Clinicopathological characteristics of desmoplastic ameloblastoma: A systematic review

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J Invest Clin Dent. 2018;9:e12282. wileyonlinelibrary.com/journal/jicd |_{1 of 12}

https://doi.org/10.1111/jicd.12282

R E V I E W A R T I C L E Oral Pathology

Clinicopathological characteristics of desmoplastic ameloblastoma: A systematic review

Rahul Anand

¹

| Gargi S. Sarode

¹

| Sachin C. Sarode

¹

| Mamatha Reddy

¹

|

Hemant V. Unadkat

^2,3

| Shazia Mushtaq

⁴

| Revati Deshmukh

¹

| Shakira Choudhary

¹

| Nitin Gupta

¹

| Anjali P. Ganjre

¹

| Shankargouda Patil

⁵

1Department of Oral Pathology and Microbiology, Dr. D.Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth, Pimpri, Pune, India

2National Dental Centre of Singapore, 5 Second Hospital Avenue, Singapore, Singapore

3Oral Health Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore

4College of Applied Medical Sciences, Dental Health Department, King Saud University, Riyadh, Saudi Arabia

5Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Jazan, Saudi Arabia Correspondence

Professor Sachin C. Sarode, Department of Oral Pathology and Microbiology, Dr D.Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth, Pimpri, India.

Email: drsachinsarode@gmail.com

Abstract

The aim of the present review was to systematically present the clinicopathological data of desmoplastic ameloblastoma (DA) from articles published in the literature. A comprehensive search of the databases (PubMed, Medline, SCOPUS, Web of Science, and Google Scholar) for published articles on DA was conducted. A total of 238 cases were identified and analyzed from 76 published papers. DA showed a slight male predilection (male: female=1.07:1) with a predominance in the fourth and fifth decades of life. Mandibular involvement (52.55%) was most commonly seen with a marked tendency for the anterior region (mandible: 40.9%, maxilla: 48.07%). The size of the lesion ranged from .5 cm to 20.4 cm, with the majority of cases measuring more than 3 cm in size (53.84%). Radiologically, most of the lesions presented mixed radiolucency and radiopacity (62%), and root resorption was observed in only seven cases. The majority of the lesions showed ill- defined margins upon radiographic examination (65.78%).

Most of the cases were treated with resection (78.57%), and five of the 10 recurrent cases were treated by enucleation/curettage. DA is characterized by the unique presentation of clinicopathological parameters. It is not possible to comment on its aggres- sive/recurrent nature and best treatment modality due to inadequate follow- up data.

K E Y W O R D S

ameloblastoma, desmoplastic ameloblastoma, jaw tumor, odontogenic tumors, systematic review

1 | INTRODUCTION

Desmoplastic ameloblastoma (DA) is a unique variant of ameloblastoma with peculiar clinical, imaging, and histologic features (International Classification of Diseases for Oncology code: 9310/0). It was first reported by Eversole et al. in 1984.¹ Later, in 1987, Waldron et al. con- sidered it as a separate clinicopathological entity.² However, the 2017 World Health Organization classification included it as a follicular pat- tern variant and not as a separate clinicopathological entity.³ It is also known as ameloblastoma with pronounced desmoplasia, and accounts for approximately 4%- 13% of ameloblastomas, which is consistent with the global incidence of 0.9%- 12.1% of DA relative to ameloblastomas

in general.^4-8 Approximately 238 cases have been reported in the literature to date. This tumor is more commonly seen in the anterior region of the jaw as a mixed radiopaque- radiolucent lesion resembling benign fibro- osseous lesions because of hyalinization seen in the stroma. Histologically, DA is characterized by small nests and strands of “compressed” odontogenic epithelia supported by pronounced col- lagenized stroma with a tendency of penetration into the surrounding bone. Investigators have observed that recurrence in cases with DA is almost as high as with the conventional ameloblastomas.^9,10 Despite the fact that so many cases of DA have been reported in the scientific literature, the true biologic profile of DA is still not well understood. The aim of the present review was to comprehensively appraise the clinical,

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radiological, histopathological, histogenetic, and therapeutic aspects of DA, and thus attempt to further speculate on the possible biologic profile of the tumor to enhance knowledge of this unusual variant.

