Accepted Manuscript

Title: Unusual osteolytic lesion of the jaw

Author: Karine Duarte da Silva, Isadora Luana Flores, Adriana Etges, Ana
Carolina Uchoa Vasconcelos, Ricardo Alves Mesquita, Ana Paula Neutzling
Gomes, Sandra Beatriz Chaves Tarquinio

PII: S2212-4403(17)30985-9
DOI: http://dx.doi.org/doi: 10.1016/j.oooo.2017.06.123
Reference: OOOO 1802

To appear in: Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology

Received date: 23-2-2017

Revised date: 24-6-2017
Accepted date: 30-6-2017

Please cite this article as: Karine Duarte da Silva, Isadora Luana Flores, Adriana Etges, Ana
Carolina Uchoa Vasconcelos, Ricardo Alves Mesquita, Ana Paula Neutzling Gomes, Sandra
Beatriz Chaves Tarquinio, Unusual osteolytic lesion of the jaw, Oral Surgery, Oral Medicine,
Oral Pathology and Oral Radiology (2017), http://dx.doi.org/doi: 10.1016/j.oooo.2017.06.123.

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UNUSUAL OSTEOLYTIC LESION OF THE JAW

Karine Duarte da Silva, DDS, MSc1

Isadora Luana Flores, DDS, MSc, PhD2

Adriana Etges, DDS, MSc, PhD1

Ana Carolina Uchoa Vasconcelos, DDS, MSc, PhD1

Ricardo Alves Mesquita, DDS, MSc, PhD3

Ana Paula Neutzling Gomes, DDS, MSc, PhD1

Sandra Beatriz Chaves Tarquinio, DDS, MSc, PhD1

1
Oral Diagnosis Area, Semiology and Clinics Department, Federal University of

Pelotas, UFPel, Rio Grande do Sul, Brazil

2
Oral Pathology Area, Dentistry Department, Federal University of Juiz de Fora

Campus Governador Valadares, UFJF/GV, Minas Gerais, Brazil

3
Oral Pathology Area, Oral Pathology and Surgery Department, Federal

University of Minas Gerais, UFMG, Minas Gerais, Brazil

*Corresponding Author:

Sandra Beatriz Chaves Tarquinio

Federal University of Pelotas, School of Dentistry

Gonçalves Chaves Street, 457, ZIP Code 96015-560, Pelotas-RS, Brazil.

Business fax number: +55 53 32256741 (extension 162)

Home telephone: +55 53 81112894

Email adress: sbtarquinio@gmail.com

Page 1 of 18
This work was presented and awarded in the panel category of clinical cases in

the XXIII Congresso Brasileiro de Estomatologia e Patologia Oral/5th World

Congress of the International Academy of Oral Oncology (São Paulo, Brazil,

2015)

Conflict of Interests: None

Funding: This work was supported by the MCT/CNPq/MEC/CAPES/Brazil -

Casadinho/Procad [grant #552662/2011-9] and by a grant to K.D.S.

(scholarship) from the National Council for Scientific and Technological

Development (CNPq/Brazil).

Manuscript word count (to include body text and figure legends): 2714

Number of references: 25

Number of figures: 4

Page 2 of 18
Clinical presentation

An excisional biopsy specimen from a 79-year-old Caucasian man with a

chief complaint of a painful swelling in the posterior left mandible was sent to

the Center of Diagnosis of Oral Diseases at the Dentistry School, Federal

University of Pelotas, Brazil, in 2015. The patient was fully edentulous. The

color and texture of the oral mucosa were found to be normal by the surgeon.

No positive lymph nodes were noted on extraoral examination. Comorbidities

and evolution time of the lesion were unknown. The patient did not report a

habit of smoking or daily drinking of alcoholic beverages. Radiographically, an

ill-defined bilocular radiolucency was observed in the alveolar ridge, specifically

in the molar region near the ramus, with an irregular osteolytic aspect (Figure

1). The clinical diagnosis established by the surgeon was ossifying fibroma

(OF). Informed consent from the patient was obtained for publication of this

report.

