Association of MDM2 Overexpression in Ameloblastomas with MDM2 Amplification and BRAFV600E Expression.

Ameloblastoma is a rare tumor but represents the most common odontogenic neoplasm. It is localized in the jaws and, although it is a benign, slow-growing tumor, it has an aggressive local behavior and high recurrence rate. Therefore, alternative treatment options or complementary to surgery have been evaluated, with the most promising one among them being a targeted therapy with the v-Raf murine sarcoma viral oncogene homologue B (BRAF), as in ameloblastoma the activating mutation V600E in BRAF is common. Studies in other tumors have shown that the synchronous inhibition of BRAF and human murine double minute 2 homologue (MDM2 or HDM2) protein is more effective than BRAF monotherapy, particularly in the presence of wild type p53 (WTp53). To investigate the MDM2 protein expression and gene amplification in ameloblastoma, in association with BRAFV600E and p53 expression. Forty-four cases of ameloblastoma fixed in 10% buffered formalin and embedded in paraffin were examined for MDM2 overexpression and BRAFV600E and p53 expression by immunohistochemistry, and for MDM2 ploidy with fluorescence in situ hybridization. Sixteen of forty-four (36.36%) cases of ameloblastoma showed MDM2 overexpression. Seven of sixteen MDM2-positive ameloblastomas (43.75%) were BRAFV600E positive and fifteen of sixteen MDM2-positive ameloblastomas (93.75%) were p53 negative. All MDM2 overexpressing tumors did not show copy number alterations for MDM2. Overexpression of MDM2 in ameloblastomas is not associated with MDM2 amplification, but most probably with MAPK activation and WTp53 expression. Further verification of those findings could form the basis for the use of MDM2 expression as a marker of MAPK activation in ameloblastomas and the trial of dual BRAF/MDM2 inhibition in the management of MDM2-overexpressing/BRAFV600E-positive/WTp53 ameloblastomas.

Fluorescence in-situ hybridization identifies Mastermind-like 2 (MAML2) rearrangement in odontogenic cysts with mucous prosoplasia: a pilot study.

AIMS: The pathogenesis of intraosseous mucoepidermoid carcinoma (IMEC) remains unknown. Coexistence with odontogenic cysts (ODC) has been reported in 32-48% of IMEC. Furthermore, prosoplastic mucous cells are often seen in the epithelial lining of ODCs. MECT1-MAML2 fusion transcripts have been identified in >66% of salivary gland MEC cases. The aim of this study was to investigate the presence of MAML2 rearrangement in ODCs featuring mucous prosoplasia. METHODS AND RESULTS: Ten cases of ODC with a mucous cell component and three cases of IMEC were evaluated using fluorescence in-situ hybridization. All cases occurred in the mandible. The ODCs exhibited a M:F ratio of 4:1 (mean age 49.2 years), while all IMECs occurred in women (mean age 68.3 years). All three IMECs demonstrated MAML2 rearrangement, in 26-61% of tumour cells. Successful hybridization was observed in nine of 10 cases of ODC. In two of these nine, there was MAML2 rearrangement in 12% and 24% of the lining epithelial cells, while three of the nine showed rearrangement in 7-8% of cells; the remaining four cases were negative. CONCLUSIONS: We identified MAML2 rearrangements in five of nine ODCs lined by mucus-secreting cells. This suggests that at least a subset of ODCs with mucous prosoplasia are characterized by molecular events considered diagnostic for intraosseous and extraosseous MEC.

Localized juvenile spongiotic gingival hyperplasia featuring unusual p16INK4A labeling and negative human papillomavirus status by polymerase chain reaction.