2 | MATERIALS AND METHODS

2.1 | Search strategy and selection criteria

The present systematic review was conducted according to the guide- lines of the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) statement. We performed a comprehensive search of the databases (PubMed, Medline, SCOPUS, Web of Science, and Google Scholar), along with cross- references to published articles on DA for eligible studies/case reports published since 1987 up until now. Keywords included a combination of “ameloblastoma”, “desmoplastic ameloblastoma”, and/or “odontogenic tumors”. Additional cita- tions identified through the reference lists of selected references and bibliographical linkages were included in the review. Journals related to oral pathology, oral surgery, and oral medicine were also searched for these keywords. The inclusion criterion was human case reports of DA; cases of peripheral, malignant, metastatic, recurrent, and hybrid cases were excluded from the study. For the analysis, the following clinicohistopathological data were pooled: age, sex, size, site of lesion, duration, histopathologic characteristics, radiographic presentation, immunohistochemical observations, treatment rendered, and recurrence status.

3 | RESULTS

In the present review, a total 238 cases were identified and analyzed from 76 papers1,2,5-12,16-86 published in the English medical literature (Table 1). The clinicopathological data of 238 cases are summarized in Table 2.

4 | DISCUSSION 4.1 | Clinical features

4.1.1 | Incidence

As it is rare, the incidence of this entity is quite low, and is difficult to determine from the currently- available literature. However, it is possible that the incidence of DA could be escalating because of increased awareness and accurate diagnoses being made. The reported incidence for DA was 8.8% in a case series by Keszler et al.,¹¹ which is lower than the 12.7% reported by Waldren and el- Mofty.² Of the 89 cases of ameloblastomas studied by Takata et al., 7.9% were diagnosed as DA, and only 1.1% were diagnosed as hybrid lesions.¹² In Japan, DA account for 5.3% of all cases of intraosseous ameloblastomas diagnosed before the age of 27 years.^13,14 In an Indian study, ameloblastomas were found to account for 1.18% of the total surgical specimens received over a period of 25 years, with DA accounting for only 2.25% of the various histological variants of ameloblastoma.¹⁵

4.1.2 | Age and sex distribution

The reported mean age for DA is 38.8 years, with a known male predilection, although Keszler et al. found a higher female prevalence in their case series.¹¹ The observation of a mean age of 41.11±13.46 years, with an age range of 13- 83 years in this series, is slightly lower than the 42.9 years reported by Philipsen et al.,⁹ but falls within the age range of the third and fifth decades, as recently reported by Sivapathasundharam et al.¹⁰ A male (88)- to- female (82) ratio of 1.07:1 was observed in our review, which is in accordance with the findings by Waldron and el- Mofty.²

4.1.3 | Location and clinical presentation

DA presents itself as a tumor or swelling in a similar fashion to other ameloblastomas. According to our findings, a maximum number of cases reported with a chief complaint of painless swelling of the jaw- bone. Previously- reported cases of DA have shown this variant to have a strong predilection for the anterior premolar region of the jaw, occur- ring with equal frequency in both the maxilla and the mandible, in con- trast to solid multicystic ameloblastomas.1,5,10,11,17,22,45 In the present analysis, the site was stated in 137 cases, of which 65 (47.44%) occurred in the maxilla, and 72 (52.55%) in the mandible. Of the 52 cases of maxillary involvement, the anterior region (25/52, 48.07%) showed the most common involvement, followed by the anterioposterior region (21/52, 40.38%) and posterior region (6/52, 11.53%). Similarly, in the case of the mandible, the anterior region (18/44; 40.9%) was the most commonly- affected area compared to the anterioposterior region (10/44; 22.72%) and the posterior region (16/44; 36.36%). The most common clinical presentation was expansion of the cortical plates. The size of the tumor generally varied between 1.0 and 8.5 cm in diam- eter,¹⁸ but in the present series, the size of the lesion ranged from 0.5 to 20.4 cm, with 53.84% (35/65) cases found to be more than 3 cm in size.