Differential diagnosis

For a clinical presentation of painful swelling of the posterior mandible, a

number of differential diagnoses must be considered. In this case, malignant

entities were more likely, owing to the clinical-radiographic aspect of the lesion,

but certain benign but locally aggressive odontogenic tumors should also be

considered because of certain radiographic similarities. Ameloblastoma, a

tumor of epithelial origin that mainly affects the mandible, is one such benign

tumor. There is no difference in prevalence between the sexes, and the mean

age at diagnosis is 36 years.1,2 Radiographically, it presents as a lytic lesion

with scalloped margins and resorption of the tooth roots, with the appearance of

"soap bubbles" in the classic multilocular/solid type.1 This shares some

Page 3 of 18
similarity with our case. In contrast to our case, however, ameloblastoma is

generally painless, and, in most cases, found radiographically, although large

tumors can result in a painless swelling of the involved bone.2

Another possibility is ameloblastic fibroma (AF), which is a benign mixed

tumor that occurs preferentially in the mandible, especially its posterior region,

with a slight predilection for occurrence in men.3 Unlike our case, this lesion

normally presents as a painless lesion and is more common in young people.3

Additionally, AF is mainly associated with an impacted tooth.4 Radiographically,

it presents as an asymptomatic unilocular or multilocular radiolucency, with well-

defined borders in the majority of cases, frequently with a sclerotic rim.3 This

lesion usually does not lead to swelling and is often a radiographic finding;

however, in some cases, it can cause bone expansion.3 This feature, along with

the radiographic appearance, makes AF a possible differential diagnosis for the

presented case.

Odontogenic myxomas (OMs) can also have a radiographic appearance

similar to the one in our case, although they are frequently painless and most

commonly reported in women, especially between the second and fourth

decades of life.5 OMs normally occur in the posterior mandible and they present

as a locally aggressive growth with a classic honeycomb appearance on

radiographic examination.5,6 Normally, the borders are well-defined.6 This type

of tumor can lead to bone expansion.6 Although the location on the alveolar

ridge and the presence of pain are not exclusive to OMs, it should also be

considered as a differential diagnosis.

Malignant odontogenic tumors such as ameloblastic fibrosarcoma (AFS),

ameloblastic carcinoma (AC), odontogenic carcinosarcoma (OCS) and

Page 4 of 18
odontogenic clear cell carcinoma (OCCC) should also be listed as differential

diagnosis, as they share many similarities to our case.4,7,8 AFS is a rare

malignant tumor that occurs preferentially in the mandible, with no difference in

incidence by sex or age.9 Radiographically, the lesion causes bone destruction

and swelling with pain, similar to the present case.9 This tumor is histologically

characterized by a malignant mesenchymal component with pleomorphic

fibroblasts presenting hyperchromatic nuclei and atypical mitosis and an

epithelial component within the normal aspect.9,10

AC is another malignant odontogenic neoplasm that exhibits aggressive

behavior and shows clinically rapid growth, cortical perforation, and peripheral

extension.11 ACs typically have ill-defined margins radiographically,11 similar to

the radiographic findings in our case. Cytological malignant characteristics of

the epithelial component of ACs can be seen in primary tumors, recurrences of

an ameloblastoma, or metastatic lesions.11 The epithelial component contains

many common features of malignancy, such as cellular atypia, nuclear

pleomorphism, hyperchromatic nuclei, increased mitotic activity, and an

increased nuclei to cytoplasm ratio.12 The spindle cell variant of AC contains a

prominent population of malignant epithelial spindle cells arranged in streaming

fascicles in addition to the epithelial component.10,12 Whether this lesion

represents a unique entity or should be histologically grouped with other ACs is

unclear.10,12 “Spindle-cell ameloblastic carcinomas” or "biphasic ameloblastic

sarcomatoid carcinomas” should be distinguished from OCS.10

A jaw tumor displaying both a carcinomatous and malignant spindle cell

component can be an OCS.4,10 Radiographically, this extremely rare neoplasm

is quite similar to the present case, having a radiolucent aspect without defined

