SUBMITTED 28 DEC 22 1 REVISION REQ. 31 JAN 23; REVISION RECD. 15 MAR 23 2 ACCEPTED 11 APR 23 3 ONLINE-FIRST: MAY 2023 4 DOI: https://doi.org/10.18295/squmj.5.2023.021 5 6 Papilliferous Keratoameloblastoma 7 A systematic review 8 *Sanpreet S. Sachdev, Tabita J. Chettiankandy, Yogita B. Adhane, Manisha 9 A. Sardar, Akshay Trimukhe, Riya Jain 10 11 Department of Oral Pathology and Microbiology, Government Dental College and Hospital, 12 Mumbai, India 13 *Corresponding Author’s e-mail: sunpreetss@yahoo.in 14 15 Abstract 16 Papilliferous Keratoameloblastoma (PKA) is a rare entity and not much is known about its 17 clinicodemographic features or biological nature. Our review aimed to provide clarity with respect 18 to the characterization of demographic, clinical, radiological, and histopathological features of 19 PKA. Case reports of PKA were identified by means of a systematic search across multiple 20 databases. The search yielded a total of 10 cases, half of which were of Indian origin. All the cases 21 invariably occurred in the mandibular posterior region and involved the right side, except for one 22 case which primarily involved the left side of the mandible. PKA should be considered as a variant 23 of conventional ameloblastoma but towards the more aggressive end of the spectrum. It tends to 24 occur in older individuals (fifth decade or older), with a marked propensity to occur in the right 25 mandibular posterior region. Surgical resection with diligent follow-up is warranted in the 26 treatment of PKA. 27 Keywords: Odontogenic tumors; Ameloblastoma; Keratin; Odontogenic keratocyst 28 29 30 Introduction 31 An array of metaplastic changes can occur in the epithelial component of ameloblastoma (AM) 32 that are attributable to the potentiality of odontogenic epithelium. The epithelial cells within 33 ameloblastic follicles or plexuses may exhibit squamous, basaloid cell, granular cell, clear cell or 34 even mucous metaplasia. These metaplastic changes give rise to a polymorphic histopathological 35 picture in AM. Consequently, numerous corresponding variants of AM such as acanthomatous, 36 basaloid, granular, clear cell have been recognized [1]. 37 38 Squamous metaplasia in the central stellate reticulum-like cells of AM is the hallmark of 39 acanthomatous ameloblastoma (AA). The terminal fate of squamous cells is to form keratin and 40 desquamate. As a result, extensive keratinization to the extent of keratin pearl formation may occur 41 in AM. Four types of histopathological pictures have been reported in line with the spectrum of 42 keratinizing AMs. These include- 1) Simple histology: Ameloblastomatous follicles filled with 43 ortho- or para- keratin centrally, 2) Simple histology along with features of conventional 44 Odontogenic keratocyst (OKC), 3) Complex histology: extrusion of keratin masses into the stroma 45 along with features of simple histology with or without hard tissue formation, 4) Papilliferous 46 histology: Papillary projections of the odontogenic epithelium into the cystic lumen or microcystic 47 spaces [2]. 48 49 The World Health Organization in 1992, recognized such AM with extensive keratinization as 50 keratoameloblastoma (KA). While some authors consider KA as a subset of AA, others have 51 reported it as a distinct variant of AM [2,3]. The centrally desquamated cells lead to the formation 52 of microcystic areas within the ameloblastomatous follicles. The presence of papillary ingrowths 53 of odontogenic epithelium within these microcysts or in the primary cystic lumen is an even rarer 54 phenomenon. The first such case was described by Pindborg and Weinmann as a subset of AM 55 and the term ‘papilliferous keratoameloblastoma’ (PKA) was suggested [4]. While an ample 56 number of cases of KA displaying either simple or complex histology have been identified, the 57 PKA variant is exceedingly rare [3,5]. As a result, not much is known about the clinicodemographic 58 characterization and biological nature of PKA. 59 60 The question whether PKA differs from other variants of AM in its biological behavior or it 61 belongs to spectrum of AA without any clinical significance is not yet answered. The present 62 systematic review aims to gain a better understanding of the rare entity by identifying and 63 analyzing all the reported cases of PKA in scientific literature. The objectives of our review are to 64 describe the demographic, clinical, and histopathological characteristics of PKA. 65 66 Methods 67 Case reports of PKA were retrieved by a systematic search of the databases: Medline (Ovid), 68 PubMed, PubMed Central, Web of Science Citation Index Expanded, (SCIEXPANDED), and 69 Google Scholar. A systematic search with keywords ((ameloblastoma) AND (papillae)) OR 70 (papilliferous ameloblastoma). An additional search with keywords- ((ameloblastoma) AND 71 (keratin)) OR (keratoameloblastoma) OR (keratinizing ameloblastoma), was performed and 72 screened for potential presence of papilliferous areas in the microscopic picture. The cross 73 references cited in the retrieved literature were also screened for identification of possible cases of 74 PKA, in case if any were missed by the search strategy. 