4.2 | Radiographic examination

Multilocular appearance (n=36, 50%) is the most common radiographic presentation as compared to the unilocular (18, 25%). Eighteen (25%) cases did not show any locularity. Of the 76 cases, the majority of the lesions exhibited ill- defined borders (n=50, 65.78%). According the present review, mixed radiographic appearance was the most common presentation (62/100, 62%). This appearance could be because of hyalinization seen in the stroma of DA. Root resorption was present in eight cases (22.22%), and was absent in 22 cases (61.11%).

Twenty- seven cases revealed tooth displacement. The ill- defined borders of DA make high- resolution computed tomography images and magnetic resonance imaging helpful in treatment planning.¹⁹

4.3 | Histopathology

DA show some variation from the typical core characteristics demonstrated by other histological ameloblastoma subtypes. It has a greater tendency to grow in thin strands, cords, and islands of odontogenic

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TABLE 1 Distribution of clinicopathological data for desmoplastic ameloblastomas YearAuthorNo. of casesAge (years)SexRaceLocationSizeLocularityBordersRadiodensity

Tooth resorp- tion

Tooth displace- mentTreatmentFollow up 1984Eversole et al.1348FemaleMalaysianMaxilla P>3No loculesIMixedNANAResNR2Y 50FemaleCaucasianMandible A+P<3UnilocularIRLNANANANA 47FemaleBlackMandible ANANo loculesIMixedNAYesRes+BGNA 1987Waldron & el- Mofty.21421- 68, 45.57 male, 7 female

NA2 mandible A, 5 mandible P, 6 maxilla A, 1 maxilla P

13:<3, 1:>31 unilocular, 5 no locules5 I, 1 W4 mixed, 2 RLNANANA2R, 1NR, 11 NA 1990Yoshimura & Saito37136FemaleJapaneseMaxilla A+P>3MultilocularIMixedNANAResNR/9Y 1991Huguchi et al.6346MaleNAMaxilla A>3MultilocularIMixedNoYesNANA 38FemaleNAMandible A>3MultilocularWMixedYesYesNANA 53MaleNAMaxilla P<3UnilocularWMixedNoYesNANA 1991Tanimoto et al.39124FemaleJapaneseMandible A+P>3NAIRLNoYesResNR1Y 1992Philispen et al.86221MaleChineseMaxilla A+P>3MultilocularIRLYesYesRes+BGNA 53MaleChineseMaxilla A+P>3MultilocularIRLYesYesResNA 1993Kaffe et al.41141MaleNAMaxilla A+P>3No loculesIMixedNANAResNR3Y 1993Ng et al.81721FemaleChineseMandible A<3NAIRLNANAResNA 25MaleChineseMaxillaNANANAMixedNANAResNA 25MaleMalaysianMandible ANAMultilocularNARLNANAResNA 27FemaleChineseMandible ANANANAMixedNANANANA 29FemaleKadazanMandible A+PNAMultilocularNAMixedNANAResNA 32FemaleIndianMaxilla ANANANANANANANANA 33MaleMalaysianMaxilla A3NANAMixedNANANANA 33FemaleMalaysianMaxilla A+PNANAINANANAResNR1Y 38MaleMalaysianMaxilla A<3NANANANANAResNA 40FemaleChineseMandible ANAMultilocularNARLNANANANA 41FemaleMalaysianMaxilla ANANANANANANAResNA (Continues)

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YearAuthorNo. of casesAge (years)SexRaceLocationSizeLocularityBordersRadiodensity

Tooth displace- mentTreatmentFollow up 42FemaleChineseMandible PNANANANANANANANA 43FemaleMalayMandible ANANANANANANANANA 43FemaleChinMandible ANAMultilocularNARLNANANANA 44FemaleIndianMandible A<3NANANANANAResR4Y 46FemaleIndianMaxillaNANANAMixedNANAResNR1Y 60MaleChineseMandible ANAMultilocularNARLNANANANA 1993Ashman et al.40153MaleBlackMandible A+P>3No loculesWMixedNAYesResNR9M 1995Raubenheimer et al.71NANANANANANANANANANANANA 1996Keszler et al.11 1419- 62, 37.8 in 13, 1 NA11 female, 2 male, 1 NA