BACKGROUND: Localized juvenile spongiotic gingival hyperplasia (LJSGH) is a distinct type of gingival hyperplastic lesion with specific clinicopathologic features. Evaluation of the morphological characteristics of LJSGH indicates the potential role of human papillomavirus (HPV) infection as an underlying etiopathogenetic mechanism. METHODS: All cases of LJSGH from 2008 to present were retrieved. Clinical and demographic data were collected. HPV status was investigated by p16INK4A immunohistochemistry and HPV-Polymerase chain reaction (PCR). RESULTS: Twenty-one cases of LJSGH were identified, 14 (66.7%) affecting males and seven (33.3%) females (M:F = 2:1, age range: 8-36, mean: 13 years). All lesions were well-demarcated, exophytic, erythematous, and hemorrhagic with granular or slightly papillary surface. Preponderance for the maxillary gingiva (19, 90.5%) was observed. Two (9.5%) patients presented with recurrence 20 and 21 months after excision (mean follow-up: 18.7 months). Histopathologically, all LJSGH lesions featured epithelial hyperplasia with intense neutrophilic exocytosis and spongiosis. All cases demonstrated positivity for p16INK4A with the majority of specimens (47.6%) intensely decorated in >50% of the overlying epithelium with focal immunostaining observed in 47.6% and diffuse in 52.4%. Thirteen cases (61.9%) were negative for HPV DNA by PCR, while two (9.5%) were suspicious for the presence of low levels of HPV DNA but definitive genotyping was not possible. One case (4.8%) displayed positivity for HPV-31. The remaining five cases failed the PCR reaction. CONCLUSIONS: Human papillomavirus does not participate in the pathogenesis of LJSGH. P16INK4A expression in the absence of detectable HPV DNA can likely be attributed to the intense inflammation associated with LJSGH.

Comparison between p16 INK4A immunohistochemistry and human papillomavirus polymerase chain reaction assay in oral papillary squamous cell carcinoma.

PURPOSE: Oral papillary squamous cell carcinoma (OPSCC) is a histologic variant of SCC with a growth pattern suggesting human papillomavirus (HPV) infection. The aim of this study was to investigate the presence of HPV genotypes in OPSCC. MATERIALS AND METHODS: All cases with a histologic diagnosis of OPSCC from 1993 through 2008 were retrieved and confirmed. Immunohistochemical evaluation for the surrogate marker p16(INK4A) and HPV polymerase chain reaction were performed in tissue and DNA derived from formalin-fixed paraffin-embedded tissue. RESULTS: Forty-four patients with confirmed OPSCC (mean age, 71.96 yr; female-to-male ratio, 1.75:1) comprised the study population. The most common site of involvement was the gingiva followed by the palate and buccal mucosa. Forty cases exhibited an invasive component, 1 was noninvasive, and in 3 cases invasion could not be confirmed owing to suboptimal thickness of the biopsy. Paraffin tissue blocks were available in 41 cases. Twenty-three cases (56.1%) exhibited positive p16(INK4A) staining, which was primarily weak to moderate with a generally focal pattern. Polymerase chain reaction assays were negative for HPV DNA in all cases. CONCLUSIONS: In this study, there was a clinical predilection of OPSCC in older women, with most cases occurring in the masticatory mucosa. Weak to moderate and focal p16(INK4A) staining was appreciated in contrast to reported staining properties in genital and oropharyngeal PSCC. Failure of the polymerase chain reaction assay to exhibit transcriptionally active HPV genotypes suggests that HPV is not associated with OPSCC tumorigenesis.

An Unusual Gingival (Peripheral) Tumor with Features of Keratoameloblastoma with Cytologic Atypia or Possible Malignant Transformation Exhibiting ARID1A Mutation.

BACKGROUND: Keratoameloblastoma is a poorly characterized and rarely reported odontogenic neoplasm that can exhibit overlapping histopathologic features with conventional ameloblastoma and keratocystic odontogenic tumor (KCOT), with an ambiguous relationship to the so-called solid KCOT. METHODS: A peripheral maxillary tumor causing bone saucerization in a 54-year-old male is described and investigated with immunohistochemistry and Next-Generation Sequencing (NGS). RESULTS: Microscopically, the tumor comprised of a predominantly plexiform proliferation of odontogenic epithelium with central keratinization and evidence of surface origin. Peripheral cells exhibited nuclear palisading with variable reverse polarization, while stellate reticulum-like areas were observed internally. A few follicles and a few foci in the lining of cystic spaces revealed increased cellularity with cells exhibiting small but conspicuous nucleoli, focal nuclear hyperchromatism, and a few mitoses mostly seen in the peripheral outer cell layer. Nuclear staining for ki-67 was increased in those areas when compared with the other cystic, follicular, and plexiform areas. These features were interpreted as cytologic atypia suggesting also the possibility of a malignant process. Immunohistochemically, the tumor was positive for CK19 and negative for BRAF VE1, calretinin, and CD56. Ber-Ep4 was only focally positive. By sequencing, an ARID1A c.6527_6538delAG frameshift mutation (VAF: 5.8%), classified as likely oncogenic, and an FBXW7 c.1627 A > G missense mutation (VAF: 8.0%), classified as a variant of uncertain significance, were detected. Two mutations, probably germline (VAF ~ 50%), were recorded for RNF43 and FBXW7. No pathogenic variants were identified in PTCH1, BRAF, NRAS, HRAS, KRAS, FGFR2, or SMO genes. CONCLUSION: The significance of an ARID1A variant in keratoameloblastoma is uncertain since this variant has not been reported in ameloblastoma or KCOT, to date. Alternatively, it may characterize malignant transformation in the present case since ARID1A mutations have been encountered in various cancers. Sequencing of additional cases is necessary to determine whether this may represent a recurrent genomic event.

