular borders and no signs of persistent tumour.

Discussion

Odontogenic cysts are quite common in the general population, and the great majority are benign. Nevertheless, clinicians should be familiar with the clinical and imaging features that may portray a more aggressive lesion with a less favourable outcome if not appropriately treated. Challenging odontogenic lesions, prone to local recurrences, a destructive course and with the potential for malignant transformation include ameloblastoma, CEOT, AOT, SOT and COC.⁴ Being familiar with these entities facilitates their correct diagnosis, adequate treatment and follow-up. In the most recent WHO classification of odontogenic lesions from 2017, odontogenic ghost cell tumours were placed under the mixed (epithelial–mesenchymal) group.¹ Whereas OGCLs feature the presence of ghost cells, these cells may also be present in other odontogenic and non-odontogenic lesions such as ameloblastoma, odontoma, AOT, ameloblastic fibroma, pilomatrixomas and craniopharyngiomas.¹² The histogenesis of these cells has been a matter of debate. Ghost cells are swollen epithelial cells with eosinophilic cytoplasm and lacking a nucleus accounting for their empty/‘ghost’ appearance on H&E stains. They are thought to result from aberrant keratinisation/dyskeratinisation secondary to necrobiosis of the odontogenic epithelium, resistant to resorption, tend to calcify and induce a foreign body reaction in the adjacent connective tissue.^12–14 In OGCLs, these cells are seen in higher numbers in the basal epithelium layer and are associated with an absent basement membrane with islands of ghost cells seen in the submucosal connective tissue. Other critical diagnostic features include the proliferation of odontogenic epithelium and the presence of dysplastic dentin/dentinoid material.¹²

OGCLs encompass a spectrum of lesions with increasing biological aggressiveness: COC, DGCT and, the malignant counterpart, GCOC. Interestingly, these lesions’ incidence peak advances with age: second decade for COC, fourth decade for DGCT and the fifth decade for GCOC.³ As opposed to most odontogenic lesions that are more prevalent in the molar region of the jaws, OGCLs have a predilection for the anterior, incisor region, as our case illustrates. Although COC and DGCT are more common in the mandible, GCOC is more common in the maxilla.³ COCs are usually asymptomatic and are found incidentally during dental investigations. They can be treated by simple enucleation as, according to the available literature, recurrence is rare (4% over a median follow-up of 42 months).³ DGCTs have a slight male predilection and the median time from symptom onset to diagnosis approximates 30 months. Complete surgical resection with a 5 mm free margin is advocated as these rare tumours may recur and undergo malignant transformation.³

GCOCs are extremely rare, accounting for less than 3% of OGCLs.^{1 15} This entity is scarcely found in the literature, with approximately 44 cases published until 2017, more than half reported in the Asian population.^{1 3} So far, only one systematic review, few case series and mostly isolated cases were reported.^{3 15} The peak incidence of GCOCs is between the fifth and seventh decades, and they are four times more frequent in men.¹ GCOCs affect the maxilla twice as often when compared with the mandible. When in the mandible, most involve the molar area.^{1 3} The origin of GCOCs can be attributed to two main pathogenic mechanisms: de novo, with no previous associated lesions, or related to benign precursors such as DGCT or COC, as this present patient, comprising 40% of cases.^{1 2}

Histologically, GCOCs contain malignant and ghost cells. Malignant cells have high mitotic activity, nuclear atypia, cellular pleomorphism, necrosis, infiltrative growth pattern, and sometimes mineralised material with dentinoid formation.¹ The presence of ghost cells can be the key to the differential diagnosis with ameloblastic carcinoma.¹ GCOCs show a higher proliferative index and TP53 mutation (in 2/3 of the cases), compared with DGCT.¹ Genetic profiling of these tumours has shown substantial alterations of the Wnt/β-catenin/TNF pathway.¹³

The primary treatment of GCOC is wide surgical resection with at least 5 mm free margins, which is successful in two-thirds of patients.¹ The most frequent procedures include marginal, segmental or partial resection or total maxillectomy, depending on the size of the lesions.³ Only a minority of patients have received adjuvant radiotherapy, and its benefits remain unclear.^{15 16} Aggressive multimodality treatment and immunotherapy have also been advocated for patients with lymph node metastasis.¹⁶

The prognosis for GCOC is unpredictable due to the low number of reported cases and the wide range of features and aggressiveness. In a OGCL review including 25 patients with GCOCs, three died following local recurrence and two from distant metastases. The reported overall 5-year survival rate in this study was 73%.¹⁷ Therefore, it is important to keep reporting rare odontogenic diseases and follow these patients for long periods to support more consistent data and improve therapeutic interventions for these diseases.

Patient’s perspective.

My reaction to the diagnosis was drastic. I felt fear, anxiety and anger. Being only 25 years old I felt the world collapsing. I was not aware of the impact of this type of cancer and my main was concern was to become disfigured. Also, being such a rare tumour, I am not really sure what to expect and it is difficult to learn how to live with this uncertainty.

Learning points.

• Most odontogenic neoplasms are benign and surgically treated by enucleation.

• Rapid growth, pain, gingival ulceration and nerve dysfunction are worrisome clinical features.

• Radiologically, the presence of solidly enhancing components, bone erosion, teeth loosening and root resorption should raise the suspicion for an aggressive tumour.

• GCOC is a rare odontogenic malignancy most often seen in the maxilla.

• GCOC may occur de novo or from the malignant transformation of its benign counterparts (COC and DGCT).

• These aggressive lesions require wide surgical resection with free margins and long-term follow-up.