NA2 maxilla, 10 mandible, 1 NA NA4 unilocular, 5 multilocular

4 W9/RL, 3/MixedNANA5 res, 9 cur3 R, 11 NR 1996Thompon et al.19131FemaleBlackMaxilla A+P>3No loculesIMixedYesYesRes+BGNR3Y 1996Lo et al.421NANANAMandibleNANANANANANANANA 1997Fukushima et al.43170MaleNAMaxilla P>3No loculesIMixedNAYesResNR18M 1998Lam et al.5564MaleChineseMaxilla A+P>3No loculesIRLNANAResR2Y 18MaleChineseMaxilla A>3MultilocularIRLNANAResNR53M 68FemaleChineseMaxilla P<3MultilocularIRLNANACurR74M 37FemaleChineseMandible A<3MultilocularIRLNANAResNR77M 37MaleChineseMandible A<3No loculesIRLNANAResNR32M 1998Lee et al.44183FemaleAsianMandible A<3MultilocularWMixedNAYesResNR 1998Sakashita et al.70160FemaleJapaneseMaxilla A>3MultilocularIRLNANAResNR 1998Ludvikoya et al.71250MaleNAMandible P>3No loculesIRLNANAResNR 42FemaleNAMandible P<3No loculesIRLNANAResNR3Y 1999Kawai et al.21156MaleJapaneseMandible PNAUnilocularWRLNANAResNA 1999Takata et al.45 653MaleJapaneseMaxilla A>3No loculesWRLYesNAResNR 33FemaleJapaneseMaxilla A3MultilocularIMixedNoNACurNR 51MaleJapaneseMaxilla A+P<3UnilocularWRLNoNAResNR 52MaleJapaneseMaxilla A+P>3MultilocularIMixedNoNAResNR

TABLE 1 (Continued) (Continues)

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Tooth displace- mentTreatmentFollow up 54MaleJapaneseMandible A+P>3No loculesWMixedNoNAResNR 17MaleJapaneseMandible A+P<3MultilocularIMixedNoNACurR4 2000Louis et al.72133MaleBlackMaxilla A+P<3NAIMixedNoYesRes+BGNR18M 2000Takata et al.12 6NANANANANANANANANANANANA 2000Saran et al.46125FemaleIndianMaxilla A+P<3UnilocularWNANANAResNR10M 2001Kishino et al.22941MaleJapaneseMaxilla A+P>3MultilocularWRLNoNAResNR17Y 28MaleJapaneseMaxilla A>3NAIMixedNoNAResNR72M 57MaleJapaneseMaxilla A<3NAWRLNoNAResNR8Y 58FemaleJapaneseMaxilla A3UnilocularWRLNoNACurNR16Y 17MaleJapaneseMandible P<3UnilocularWRLNoNACurNR5Y 50MaleJapaneseMandible P>3NAIMixedNoNAResNR6Y 51MaleJapaneseMandible P>3NAIMixedNoNARes+BGNR23Y 47MaleJapaneseMandible A+P>3NAIMixedNoNARes+BGNR20Y 42MaleJapaneseMandible P>3NAIMixedNoNANANA 2001Philipsen et al.9142FemaleCaucasianMandible ANAUnilocularIMixedNAYesRes+BGNR36M 2001Kumamoto et al.244NANANANANANANANANANANANA 2002Mintz & Velez47252MaleNAMaxilla A+PNAMultilocularIMixedNAYesResNR 51FemaleNAMandible PNAMultilocularIMixedNAYesRes+BGNR1Y 2002Manuel et al.73120FemaleNAMaxilla A<3UnilocularWMixedNoYesResNR22M 2002Iida et al.74152MaleJapaneseMaxilla A+PNAMultilocularIMixedNAYesResNR 2002Fukumashi et al.333NANANANANANANANANANANANA 2002Beckely et al.75131MaleHispanicMandible A+P<3No loculesIMixedNoYesRes+BGNR19M 2003Durmus et al.49168MaleTurkishMandible A<3UnilocularWRLYesNACurNR32M 2003Maresi et al.48162MaleNAMandibleNANANAMixedNANANANA 2004Piilai et al.76124FemaleIndianMaxilla A+P<3MultilocularIRLNoYesCur+BGR2M 2004Kumamoto & Ooya254NANANANANANANANANANANANA 2005Kumamoto et al.264NANANANANANANANANANANANA