Page 5 of 18
borders and causing the destruction of the cortical plates.4,8,13-16 Owing to the

scarcity of reported cases in the literature, the clinical significance of OCS is

unclear, making it difficult to determine its prevalence with respect to age, sex,

or location, although the few reported cases have shown very aggressive

clinical behavior, frequent recurrence, and metastasis.4,8,13-16 Because there is

so little known about OCS, it was removed from the World Health Organization

classification of odontogenic neoplasms published in 20056; however, it was

relisted in the current edition.17

OCCC is a rare malignant odontogenic tumor that can appear

radiographically similar to the lesion in our case, as an osteolytic lesion with

irregular margins.7 This lesion normally occurs in adult women, leading to a

painless or painful slow-growing progressive swelling, especially in the posterior

mandible. Cortical perforation and soft tissue invasion may occur, and

recurrence and metastasis are common.7

Some non-odontogenic lesions, such as mucoepidermoid carcinoma,

osteosarcoma, and metastatic neoplasms, also need to be listed as differential

diagnosis. Mucoepidermoid carcinoma preferentially occurs in the parotid gland,

but can also occur in the minor salivary glands and jaw bones. When in an

intraosseous site, this lesion has female predilection, and occurs mostly in the

mandible.18,19 It sometimes presents with swelling and pain.18,19

Radiographically, mucoepidermoid carcinoma usually appears as a unilocular or

multilocular radiolucent lesion with sclerotic and well-defined margins.19

Normally, the cortical bone is preserved. However, cortical rupture and invasion

into the surrounding soft tissue do not exclude the possibility of this diagnosis.

These characteristics can also be found in other malignant tumors.6,19 For these

Page 6 of 18
reasons, central mucoepidermoid carcinoma may be considered in cases of

proliferative and osteolytic lesions in the oral cavity,19 similar to the lesion

presented in this report.

Osteosarcoma, the most common malignant jaw bone tumor with a bone

origin, arises from mesenchymal cells displaying osteoblastic differentiation and

producing malignant osteoid.20 In addition, it occurs principally in the mandible,

with no difference in incidence by sex or age.20,21 It clinically presents as a

painless or painful swelling with ulceration and paresthesia normally associated;

radiographically, bone destruction may be visible,21 similar to what we observed

in this case. Different from our case, radiopaque foci can be evident with the

evolution of the lesion, as well as expansion and perforation of the cortical

plates.20,21 A “sunburst” radiopaque pattern is also visible in some cases.20,21

Finally, metastatic neoplasms can be another possible diagnosis for this

case. Metastases from prostate, lung, thyroid, and kidney cancers may occur in

the jawbones. They principally present as a rapidly progressing mass located in

the mandible, accompanied by pain and paraesthesia.22 Radiographically,

jawbone metastases are non-specific, but can indicate malignancy. They have a

lytic radiolucent aspect with ill-defined margins and occasionally a “moth-eaten”

appearance.22

Diagnosis

The histopathological findings from excisional biopsy revealed a distinct

biphasic neoplasm with well-demarcated islands and cords of invasive

malignant epithelial cells embedded in the pleomorphic and hyperchromatic

hypercellular mesenchymal cells. The epithelial neoplastic cells were polygonal

or ovoid, with hyperchromatic or vesiculous nuclei, bordered by cuboidal or low

Page 7 of 18
columnar cells with inverted polarization. Some mitotic figures were also noted

(Figure 2). The lesion displayed prominent immunoreactivity to p53 in both the

mesenchymal and odontogenic epithelial components. Some cells of the nests

and epithelial islands and some cells in the mesenchymal component were

positive for Ki-67. The total proliferative index, expressed as the percentage of

Ki-67-positive cells, was 10.1%. Moreover, the odontogenic epithelium was

highly positive for multi-cytokeratin (AE1/AE3 antibody) and cytokeratins 14 and

19, and the mesenchymal counterpart was strongly positive for vimentin (Figure

3). The final diagnosis was OCS.

Management

According to the surgeon, the patient did not present with malignancy in

any other sites. The tumor was stage T1N0M0. Four months after the initial

curettage, a relapse of the tumor was observed. Cone beam computed

tomography showed a hypodense irregular image smaller than the previous

lesion (Figure 4). A marginal resection was performed, and histopathological

analysis revealed the same characteristics of the initial OCS, probably denoting

a tumor recurrence. The patient is currently under follow-up by the surgeon, and

no evidence of recurrence or metastasis has been observed 15 months after

the last surgery (Figure 4).