75 76 Full text articles of all the cases belonging to the spectrum of keratinizing AMs were scrutinized 77 for histopathological features of PKA. The quality of case reports was evaluated by means of JBI 78 critical appraisal tool for case reports [6]. To further minimize bias in quality assessment, the 79 authors were divided into two groups (SS and TC; MS and YA) which independently evaluated 80 the case reports for their inclusion in the present review (Figure 1). 81 82 The criterion for inclusion of the cases was the histopathological presence of papilliferous 83 proliferations of odontogenic epithelium into the primary cystic lumen or microcysts formed 84 within the ameloblastoma follicles along with the formation of keratin (Figure 2). For a better 85 understanding of the histopathological features, photomicrographs (Figure 3) were obtained from 86 the case reported by Bedi et al.[2] Cases with an ambiguous description or unclear histopathological 87 demonstration of a papilliferous component or keratin formation were excluded from the review. 88 The presence or absence of additional histopathological features besides papilliferous patterns such 89 as budding of cells, dentinoid formation, calcifications, ghost cells or OKC-like features, were also 90 recorded. However, these additional features were not considered definitive criteria for diagnosis 91 of PKA as they represent variations that can occur in the odontogenic neoplasm. 92 Data extraction: 93 The demographic, clinical, radiological, and histopathological features of all the cases was 94 extracted. Additional investigations such as special stains, immunohistochemistry (IHC) or gene 95 expression was also elicited. The treatment performed in all the cases, number of recurrences, 96 period between the recurrences and time with no evidence of disease after treatment was recorded. 97 The quality of articles included in the review was also assessed using the GRADE approach [7]. 98 The extracted data was entered and tabulated in into worksheets (Microsoft Office Excel 2016, 99 Redmond, Washington, USA). 100 101 The review title and search protocol are registered in the International prospective register of 102 systematic reviews - PROSPERO under the registration number: CRD42021282930. 103 104 Results and Discussion 105 A total of 10 reported cases of PKA were found in scientific literature available in English [2-5,8-13]. 106 Half of the patients (n=5, 50%) in these reported cases were of Indian origin [2,5,11-13]. The 107 clinicodemographic data extracted from all the cases of PKA are tabulated in Table 1. The age of 108 patients ranged from 18 to 76 years with a mean age of 49.7 years (S.D = +20.95). Bedi et al., in 109 their review, reported a slightly lower mean age of 40 years for KA exhibiting papilliferous 110 features [2]. Conventional AM shows a peak of occurrence in the third and fourth decades [1,14]. 111 However, the cases of PKA were evenly distributed amongst all the decades with majority of cases 112 occurring in fifth decade or later (n=7, 70%). Only three cases occurred in patients of age less than 113 30 years, while no case of PKA occurring in the fourth decade has yet been reported. These 114 findings indicate that PKA may occur at any age, but commonly occurs in patients of older age 115 groups. 116 117 There was a slight male predilection observed with 60% of the cases occurring in males (n=6) and 118 40% in females (n=4). The male-to-female ratio was found to be 1.5: 1. Data from a recent 119 systematic review of the global profile of AM has suggested that conventional AM also exhibits a 120 slight male predilection in Africa, North America and Asia [15]. A higher male predilection with 121 two-thirds of cases occurring in males was reported by Konda et al., and a ratio as high as 3:1 was 122 found by Bedi et al. in their respective reviews of PKA [2,12]. On the contrary, an equal sex 123 distribution (1:1) in reported cases of PKA was reported by Rathore et al [13]. However, the 124 omission of certain cases or reports of additional cases after the reviews conducted by these authors 125 has led to a variation in the sex distribution of PKA. 126 127 All the patients (n=9, unknown for one case) complained of swelling of duration ranging from 3 128 months to 5 years. The swelling was asymptomatic in most of the cases (n=6, 60%), which is a 129 common mode of presentation of AM. Pain was present in 3 cases, while mobility of teeth was 130 present in one case. Pain is an uncommon feature in AM, and is usually noted in lesions of larger 131 size that tend to impinge on adjacent or involved nerves or due to secondary infection [16]. 