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Tooth displace- mentTreatmentFollow up 2005Hirota et al.77117FemaleJapaneseMaxilla PNAMultilocularWMixedNAYesResNR7Y 2006Desai et al.50132MaleIndianMandible P>3UnilocularWRLNANACurNR2Y 2006Adebeyi et al.51436.5±4.44 maleNA4 mandibleNANANANANANANANA 2007Shashikanth et al.78132FemaleIndianMaxilla A<3MultilocularIMixedYesYesResNR1Y 2007Kumamoto & Ooya294NANANANANANANANANANANANA 2007Sivapathasundaram et al.10425MaleIndianMaxilla A+PNAUnilocularWMixedNoYesResNA 40MaleIndianMaxilla A+PNAUnilocularWMixedNoNoResNA 30FemaleIndianMaxilla A+PNANAIMixedNoNoResNA 32FemaleIndianMaxilla A+P3MultilocularIMixedYesYesResNR1Y 2008Curran & Byerly79156MaleBlackMandible P<3NAWNANoNAResNR51M 2008Smullin et al.80144FemaleNAMaxilla A+P<3NAWNANANAResNR1Y 2008Punnya et al.52132MaleIndianMaxilla A>3NAIMixedNANACurNA 2008Kummamoto & Ooya303NANANANANANANANANANANANA 2008Ide et al.53352MaleNAMaxilla ANANANAMixedNANANANA 31MaleNAMaxilla ANANANAMixedNANANANA 36MaleNAMaxilla ANANANAMixedNANANANA 2008Sathi et al.54450MaleNAMandibleNANANANANANANANA 38MaleNAMandibleNANANANANANANANA 33FemaleNAMaxillaNANANANANANANANA 59MaleNAMaxillaNANANANANANANANA 2009Bologna- Molina et al.274NANANANANANANANANANANANA 2010Fulco et al.55334.3NANA3 mandible3.5NANANANANANANA 2010Amaral et al.56125MaleNAMandible>3NANAMixedNANAResNR12M 2010De Medeiros et al.234NANANANANANANANANANANANA 2011Sheikh et al.57145FemaleNAMaxilla A>3NaIMixedNAYesResNA 2011Effiom & Odukoya5817NA10 male, 7 female

NANANANANANANANANANA

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Tooth displace- mentTreatmentFollow up 2011Kato et al.59129FemaleNAMaxillaNANANAMixedNANANANA 2011Katsura et al.60145FemaleNAMaxilla A+PNAMultilocularNAMixedNANAResNA 2012Medeiros et al.611NANANAMandibleNANANANANANANANA 2012Siar et al.328NANANANANANANANANANANANA 2012Siar et al.852244.8±13.713 male, 9 female

NANANANANANANANANANA 2012Cervelli et al.62113MaleIndianMandible>3NANAMixedNANANANA 2013Bologna- Molina et al.285NANANANANANANANANANANANA 2013Nair et al.16160MaleNAMandibleNAMultilocularNAMixedNANAResNA 2013Belgaumi et al.38147FemaleNAMaxillaNAMultilocularIMixedNANAResNA 2013Savithri et al.20126FemaleNAMaxillaNANANAMixedNANANANA 2014Ramesh et al.63145FemaleNAMaxilla>3NANAMixedNANANANA 2014Majumdar et al.64155MaleNAMandibleNANANAMixedNANANANA 2014Figueiredo et al.65149FemaleNAMaxillaNAMultilocularNANANANANANA 2014Filizzola et al.662431 male, 1 female