Discussion

To the best of our knowledge, the present case is the seventh case of

OCS described in the English literature.4,8,13-16 OCS is an extremely rare

odontogenic tumor with both epithelial and ectomesenchymal components

showing cytological aspects of malignancy.8 It occurs commonly in the

mandible, with no sex or age predilection, and it is normally associated with pre-

Page 8 of 18
existing lesions, such as ameloblastoma, AF, and AFS.4,8,14-16 Interestingly,

OCS may arise de novo with no pre-existing disease, after several surgeries or

radiation therapy.4

Considering the clinical features, an isolated painful swelling, as

observed in this case, could indicate the development of a malignant tumor.

Generally, malignancies in the jaws may be accompanied by a variety of clinical

symptoms, the most common being pain, swelling, facial edema, bleeding,

increasing tooth mobility and loosening, periodontal involvement, and

trismus.6,9,11,21

OCS displays aggressive clinical behavior, with frequent recurrence and

metastasis.4,15 Radiographically, OCS has a radiolucent appearance with no

defined borders, as well as disruption of the cortical plates in most cases.4,8,13-16

Some cases of OCS can easily be misdiagnosed as ameloblastomas by

inexperienced pathologists, owing to a failure in identifying the malignant

mesenchymal component.

In the recently published 4th edition of the World Health Organization’s

Classification of Head and Neck Tumors, OCS was again included, after its

previous exclusion. The classification of OCS as a true mixed malignant

odontogenic neoplasm reveals that both the epithelial and mesenchymal

components have malignant features.8,10,15,17

The epithelial component of OCS shows cords, nests, and islands of

neoplastic cells presenting with enlarged and hyperchromatic nuclei.

Ameloblastic architecture, with epithelial elements bordered by cuboidal or

columnar cells with inverted polarization and inner stellate reticulum, can be

Page 9 of 18
observed in some areas. In addition, the tumor can show atypical mitosis and

coarse chromatin.15,18

The sarcomatous component of OCS shows hypercellularity and

pleomorphism, with cells displaying enlarged and hyperchromatic nuclei, and

some are binucleated.15,18 Some reported cases fail to reveal the malignancy of

the mesenchymal component.

These characteristics are important in defining the tumor as a biphasic

malignant odontogenic neoplasm. Additionally, both the epithelial and

sarcomatous components grow simultaneously and at similar rates,8,10 and the

lesion does not shows an epithelial-mesenchymal transition to spindle cell

carcinoma.17

Immunohistochemistry is a helpful tool that can be applied in confirming a

diagnosis. In an OCS case, Kim et al.4 observed positivity for cytokeratins and

anti cytokeratin CAM 5.2 in the carcinomatous component, and vimentin in the

sarcomatous component. Similarly, we observed positivity for cytokeratins 14

and 19, as well as multi-cytokeratin (AE1/AE3 antibody). We also observed

remarkable immunoreactivity for p53 in the epithelial and mesenchymal

components, and for Ki-67 in some cells from both components. The labeling of

p53 in both the epithelial and mesenchymal components adds support to the

diagnosis of malignancy of the two components and reinforces the diagnosis of

OCS, similar to the observations of De Lair et al.8 Ki-67, an important marker of

cell proliferation, is highly expressed in malignant tumors.23 However, high Ki-67

expression was not observed in the majority of cases in a retrospective analysis

of malignant tumors from different origins and sites of malignancy.7,24 In our

case, we found a total Ki-67 proliferative index of 10.1%.

Page 10 of 18
 The low Ki-67 positivity in this case was unusual for a malignant tumor;

however, Ki-67 is a sensitive cell cycle-associated nuclear protein that has

variable expression during the active phases of the cell cycle, and is not

expressed in G0.23 Additionally, of the six OCS case reports in the literature,

only two presented immunohistochemical analyses for Ki-67.8,15 These authors

found a high proportion of proliferating cells in both components of OCS. As

there are so few OCS cases reported in the literature, it is difficult to determine

whether the pattern of Ki-67 labeling in this specific neoplasm is consistent.