Intraoral salivary lymphoepithelial carcinoma: clinicopathologic and immunophenotypic characterization of 3 cases indicates elevated programmed death-ligand 1 expression.

OBJECTIVE: Intraoral salivary lymphoepithelial carcinoma (ISLEC) is a rare malignancy with programmed death-ligand 1 (PD-L1) expression levels that have been greatly understudied. We examined the clinicopathologic and immunophenotypic characteristics, including PD-L1 levels, of 3 cases of ISLEC. STUDY DESIGN: We searched the archives of 2 oral and maxillofacial pathology laboratories for specimens diagnosed as ISLEC between 1985 and 2022. We collected patient demographic and clinical data. Immunostaining for AE1/AE3, CK7, CD3, CD20, p16, p53, Ki67, and PD-L1 (SP263), as well as Epstein-Barr virus-encoded small RNAs (EBER) in situ hybridization (ISH) were performed. RESULTS: All 3 cases affected males aged 42 to 84 years (median = 61y) and involved the floor of the mouth, soft palate/uvula, and tongue. The lesions showed diffuse infiltration by non-keratinizing sheets and islands of undifferentiated carcinoma cells with associated dense lymphoplasmacytic inflammation. Immunohistochemically, all tumors showed AE1/AE3 positivity, selective p53 staining, and negativity for CK7 and p16. Ki67 highlighted 20%-80% of lesional cells. The inflammatory infiltrate comprised a mixed population of T and B lymphocytes. EBER ISH was positive in one case. All ISLECs displayed membranous, focal-to-diffuse, PD-L1 staining with tumor proportion score > 95% in two and 40-50% in the third case. CONCLUSIONS: The clinicopathologic and immunophenotypic characteristics of the cases we examined highlight the rarity of ISLEC and indicate overall high PD-L1 levels in this type of malignancy, rendering patients with ISLEC potential candidates for targeted α-PD-1/PD-L1 immunotherapy.

Oral verruciform hyperkeratotic lesions indicating the presence of plantar or palmoplantar keratodermas.

OBJECTIVE: Oral verruciform hyperkeratotic lesions (OVHLs) affecting the gingiva and palate are frequent in proliferative verrucous leukoplakia (PVL). Intraoral hyperkeratotic lesions can also be observed in epidermolytic keratodermas, albeit such association has received limited attention in oral and maxillofacial pathology. The authors report on 5 individuals whose plantar (PK) or palmoplantar keratodermas (PPKs) were confirmed after evaluation of gingival leukoplakic biopsies. STUDY DESIGN: Two women and 3 men, ages 18 to 64, presented with solitary or diffuse leukoplakias of the attached gingiva and hard palate, clinically interpreted as PVL. All individuals underwent diagnostic gingival and/or palatal biopsies. RESULTS: Microscopically, the lesions featured verruciform hyperparakeratosis, occasionally conspicuous hypergranulosis and acanthosis. In the spinous cell layer, numerous cells presented with vacuolated cytoplasm and paranuclear eosinophilic condensations that, infrequently, engulfed the nucleus. The histopathologic findings were interpreted as verrucous hyperkeratosis consistent with those described in epidermolytic PPKs. Further evaluation of the individuals for cutaneous lesions disclosed PK or PPKs in all 5 patients. Additionally, the men exhibited elbow and subungual hyperkeratoses. A family history of keratodermas was confirmed in all 3 male individuals. CONCLUSIONS: Gingival and/or palatal OVHLs associated with PK and PPKs display pathognomonic histopathologic features and exhibit indolent biologic behavior. Therefore, any confusion with PVL should be avoided to prevent overtreatment.