132 Infiltration of the lesions within the bony trabeculae and subsequent resorption could account for 133 the occasional mobility of teeth noted in conventional AM or its variants such as PKA. Difficulty 134 in mandibular movement was present in the case reported by Collini et al., which was attributable 135 to the involvement of condylar process by the lesion [10]. 136 137 All the cases invariably involved the posterior region of the mandibular jaw (n=10, 100%) and 138 none of the reported cases of PKA to date has occurred primarily in the maxilla or in the anterior 139 region of the mandible. This propensity of PKA to occur in the mandible is similar to that displayed 140 by conventional AM, wherein 90% of cases involve the mandibular jaw [17]. The lesion exhibited 141 a marked predilection to occur on the right side (n=9, 90%), while only one case primarily 142 involving the left side of the mandible was noted. This finding was in contrast to conventional 143 AM, which involves both sides almost equally [1]. In one case, the lesion was extensive enough to 144 involve the entire right side of the mandible, cross the midline and involve the anterior region of 145 the left side. 146 147 The lesion was described radiologically as a radiolucency (n=9, 90%), which was unilocular in 2 148 cases and multilocular in 7 cases. The radiolucency was well-defined in 5 cases and ill-defined in 149 3 cases. In one case, it was described as an osteolytic lesion with irregular calcifications [10]. The 150 radiological features demonstrated by PKA are not pathognomonic and are shared by several other 151 entities [18]. Therefore, odontogenic keratocyst, various benign and malignant odontogenic tumors, 152 benign fibrosseous lesions and central giant cell granuloma constitute the clinicoradiological 153 differential diagnosis of PKA. The extensively destructive nature of PKA was evident in 154 radiographs of all the cases wherein the majority of the cases involved the body, angle and ramus 155 of the mandible (n=7, 50%). Out of these, 2 cases exhibited extended involvement up to the 156 sigmoid notch and condylar process. 157 158 Additionally, all the cases that reported findings of computed tomography, found that the buccal 159 and lingual cortical plates exhibited expansion as well as perforation. AM displays a tendency to 160 cause extensive bone destruction and aggressively invade local structures. Increased motility of 161 neoplastic cells due to loss of Syndecan-1 coupled with increased expression of matrix 162 metalloproteinases (MMPs) and receptor activator of nuclear factor-kappa B ligand (RANKL) has 163 been suggested as the possible reasons for the aggressive biological nature of AM [19,20]. However, 164 none of the authors has investigated the expression of these markers or genes involved in the 165 reported cases of PKA. Expression of similar markers needs to be studied in cases of PKA, to 166 further elucidate the reasons for its aggressive nature. 167 168 Histopathologically, all the lesions exhibited an AM component with keratinization and 169 papilliferous areas. The histopathological features of PKA described by various authors in their 170 respective cases are tabulated in Table 2. When considering the AM component, the follicular 171 pattern of ameloblastoma was observed most commonly (n=5). The plexiform pattern of AM was 172 predominant in the case reported by Konda et al., which also exhibited areas of desmoplastic 173 changes within the stroma. Two cases exhibited an admixture of the follicular and plexiform 174 pattern [12]. In one case, the papilliferous proliferations were present in the primary lumen of a 175 Unicystic ameloblastoma (UAM) [13]. In the case reported by Collini et al., the architecture of 176 tumor cells was described as nests, tubules, islands and even single-file pattern, which simulated 177 the appearance of a salivary gland neoplasm [10]. 