NA1 maxilla, 1 mandibleNANANANANANANANA 2014Selvamani et al.67134FemaleNAMandibleNANANANANANANANA 2015Bologna- Molina et al.312NANANANANANANANANANANANA 2015Diniz et al.682NANANANANANANANANANANANA 2015Khalil et al.69 1NANANANANANANANANANANANA 2016Milman et al.816NANANANANANANANANANANANA 2016Lamichhane et al.82143FemaleChineseMandible A>3MultilocularIMixedNoYesResNR10M 2016Wankhede & Dive83117FemaleIndianMandible A+P>3NAINANoYesNANA 2016Imran et al.84144MaleIndianMandible A+P>3NAIMixedNoYesResNA

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epithelia. The stromal component dominates, compressing the odontogenic epithelial components. The epithelial tumor islands are irregular or bizarre in shape, with a pointed or stellate appearance (kite shaped or animal configurations).²⁰ The epithelial cells at the periphery of the islands are cuboidal, with few hyperchromatic nuclei. Columnar cells with nuclear polarity are rarely evident. The islands have a swirled, hypercellular center, with spindle- shaped or squamous epithelial cells.

Intrafollicular microcysts might occur centrally.¹⁰ Connective tissue YearAuthorNo. of casesAge (years)SexRaceLocationSizeLocularityBordersRadiodensity

Tooth displace- mentTreatmentFollow up Total23841.11±13.4688 male, 82 female, 68 NA

13 maxilla, 25 maxilla A, 6 maxilla P, 21 maxilla A+P, 28 mandible, 18 mandible A, 16 mandible P, 10 mandible A+P, 101 NA

35 >3 30 ≤3 173 NA

18 unilocular, 36 multilocular, 18 no locules 166 NA

26 W, 50 I, 162 NA

62 mixed, 38 RL, 138 NA8 yes, 28 no, 102 NA 27 yes, 2 no, 109 NA 66 res, 18 cur, 154 NA

10 rec A, anterior; BG, bone graft; Cur, curettage; I, Ill-defined; NA, not applicable; NR, non- recurrent; P, posterior; Rec, recurrent; Res, resection; W, well-defined.

TABLE 1 (Continued)

T A B L E 2 Summary of clinicopathological data for desmoplastic ameloblastomas

Parameter Values %

Papers 76

Total cases 238

Age

Mean 41.11±13.46

Range 13- 83 years

Sex (n=170)

Male 88 51.76

Female 82 48.23

Jaw (n=137)

Mandible 72 52.55

Maxilla 65 47.44

Mandibular Region (n=44)

Anterior 18 40.9

Anterior+posterior 10 22.72

Posterior 16 36.36

Maxillary region (n=52)

Anterior 25 48.07

Anterior+posterior 21 40.38

Posterior 6 11.53

Size (n=65) 0.5- 20.4 cm, 35 cases ≥3 cm Radiographic features

Locularity (n=72)

Multilocular 36 50.00

Unilocular 18 25.00

No locules 18 25.00

Borders (n=76)

Ill defined 50 65.78

Well defined 26 34.21

Radiodensity (n=100)

Mixed 62 62

Radiolucent 38 38

Root resorption (n=30) 8 22.22

Tooth displacement 27 cases Treatment (n=84)

Resection 66 78.57

Curettage 18 21.42

Recurrence 10 (5 curettage)

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stroma shows desmoplasia with hyalinization. (Figure 1). Myxoid changes of the juxta- epithelial stroma are often found.³⁸ Formation of metaplastic osteoid trabeculae (osteoplasia) could be present.³⁸ DA has ill- defined borders, suggesting its infiltrating process and aggres- sive biologic behavior.²⁰

Kawai et al. reported a unique case of DA associated with a large cystic lesion.²¹ The tumor epithelial cells, however, were not similar to the epithelial cells lining the lumen of the cyst. It was proposed that the cyst was formed by cystic degeneration of the tumor epithelial nests, because the epithelial cells lining the cyst wall consisted of “degenerated” epithelial cells.

4.4 | Immunohistochemistry

Kishino et al.²² observed that some fibers of the DA tumor stroma stained brilliant purple with potassium monopersulfate- aldehyde fuchsin staining. These fibers continued from the oxytalan fibers of the periodontal membrane in the specimen involving a tooth. It was presumed that DA might have developed in the periodontal membrane of the related tooth.