An Unusual Maxillary Tumor with Tubuloductal Epithelial Structures, Solid Epithelial Nests and Stromal Odontogenic Ameloblast-Associated Protein Deposits. Tubuloductal/Syringoid Variant of Central Odontogenic Fibroma with Amyloid?

Glandular tumors of jaw bones present, most often, histopathologic features of salivary gland and, rarely, of cutaneous glandular neoplasms. They are thought to originate from odontogenic epithelium. An unusual maxillary tumor presenting as a radiolucency in the periapical area of the right permanent lateral incisor of a 74-year-old male is presented causing root resorption. Preparations revealed occasionally branching tubular cords and ductal structures characterized, mostly, by a bilayer composed of luminal cuboidal to low columnar cytokeratin (CK) 7, Ber-EP4 and occasionally CK8/18 positive cells, and abluminal, CK5/6 positive, basal/basaloid cells revealing nuclear reactivity for p63/p40. Smooth muscle actin and calponin were negative, save for a single focus of calponin positive cells, confirming absence of myoepithelial support or epithelial mesenchymal transition. CK19 exhibited staining of both layers, the luminal being more intense. Eosinophilic secretory material and, occasionally, a luminal pellicle were decorated with CK8/18 and polyclonal carcinoembryonic antigen (CEA). CD1a identified only rare Langerhans' cells and Ki67 decorated 1-2% of abluminal cell nuclei. Small solid nests of epithelial cells were also present. Infrequently, an apparent transition of a nest into a tubular structure was appreciated. The partially inflamed stroma featured multiple hyalinized acellular deposits consistent with amyloid, as confirmed by bright orange Congo red reactivity with apple-green birefringence, which reacted with odontogenic ameloblast-associated (ODAM) protein antibody but not with antibodies for amelotin and secretory calcium-binding phosphoprotein proline-glutamine rich 1. Based on the above, the diagnosis of tubuloductal/syringoid variant of central odontogenic fibroma with ODAM amyloid is favored.

Whole Exome Sequencing Identifies Somatic Variants in an Oral Composite Hemangioendothelioma Characterized by YAP1-MAML2 Fusion.

Composite hemangioendothelioma (CHE) is considered a borderline malignant vascular tumor defined by an admixture of distinct vascular neoplastic components. A 21-year-old female is presented herein with a 1 cm painless mandibular vestibular mass of less than a year duration. The infiltrating tumor was characterized by dilated vascular channels lined by endothelial cells with bland ovoid or round nuclei exhibiting, occasionally, hobnail/matchstick-like arrangement. Intravascular cell proliferations with hyaline globular deposits were also present. Additionally, lobular spindle and epithelioid cell aggregates, as well as slit-like spaces exhibiting a retiform or angiosarcomatous morphology were observed. Intracytoplasmic signet-ring or lipoblast-like vacuolization was also noted. Mitotic activity was exceptionally rare. Vascular spaces and the stroma featured lymphocytes and plasma cells. Neoplastic cells were positive for CD31, CD34, D2-40 and ERG, negative for CAMTA1 and synaptophysin, while type IV collagen highlighted the plasmalemma of most vessels and hyaline globules. Fluorescence in situ hybridization revealed gene rearrangements in both YAP1 and MAML2 genes, in keeping with a YAP1-MAML2 fusion. Whole exome sequencing (WES) identified three missense mutations FLT1 [p.R1016G], PIK3CA [p.H1047L], and C11orf42 [p.A304P] and a mitochondrial frameshift insertion MT-ND4 [c.1107_1108insC; p.P370fs]. These WES results suggest that FLT1 and/or PIK3CA variants may contribute to tumor growth/transformation while the MT-ND4 variant may relate to proliferation, angiogenesis and/or inhibition of apoptosis.

FET(EWSR1)-TFCP2 Rhabdomyosarcoma: An Additional Example of this Aggressive Variant with Predilection for the Gnathic Bones.

An example of a mandibular rhabdomyosarcoma in a 15-year-old male is described featuring EWSR1-TFCP2 fusion with homolateral lymph node metastasis and apparent metastasis to the thoracic vertebra T7. This type of rhabdomyosarcoma has preference for the craniofacial skeleton. Histologically, the tumor was composed of spindle and epithelioid cells characterized by nuclear pleomorphism, cytologic atypia and brisk mitotic activity. Immunohistochemically, it featured diffuse positive nuclear staining MYOD1, only focal staining for myogenin and patchy cytoplasmic staining for desmin. Tumor cells were positive for keratins and nuclear staining for SATB2 was also observed. Interestingly, tumor cells were diffusely positive for calponin. Currently, the patient is under chemotherapy treatment.