178 179 Ameloblast-like cells were present in the majority of lesions wherein low to tall columnar 180 ameloblast-like cells exhibiting nuclear hyperchromatism and reversal of polarity were present in 181 almost all the cases (n=8, 80%). These cells were present peripherally in the tumor follicles or 182 plexuses. Of these 7 cases exhibited stellate reticulum-like cells, while one case had granular cells 183 towards the centre. Besides ameloblastomatous follicles, some of the follicles were lined by only 184 squamous cells with or without keratin formation. 185 One case of AM exhibiting papilliferous proliferations reported by Adeyemi et al. had basaloid 186 metaplasia within the centre of the follicles [21]. We believe that their case represents a basaloid 187 variant of AM exhibiting papilliferous changes or possibly a hybrid odontogenic tumor. However, 188 since there was no keratin formation within the tumor islands, it did not fulfil the criteria for 189 diagnosis of PKA. The earliest cases of PKA reported by Pindborg and Altini et al. did not exhibit 190 ameloblast-like cells lining the follicles [4,8]. Instead, single to multiple layers of parakeratotic 191 squamous epithelial cells were observed, half of which formed tumor islands while the other 192 demonstrated papilliferous epithelium within a central cystic lumen. Similar parakeratotic 193 stratified squamous cells were noted in the tumor islands of cases reported by Kuberappa et al. and 194 Rathore et al., but with the presence of AM-like features in some follicles [5,13]. 195 196 The majority of the cases exhibited cystic degeneration centrally within the ameloblastic follicles 197 or plexuses (n=8, 80%) in which necrotic cell debris were present. It has been suggested that these 198 acantholytic cells separate from the viable epithelial cells in the follicle which continue 199 proliferating. This differential rate of proliferation and necrosis gives rise to pseudopapillary 200 structures projecting into the microcystic lumen [8]. Such phenomena are noted occasionally in 201 AM, but are common in odontogenic carcinomas. This suggests a closer histopathological 202 resemblance of PKA to the more aggressive end of the spectrum of odontogenic neoplasms. 203 204 It has also been postulated that PKA is KA in which extensive acantholysis results in 205 pseudopapillary projections [22]. However, true papillae consisting of ameloblastoma-like 206 epithelium with fibrovascular core were also present proliferating in the primary cystic lumen or 207 those formed within the follicles. The center of tumor follicles, islands, plexuses and nests were 208 packed with stacks of para- or ortho- keratin. In three cases, the stacks of keratin were extruded 209 into the connective tissue stroma and illustrated a Pacinian corpuscle-like architecture [3,9,12]. 210 211 Classically, AM has been defined as an odontogenic neoplasm of ameloblast-like cells in which 212 the cells do not undergo differentiation to the point of hard tissue formation [1]. Even so, formation 213 of hard tissues is a frequent finding in KA and was also noted in three cases of PKA. It has been 214 suggested that the extruded stacks of keratin undergo mineralization, ultimately leading to hard 215 tissue formation. Necrotic tissues may undergo a transition to bone with or without dystrophic 216 calcification; a process termed ‘pathologic ossification’. Takeda et al. described the hard tissue 217 formation as a result of pathological ossification producing cellular cementum or woven bone-like 218 material [9]. The transition between the keratin accumulated in the stroma and the forming hard 219 tissue was also evident microscopically in their case. Dystrophic calcifications in the stroma were 220 demonstrated in the case reported by Norval et al [3]. 221 222 Another entity associated with AM that comprises hard tissue formation is adenoid ameloblastoma 223 with dentinoid. This dentinoid-producing tumor exhibits characteristic histopathological features 224 of AM and adenomatoid odontogenic tumor (AOT), but is not yet recognized as an official entity 225 by the WHO. Our recent review of literature found about 30 cases of AAD reported to date [23]. 226 Similarly, it would be possible for dentinoid formation to occur in PKA which was also described 227 in one case by Bedi et al. Even so, the mechanism of dentinoid formation would be different for 228 AAD (epithelial-mesenchymal induction) and PKA (pathologic ossification), considering the 229 different pathogenesis of both entities. The term ‘Kerato-odontoameloblastoma’ was suggested for 230 such KA with odontogenic hard tissue formation [2]. 231 232 While OKC-like features are commonly noted in KA, they were absent in all the cases of PKA [24]. 