A study carried out by Takata et al. showed transforming growth factor- β (TGF- β) positivity in five cases (2[+++] and 3[++]), and negativ- ity in only one case of DA.¹² TGF- β is one of the most potent local factors for modulating extracellular matrix formation, and its presence in DA is responsible for increased matrix formation. Collagen IV was found to be positive in five cases (2[++] and 3[+]) and negative in one. The desmoplastic stroma of DA has been reported to show a strong positive reaction for collagen type VI (ruling out the scar tissue), the strong immunopositive reaction for fibronectin and type 1 collagen, and immu- nonegativity for tenascin. Moderate- to- intense immunolabeling for type I collagen has been observed in the stroma of all solid DA.²³ Fibronectin is a glycoprotein that possesses an important signaling function in cell

at specific time points, and its highest expression is observed during cell migration, in active areas of epithelial- mesenchymal interactions, and in neoplastic stroma. Type I collagen is found throughout the connective tissue, and is one of the most abundant components of the interstitial extracellular matrix, being highly resistant to proteases due to its unique supercoiled triple helix structure. Type I collagen varied expression in DA might suggest less invasive behavior.

Kumamoto found that all DA epithelial islands were diffusely positive for Fas and caspase 3 expression, while weakly reactive for Fas- L.²⁴ In another study, he discovered four cases positive for survivin (1[+], 1[++] and 2[+++]), and four for X-linked inhibitor of apoptosis protein expression (2[++] and 2[+++]).²⁵ DA express survivin reactivity, suggesting that these inhibitors of apoptosis proteins family proteins contribute to biologic properties of epithelial odontogenic tumors, as well as to cellular regulation during tooth development. These results suggest that apoptosis- related factors might be associated with the oncogenesis and cytodifferentiation of DA.

An immunohistochemistry study by Kumamoto et al. found four DA cases with positivity for p63, of which one had a moderately- positive expression in peripheral and central cells, while in three cases, it was strongly positive in most of the epithelial cells.²⁶ p73 was positive in four cases; one case exhibited mild expression in peripheral cells, while three cases showed strong positivity in peripheral and central cells.

The expression of p63 and p73 suggests that these p53 homologs play a role in the differentiation and proliferation of DA odontogenic epithelial cells. Variations of predominantly- expressed isoforms suggest that p63 and p73 might function differentially in odontogenic tissues. According to Bologna- Molina et al. , DA has a lower proliferation index (Ki- 67 and proliferating cell nuclear antigen), as well as the highest levels of syndecan- 1.²⁷ There were no apparent differences in the distribution of syndecan- 1 immunoexpression among basal and stellate reticulum- like cells. The high expression of syndecan- 1 in DA could be associated with better cell- cell and cell- extracellular matrix adhesion in epithelial ameloblastic zones (islands), suggesting less ag- gressive and invasive behavior of this neoplasia, and could explain, to some degree, the unique clinicopathological features of this neoplasia, which also involves a very slow growing lesion that induces desmoplasia. In another study by Bologna- Molina et al.,²⁸ higher expression of Ki- 67 and proliferating cell nuclear antigen was found compared to ameloblastic carcinoma. However, no differences were reported in the expression of these markers between DA and other variants of ameloblastomas. A study on platelet- derived growth factor showed expression for insulin growth factor (IGF) - 1 (+++), IGF- II (+++), IGF- I receptor (+++), platelet-derived growth factor (PDGF) - A-chain (+), PDGF B- chain (+), and PDGF α- receptor.²⁹ These results suggest that IGF, PDGF and their receptor contributes to cell proliferation and sur- vival thus contributing to the intra-osseous progression of DA.