Segmental Ipsilateral Odontognathic Dysplasia (Mandibular Involvement in Segmental Odontomaxillary Dysplasia?) and Identification of PIK3CA Somatic Variant in Lesional Mandibular Gingival Tissue.

Segmental odontomaxillary dysplasia (SOD) is a developmental condition of the middle and posterior maxilla featuring dysplastic bone overgrowth, dental abnormalities and, occasionally, various homolateral cutaneous manifestations. Herein, we describe an individual with maxillary abnormality akin to SOD and associated ipsilateral segmental odontomandibular dysplasia. Also, the result of the evaluation of lesional mandibular gingival tissue for overgrowth-related gene variants is reported. An 8-year-old girl presented clinically with congenital maxillary and mandibular alveolar soft tissue enlargement in the area of the premolars. A panoramic radiograph revealed abnormal trabeculation essentially similar to SOD in the maxilla and mandible with congenitally missing maxillary and mandibular first and second premolars and mandibular canines. Diagnostic mandibular bone biopsy was performed and lesional mandibular gingival hyperplastic tissue was obtained for variant analysis of somatic overgrowth genes PIK3CA, AKT1, AKT3, GNAQ, GNA11, MTOR, PIK3R2. Cone beam computerized tomography (CBCT) disclosed osseous abnormalities on the left side of the maxilla and mandible and very mild osseous expansion in the mandible. Histologically, abnormal bone exhibiting prominent reversal lines was present and associated with fibrocollagenous tissue. Genomic DNA analysis disclosed PIK3CAc.1571G>A; pArg524Lys which was seen at a low mosaic level in the blood, indicating a post-zygotic change. Although this case may be a unique disorder, by sharing features with SOD, one can suggest the possibility of mandibular involvement in SOD. The presence of a PIK3CA variant may support the hypothesis that these segmental disorders could be part of the PIK3CA-related overgrowth spectrum.

Self-regressing oral CD30-positive, EBV-negative, T-cell lymphoproliferative lesions. A poorly understood process highlighted by ominous clinicopathologic features and indolent behavior.

OBJECTIVE: Intraoral, primary, CD30-positive (CD30+) T-cell lymphoproliferative disorders (TLPDs) are uncommon, and their clinicopathologic presentation and management can vary and may be challenging. Herein, we present a retrospective study of 4 examples of self-regressing primary CD30+ TLPD affecting the gingiva. STUDY DESIGN: Archived files were retrospectively reviewed for oral CD30+ TLPDs featuring (1) proper immunohistochemical documentation, (2) Epstein-Barr virus negativity, (3) adequate follow-up information corroborating regression, and (4) no history of hematopoietic malignancy or related-mucocutaneous disease. RESULTS: Three women and 1 man (age range, 55-82 years; mean, 68.3 years) presented with rapidly growing gingival ulcers. Microscopic evaluation revealed diffuse infiltration by sheets of large, atypical cells admixed with lymphocytes and eosinophils, showing angiocentric distribution, focal neurotropism, and muscle infiltration. The lesional cells consistently stained for CD3 and CD30 and were variably immunoreactive against CD2, CD4, CD5, CD7, and CD8, but were negative for ALK1 and EBV-encoded small RNA. TCR-γ gene rearrangement studies revealed a monoclonal T-cell population in 1 case. All lesions showed complete regression 2 to 8 weeks postoperatively (mean follow-up, 4.5 weeks). CONCLUSIONS: Notwithstanding their alarming clinicopathologic appearance, there are CD30+ TLPDs confined to the oral cavity that have an indolent course. However, clinical staging is essential to exclude aggressive systemic malignancy.

Acinic cell carcinoma of minor salivary glands: a clinicopathologic study of 21 cases.