233 It has been suggested that OKC may occasionally serve as a source of epithelium for KA to develop 234 since it shares a common phenotype and genetic profile, to some extent, with the cells of 235 ameloblastic lineage [25]. Development of mural islands of AM from the lining epithelium of OKC 236 was demonstrated by Brannon et al. Cases exhibiting combined histopathological features have 237 been reported as ‘hybrid’ lesions by some authors while others have considered them within the 238 spectrum of KA [24,26]. There is yet lack of evidence linking OKC with PKA. 239 240 Additional histopathological features such as foreign body giant cells, cholesterol clefts, ghost 241 cells, duct-like structures and rosette-like structures were also described across the reported cases 242 of PKA by various authors [2,5,10]. The presence of foreign body giant cells and cholesterol clefts is 243 not surprising, and they represent the normal host tissue inflammatory response or constitute a part 244 of the secondary infection of the tumor. The presence of abundant keratin bodies with faint nuclear 245 outlines was implicated as the reason for the resemblance to ghost cells [5]. The follicles with cystic 246 degeneration are occasionally lined by a single layer of epithelium adherent to the basement 247 membrane that imparted a hobnail appearance [8]. A cross-section of such follicles was suggested 248 to be the reason for the apparent duct-like structures [8,21]. The presence of acantholytic cells within 249 such follicles would also impart a rosette-like appearance, leading to misinterpretation of the lesion 250 as AOT. A highly vascularized stroma was present in the case reported by Kuberappa et al. that 251 resembled hemangiomatous AM [8]. Trauma or stimulation of vessels closely associated with the 252 dental follicle has been suggested as the reason for the highly vascular transition of the stroma in 253 AM [27]. 254 255 While the tumor cells in most of the cases had a benign morphology, a high mitotic rate of 3 256 mitoses/ high power field was reported by Collini et al. Recurrences occurred after 39 and 58 257 months, respectively, in their case [10]. The patient ultimately succumbed to non-Hodgkin’s 258 lymphoma (NHL) after 6 years. They proposed that PKA should be renamed as “papillary 259 ameloblastic carcinoma” considering its clinically aggressive nature, the microscopic abundance 260 of necrosis and recurrence. Such cases may closely resemble ameloblastic carcinoma, well-261 differentiated oral squamous cell carcinoma or primary intraosseous carcinoma. Generally, PKA 262 lacks cellular pleomorphism, vascular and neural invasion, and abnormal mitoses. The presence 263 of these features can aid in distinguishing PKA from these other malignant epithelial or 264 odontogenic neoplasms. 265 266 Investigation of the biological chemistry of the tissue by special stains and biomarkers by means 267 of IHC has not been extensively studied in cases of PKA. The case reported by Collini et al. 268 resembled a salivary gland tumor owing to the presence of tubules and duct-like structures [10]. The 269 authors investigated mucin production by Alcian blue which resulted in negative staining. The 270 salivary gland origin of the tumor was ruled out by negative immunostaining for high-molecular-271 weight cytokeratins, smooth muscle α-actin, maspin, GFAP, and CD45. They found positive 272 immunoexpression of low-molecular-weight cytokeratins in the epithelial cells, and vimentin in 273 the stroma along with focal and weak expression of S100. Rathore et al. found intense 274 immunoexpression of CK19 in the basal and suprabasal layers of the lining epithelium, which was 275 indicative of its odontogenic origin [28]. Ki-67 was intensely expressed in the basal and suprabasal 276 layers along with infrequent positivity in the superficial cells, which was indicative of the high 277 proliferative potential of the cells. They also found that p53 was strongly expressed in the basal 278 and suprabasal layers, suggestive of mutation in the tumor suppressor gene. The IHC findings of 279 Collini et al. and Rathore et al. provided further evidence for the aggressive biological potential of 280 the neoplastic odontogenic cells in PKA [10,13]. 281 282 Various authors have dealt with PKA through different approaches such as wide excision (n=4, 283 40%), segmental resection (n=2, 20%), hemimandibulectomy (n=2, 20%). Considering the 284 extensive clinical involvement, presence of atypical cytological features and recurrence, Collini et 285 al. performed modified neck dissection along with the hemimandibulectomy procedure in their 286 case [10]. The lesion recurred 39 months after the treatment procedure, after which, no treatment 287 was performed for the recurrent tumor owing to presence of concomitant NHL. Another recurrence 288 was reported in the case reported by Bedi et al., which occurred three years after en bloc resection 289 [2]. The remainder of cases showed no evidence of disease for a varying follow-up period of 2 290 months to 1 year. However, considering the recurrences in the case of Collini et al. and Bedi et al. 291 after three years of treatment, the follow-up period provided by the other authors may not be 292 sufficient to declare a successful outcome. 