Owing to its clinical aggressiveness and high association with metastasis

and recurrence, OCS requires strict follow-up.4,15 Because OCS is quite a rare

condition, and not all of the reported cases have included long-term follow-up, it

is difficult to determine the prognosis of OCS patients. However, death is a

common event, especially in cases with metastasis.4 The second presentation

of the reported case represented a recurrence, which may have been caused

by neoplastic cells that remained in the site after the first intervention, despite

excision by curettage having been performed in an attempt to remove the entire

tumor.

The treatment of choice for OCS is surgery.4,8,13-16 It is common for the

patient to undergo several surgeries, owing to frequent recurrence.4,13 The use

of adjuvant radiotherapy in such cases is still under debate, partially owing to

the possibility that the tumor might not respond to the radiotherapy. 4 Therefore,

if the tumor is detected early, surgical treatment alone will most likely lead to a

better prognosis.4,8,14

Additionally, the clinical diagnosis of OF presented by the surgeon was

completed discarded. Although OF can begin as a radiolucent unilocular lesion

Page 11 of 18
usually occurring in the premolar and molar regions of the mandible, it is

generally a painless, mixed, radiolucent, and radiopaque lesion.25 It is possible

that the surgeon established the clinical diagnosis of OF by interpreting the

radiographic aspect as an initial fibro-osseous condition. However, the

radiographic aspect of the present case reflects the process of irregular bone

resorption caused by the pathologic condition, giving the appearance of

radiolucency with ill-defined limits.

In conclusion, we report the seventh case of OCS, a rare malignancy

with aggressive behavior. This condition may clinically mimic other pathological

entities. Therefore, it is important to obtain a proper anamnesis, as well as to

establish the differential diagnosis and proceed to investigate for suspected

metastases. The histopathological diagnosis of this disorder is not difficult, but

should be rigorously conducted, as an OCS diagnosis suggests high rates of

recurrence and metastasis and requires thorough and periodic follow-up.

Page 12 of 18
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Page 16 of 18
Figure 1. Panoramic radiograph: Initial aspect showing an osteolytic lesion in

the left posterior alveolar ridge.

Figure 2. Photomicrographs of OCS (Hematoxylin and eosin, A-F). A-

Odontogenic epithelial nests and islands in a hypercellular mesenchymal tissue.

Clear cells and some typical ameloblastic architecture can be seen with

peripheral cuboidal and low columnar epithelial cells showing inverted

polarization (200x). B- Odontogenic epithelial island showing pleomorfism and

mesenchymal tissue presenting mitotic figures pointed by red arrows (200x). C-

Mesenchymal component displaying nuclear anaplasia (200x). D- Odontogenic

epithelial nests embedded in a malignant mesenchymal tissue (400x). E and F-

Mesenchymal tissue displaying many fibroblasts with enlarged and

hypercromatic nuclei and some mitotic figures pointed by red arrows (400x). A

high-resolution version of the image is available as eSlide: VM04091.

Figure 3. Photomicrographs of OCS (Immunohistochemistry, 200x, A-F). A-

Odontogenic epithelium highly positive to AE1/AE3, B- cytokeratin 14 and C-

cytokeratin 19. D- Mesenchymal counterpart strongly positive to Vimentin. E-

Prominent immunorreactivity to p53 in both mesenchymal and odontogenic

epithelial components. F- Immunoreactivity to Ki-67 in scarce epithelial and

mesenchymal cells. High-resolution versions of the slides for use with the

Virtual Microscope are available as eSlides: VM04092, VM04093, VM04100,

VM04101, VM04102, VM04103.

Figure 4. Cone beam tomography (A-E). A, B and C- 4 months after the first

surgery. A- Panoramic view reflecting an incomplete excision of OCS. B and C-

Parasagittal consecutive views displaying hypodense area with irregular

borders in left alveolar ridge. D and E- 15 months after the last surgery. D-

Page 17 of 18
Panoramic view revealing no evidence of recurrence. E- Parasagittal view

showing only a bone depression with well-defined margins.

Page 18 of 18