PURPOSE: Acinic cell carcinoma (ACC) is an infrequent type of malignant salivary gland tumor. Approximately 16% of all ACCs occur in the mouth according to several small studies. This study was undertaken to 1) report on the clinicopathologic characteristics of 21 intraoral examples, 2) reconfirm the reported indolent behavior of these tumors, and 3) verify the synchronous or metachronous occurrence of other malignancies with ACC. MATERIALS AND METHODS: Twenty-one patients with intraoral ACC were identified in the previous 27 years. Demographic data and histomorphologic characteristics were evaluated and follow-up information was sought. RESULTS: Fifteen patients (68%) were male and 6 female. Seven cases (33.3%) occurred in the buccal mucosa, 6 in the palate (28.6%), 5 involved the upper lip (23.8%), 2 the retromolar mucosa (9.5%), and 1 the lower lip (4.8%). The mean age of patients was 50 years, with the youngest being 13 and the oldest 73. The duration was known in 9 patients and varied from 4 months to longer than 15 years. The size of the tumors varied from 0.6 to 1.6 cm. Where reported, lesions were asymptomatic. Histologically, different patterns that included microcystic, papillary cystic, follicular and solid, and combinations of these types characterized the lesions. Follow-up information was obtained in 12 patients. Eleven patients did not report recurrence or metastatic disease. The follow-up extended from 10 months to 17 years. One patient had 2 recurrences due to erroneous diagnosis that led to inappropriate treatment. After properly diagnosed and treated, this patient has been free of tumor for 4 years. Of interest were the metachronous occurrence of lymphoma in 1 patient and the synchronous occurrence of renal cell carcinoma in another. CONCLUSION: This study confirms the indolent behavior of ACC of minor salivary glands and previous reports on the occasional synchronous or metachronous association of malignant salivary gland tumors with other malignancies.

Mandibular melanotic neuroectodermal tumor of infancy treated conservatively with enucleation.

Melanotic neuroectodermal tumor of infancy (MNTI) is an uncommon, rapidly growing neoplasm of neural crest origin that primarily develops in the maxilla of infants during their first year of life. Mandibular lesions are rare and account for about 6% of all cases. Radical surgical excision is usually curative, but patients should be followed up closely because recurrence may occur in approximately 10% to 20% of cases. In this study, we report a case of mandibular MNTI in a 4-month-old male patient that was conservatively treated with enucleation and curettage and has shown no recurrence 11 years after surgery. Review of the English-language literature revealed that of more than 350 cases of MNTI reported so far, only 23, including the present one, have been encountered in the mandible. Most patients (91.3%) were younger than 1 year, whereas the male-to-female ratio was 1.3:1. Most lesions were treated with wide surgical excision, with only 2 cases being conservatively treated with enucleation. Recurrence was noted in 36.8% of cases at less than 3 months postoperatively. In conclusion, MNTI lesions in the mandible, albeit rare, show high recurrence rate. However, small-size mandibular MNTI lesions may be successfully treated with conservative enucleation. Close follow-up is highly recommended, in particular during the first 6 postoperative months.

Pale (Clear) Cell Acanthoma of the Palate.

Clear cell acanthoma (CCA), also known as pale cell acanthoma, represents a rare benign epidermal tumor with strong predilection for the lower extremities of middle-aged individuals and no frank gender preference. The etiology of CCA is poorly understood, although a localized psoriasiform reaction is favored. Herein, we report on the clinicopathologic and immunohistochemical features, and HPV status of an apparent example of oral CCA. A 58-year-old female presented with a well-circumscribed, asymptomatic, exophytic, sessile and erythematous nodule of the right hard palate, measuring 0.7 cm in greatest dimension. Microscopically, the lesion featured parakeratosis and acanthosis with neutrophilic microabscesses and broad elongated rete pegs. In areas, spinous epithelial cells exhibited pale or clear cytoplasm without nuclear pleomorphism, mitoses or cytologic atypia. The supporting connective tissue revealed mild chronic inflammation with few scattered neutrophils and numerous capillary vessels. PAS histochemical stain with and without diastase disclosed the presence of cytoplasmic glycogen in the pale cells. The majority of glycogen-rich epithelial cells stained strongly for EMA and were negative for D2-40. Ki-67 immunostaining was confined only to the basal cell layer of the epithelium. A diagnosis of CCA was rendered. The lesion was negative for human papillomavirus (HPV) infection, as assessed by HPV-DNA PCR using the MY09/11 primers for the L1 conserved region, thus HPV infection does not appear to contribute to the pathogenesis of oral CCA. In conclusion, we report an intraoral example of CCA in order to raise awareness about this entity.

Orofacial overgrowth with peripheral nerve enlargement and perineuriomatous pseudo-onion bulb proliferations is part of the PIK3CA-related overgrowth spectrum.