293 294 Except for luminal and intraluminal UAM, there is no difference in the treatment of different 295 variants of AM [1]. Marx and Stern stated that classifying AM according to all the different types 296 of histopathological features would only serve to complicate the classification system, ultimately 297 confusing the clinicians [29]. Even so, the different histopathological types have academic 298 importance and are of interest to pathologists. Therefore, as long as there is no significant 299 difference in the biological behavior, including different histopathological types of an entity as 300 variants seems the most rational approach. Reports of more cases in future with extensive long-301 term follow-up of the outcome would shed more light on the subject of whether PKA is just a 302 variant of AM or a distinct entity. In view of the current evidence, we believe that PKA should be 303 considered as a variant of AM within the spectrum of keratinizing AMs 304 305 Conclusion 306 PKA is a rare entity with only 10 reported cases to date, all of which have involved the mandibular 307 posterior region. The clinicodemographic and radiological characteristics of PKA are much similar 308 to AM except that it occurs more commonly in older individuals and shows a marked predilection 309 to occur on the right side. The lesion is locally aggressive exhibiting extensive clinical involvement 310 of the mandible and adjacent structures. The radiological features of PKA are not pathognomonic 311 and resemble other odontogenic neoplasms. Histopathological presence of papilliferous 312 proliferations of the odontogenic epithelium, along with extensive keratin production which may 313 even occur in the stroma are characteristic of PKA. Based on the presence of necrotic areas, the 314 high proliferating potential of cells, and possible recurrence, we recommend it to be considered 315 within the spectrum of keratinizing AMs, towards the more aggressive end. Further studies 316 pertaining to biomarkers in PKA such as Syndecan—1, MMPs and RANKL, will aid in elucidating 317 the biological potential of the lesion. With an increasing number of reported cases, more insights 318 could be gained with respect to the possible links between the pathogenesis of OKC, AA, KA, and 319 PKA. 320 321 Authors’ Contribution 322 SS and TC conceptualised the idea and designed the review. All the authors were responsible for 323 data collection, analysis and resolution of any issues. 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Hanover Park, IL, Quintessence 420 Publishing, 2003:pp.646. 421 422 423 https://doi.org/10.1097/scs.0b013e3182a28be3 https://doi.org/10.18295/squmj.9.2021.127 https://doi.org/10.1016/0266-4356(93)90122-d https://doi.org/10.1016/0266-4356(93)90122-d https://doi.org/10.1074/jbc.m112.367680 http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3411054/ https://doi.org/10.1016/0030-4220(76)90031-1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824512/ https://dx.doi.org/10.4103%2Fjomfp.JOMFP_28_16 https://www.ncbi.nlm.nih.gov/pubmed/29491600 424 Figure 1: PRISMA Flow Chart indicating selection process of articles for final qualitative 425 synthesis of the present systematic review. 426 427 428 429 Figure 2: Line diagram illustrating histopathological features of PKA. Ameloblast-like cells (1), 430 Stacks of keratin within cystic degeneration in the follicle (2), Papillary projections into the follicle 431 (3), Acantholytic cells (4), Keratin extruded into the stroma (5), Necrotic material within the 432 follicle (6), Micropapillary structures in a follicle lined by squamous epithelial cells (7), Normal 433 ameloblastoma-like follicle with central stellate reticulum-like cells (8) 434 435 436 Figure 3: “(A) Photomicrograph exhibiting proliferating odontogenic epithelium lining the cystic 437 lumen (H&E, ×40); (B) odontogenic epithelium proliferating in plexiform pattern of odontogenic 438 epithelium (H&E, ×100); (C) papillary projections from odontogenic epithelium (H&E, ×100); 439 (D) papillary proliferation of odontogenic epithelium within a collagenous connective tissue stoma 440 (H&E, ×40); (E) extensive squamous metaplasia with in odontogenic islands lined by tall columnar 441 ameloblast-like cells (H&E, ×100); (F) squamous metaplasia with keratin pearl formation (H&E, 442 ×100); (G) “keratin filled cystic spaces” with keratin production in the stroma (H&E, ×100); (H) 443 “keratin filled cystic spaces” with keratin production in the stroma (Krebergs Stain, ×100); (I) 444 “curvilinear ribbons” of odontogenic epithelium within collagenized stroma, which is extruding a 445 “lamellar stack of keratin” into the stroma without foreign body response (H&E, ×100); (J) 446 “pacinian-like” stack of keratin (H&E, ×100); (K) parakeratin packed elongated epithelial follicles 447 showing lamellar arrangement of keratin forming “hair-like structures” (H&E, ×100); (L) 448 formation of dentinoid-like material adjacent to odontogenic epithelium (H&E, ×100); (M) 449 dentinoid-like material (H&E, ×1,000); (N) dentinoid-like material with tubular structures (H&E, 450 ×1,000); (O) granuloma with cholesterol cleft formation (H&E, ×100).” (Picture obtained from 451 the case reported by Bedi et al.[2]) 452 Table 1: Summary of demographic, clinical, radiological features and management of cases of PKA by various authors 453 Sr. No . Author Yea r Age years Se x Race Durati on Ja w Side Regio n Extent Sympto ms Radiogra phic features Final Diagnosis Treatment and Follow-up GRAD E System 1 Pindbor g et al. 197 0 57 F Unkno wn Unkno wn M n Righ t Posteri or Body, Angle, Ramus Unknow n ML RL PKA Unknown Low 2 Altini et al. 199 1 76 F South African 12 months M n Righ t Posteri or PM to Sigmoi d notch Swelling WD ML RL PKA Hemimandibulect omy 1 year, NED Modera te 3 Norval et al. 199 4 26 F South African 60 months M n Righ t Posteri or PM To 3M Swelling , Pain WD ML RL Unusual variant of KA Segmental resection + iliac crest graft High 4 Takeda et al. 200 1 76 M Japanes e Several months M n Left Posteri or C to 2M, body Swelling WD ML RL KA Surgical resection High 5 Collini et al. 200 2 62 M Italian 3 months M n Righ t Posteri or Ramus and condyl e Swelling , difficult y in mandibu lar moveme nt Osteolyti c lesion with irregular calcificati ons PKA Hemimandibulect omy + Modified neck dissection Recurrence after 39 months Resection Recurrence after 18 Died after 6 years due to concurrent lymphoma High 6 Mohant y et al 201 3 46 M Indian 12 months M n Righ t Posteri or C to Ramus Swelling ID ML RL PKA Unknown Modera te 7 Bedi et al. 201 5 27 F Indian 7 months M n Righ t Posteri or 2PM to sigmoi d notch Swelling ID ML RL KA complex histology Wide excision recurred once after 3 years of en bloc resection High 8 Konda et al. 201 6 44 M Indian 6 months M n Righ t Posteri or C to 1M Swelling , intermitt ent pain, mobility of teeth WD UL RL papilliferou s keratinizin g variant of solid multicystic ameloblast oma In toto excision 1 year, NED High 9 Kuberap pa et al. 201 7 65 M Indian 4 months M n Righ t Antero - Posteri or 31 to 47 Swelling , pain ID ML RL PKA Wide excision 2 months, NED High 10 Rathore et al. 201 7 18 M Indian 3 months M n Righ t Posteri or C to 3M Swelling WD UL RL PKA Wide excision 2 years, NED High 454 Legends for Table 1: 455 M = Male, F = Female; Mn = Mandible 456 C = Canine, PM = Premolar, M = Molar 457 WD = Well-defined, ID = Ill-defined, ML = Multi-locular, UL = Unilocular, RL = Radiolucency 458 PKA = Papilliferous keratoameloblastoma, KA = Keratoameloblastoma 459 NED = No evidence of disease 460 461 462 Table 2: Summary of histopathological features observed in cases of PKA reported by various authors 463 464 Author Epithelial component Connective tissue component Type Cystic Degeneration Necrotic material Desquamated keratin Papillary projections Ameloblast- like features Stratified squamous lining in follicles Extruded keratin Hard tissue formation Pindborg et al. Follicles/islands Present Present Present Present Present Present Absent Absent Altini et al. Follicles Present Present Present Present Absent Present Absent Absent Norval et al. Follicles Present Present Present Present Present Questionabl e Present Dystrophic calcification Takeda et al. Follicles Absent Absent Present Present Present Present Present Cellular cementum / woven bone- like Collini et al. Nests, tubules, islands, Indian file Present Minimal Present Present Present Absent Absent Absent Mohanty et al. Follicles Present Present Present Present Present Absent Absent Absent Bedi et al. Follicles, nests, chords, plexuses Present Present Present Present Present Absent Absent Dentinoid material Konda et al. Plexiform Absent Absent Present Present Present Absent Present Absent Kuberappa et al. Follicle, plexiform Present Present Present Present Present Present Absent Absent Rathore et al. UAM with mural islands Present Present Present Present Present Present Absent Absent