According to Kumamoto and Ooya. DA express immunoreactivity for the Bcl-2 homology domain 3 (BH3)- only proteins in most tumor cells.³⁰ BH3- only proteins have a role in apoptotic cell death of normal and neoplastic odontogenic epithelia. The distinctive expression pat- terns of these BH3- only proteins in ameloblastoma variants suggest F I G U R E 1 Photomicrograph of desmoplastic ameloblastoma

showing highly- collagenous stroma and small compressed odontogenic follicles. (hematoxylin- eosin stain, total magnification

×400)

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that the BH3- only proteins might be involved in the tumor cell differentiation of DA. Bologna- Molina et al. also observed that all of the DA exhibited the highest expression of glypican- 1,³¹ suggesting its possible role in the desmoplasia that characterizes DA. According to Siar et al., DA demonstrated strong expression for canonical Wnts- 1, - 8b, and - 10a, and moderately for Wnts- 3 and - 8a.³² Non- canonical Wnt proteins were not expressed in all the eight DA cases. These results suggest that the canonical Wnt pathway is most likely the main trans- duction pathway, and that Wnt- 1 might be the key signaling molecule involved in DA tumorigenesis.

DA demonstrated diminished odontogenic characteristics, as basal cells are cytokeratin (CK) 19 negative (a marker for odontogenic epithelia). Immunostaining for CK in the basal layer revealed klotho (KL) 1, CK8, and protein kinase (PK) positivity. In the suprabasal layer, interleu- kin, KL1, CK19, CK8, CK13, and PK were positive in the cytoplasm.³³ DA illustrated fibronectin immunoexpression throughout the tumor stroma, but no expression of the same at the epithelial- mesenchymal interface, which might be related to the lack of similarities between pre- ameloblasts and the peripheral epithelial cells of DA.²³

4.5 | Differential diagnoses

Histopathological features of DA involve two characteristics: exten- sive stromal desmoplasia and small tumor nests of odontogenic epithelia scattered in the stroma.¹ From these findings, other tumors that should be histologically differentiated from this type of ameloblastoma include ameloblastic fibroma, odontogenic fibroma, and squamous odontogenic tumor.^34,35

Its unique radiographic appearance resembles a mixed radiolucent-radiopaque lesion, unlike the strictly radiolucent quality of other ameloblastomas. Therefore, it is usually a surprise diagnosis from a differential list composed mostly of fibro- osseous diseases and odontogenic cysts and tumors that are characteristically radiolucent- radiopaque. These include ossifying fibromas, fibrous dysplasia, osteo- blastomas, osteosarcomas, calcifying epithelial odontogenic tumors, and calcifying odontogenic cysts.

4.6 | Treatment

Although various treatments have been proposed, complete resection is recommended for DA to avoid recurrence, because of the lack of distinct borders between the tumor and normal tissues in many cases.

It has been proven that enucleation or curettage of DA results in recurrence, but small DA lesions can easily be enucleated in toto from the intraosseous bed. It was rightly said by Marx and Stein that “the best chemotherapy for odontogenic tumors is a jar of formalin”, which is also applicable for this rare variant.³⁶ Present knowledge leads to the recommendation to apply the same treatment modality for this variant, as DA is otherwise identical to conventional ameloblastomas.

The most common surgical intervention followed in various cases in this review was resection (78.57%, 66/84) followed by partial maxil- lectomy or mandibulectomy. Ten recurrent cases of DA have been reported to date. Five of these cases were treated by enucleation

or curettage.^2,5,37 The duration of the recurrence ranged from 2 to 6 years. In the majority of the cases (81/238, 34.03%), the follow- up data were not available. Therefore, we are unable to comment on the recurrent nature and best treatment modality for this lesion. The prognosis cannot be established because of a lack of documentation, but complete resolution had been shown to occur with resection.⁸

5 | CONCLUSION

In conclusion, DA showed distinct male predilection with a predominance in the fourth and fifth decades of life, and a slight predilection for the mandible compared to the maxilla, with painless swelling as the most common presentation. The mixed radiolucent and radiopaque appearance of DA distinguishes it from conventional ameloblastomas.

This feature makes fibro- osseous lesions the most common differential diagnosis for DA. Histologically, severe desmoplasia is the most prominent, feature with interspersed epithelial cells arranged in compressed islands or strands. Due to the unavailability of follow- up data in many cases, we are unable to comment on the recurrent nature and optimum treatment modality for this neoplasm.

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How to cite this article: Anand R, Sarode GS, Sarode SC, et al.

Clinicopathological characteristics of desmoplastic ameloblastoma: A systematic review. J Invest Clin Dent.

2018;9:e12282. https://doi.org/10.1111/jicd.12282