Individuals with orofacial asymmetry due to mucosal overgrowths, ipsilateral bone and dental aberrations with perineurial hyperplasia and/or perineuriomatous pseudo-onion bulb proliferations, comprise a recognizable clinical entity. In this article, we describe three individuals with this clinical entity and mosaic PIK3CA variants c.3140A>G (p. His1047Arg), c.328_330delGAA (p. Glu110del), and c.1353_1364del (p.Glu453_Leu456del). We conclude that the identification of these mosaic variants in individuals with orofacial asymmetry presenting histopathologically perineurial hyperplasia and/or intraneural pseudo-onion bulb perineurial cell proliferations supports the inclusion of this clinical entity in the PIK3CA-related overgrowth spectrum.

An unusual ostensible example of intraoral basal cell carcinoma.

An example of oral basal cell carcinoma is presented originating on the posterior mandibular mucosa and gingiva of a 67-year-old female. Histologically, it featured a multifocal pattern. It recurred eight times in a period of 20 years. Tissue samples of the tumor were evaluated with monoclonal antibody Ber-EP4 and were compared with examples of oral mucosa, skin, oral and cutaneous squamous cell carcinoma, peripheral ameloblastoma, ameloblastoma and cutaneous basal cell carcinoma (BCC). Only neoplastic basal cells showed positive immunohistochemical staining. Additionally, microdissected neoplastic areas were evaluated for loss of heterozygosity (LOH) of the PTCH gene with markers D9S303, D9S252 and D9S287. PTCH gene mutations are reported in patients with Gorlin syndrome and sporadic cutaneous BCCs. Loss of one allele was observed with all three markers. Examples of conventional ameloblastomas did not show evidence of LOH. These observations support the inclusion of BCC in the differential diagnosis of appropriate oral mucosal neoplasms.

Solitary oral epidermolytic acanthoma: Case report of a rarely diagnosed entity.

Epidermolytic acanthoma represents a rare localized form of epidermolytic hyperkeratosis, which resembles warty lesions and shows a strong predilection for the genital skin of males. Here, we present an oral solitary epidermolytic acanthoma affecting a 71-year-old Caucasian man. Clinically, the lesion was white, well-circumscribed, and sessile, measuring 2 mm in diameter and located on the posterior mandibular buccal gingiva. Microscopically, pronounced hyperkeratosis and acanthosis, with formation of keratin crypts was observed. Lesional cells of the spinous and granular epithelial layers exhibited prominent intracellular vacuolar degeneration, as well as eosinophilic paranuclear and perinuclear condensations. Intracytoplasmic eosinophilic globules were also seen. No recurrences have been reported. Investigation for low- and high-risk human papillomavirus (HPV) infection failed to reveal positivity for HPV subtypes 6, 11, 16, and 18. Literature review revealed scarce reports of epidermolytic hyperkeratosis-like changes of the oral mucosa associated with malignant neoplasms and inflammatory processes. Epidermolytic acanthoma should be considered in the differential diagnosis of benign epithelial papillomatous lesions of the oral cavity.

Benign and malignant odontogenic neoplasms of the jaws show a concordant nondiscriminatory p63/p40 positive immunophenotype.

OBJECTIVES: Antibody p40, which recognizes exclusively ΔNp63 but not TAp63, has shown diagnostic utility in salivary gland and sinonasal tract malignancies. Although p63 immunophenotypic characterization of odontogenic lesions has been reported, p40 expression has not been previously studied. We aimed to study p40 immunoreactivity in odontogenic tumors (OTs) and odontogenic cysts (OCs) and to investigate possible discriminatory properties of the combined p63/p40 immunoprofile in OTs and OCs. STUDY DESIGN: Fourteen ameloblastomas, 7 adenomatoid odontogenic tumors, 6 calcifying epithelial odontogenic tumors, 1 squamous odontogenic tumor, 4 primary intraosseous odontogenic carcinomas, 5 calcifying odontogenic cysts, 4 glandular odontogenic cysts, 3 odontogenic keratocysts, 3 dentigerous cysts, and 1 each radicular and orthokeratinized cysts were stained for p63 (4A4) and p40 (BC28) antibodies. RESULTS: Ameloblastoma, adenomatoid odontogenic tumor, calcifying epithelial odontogenic tumor, squamous odontogenic tumor, and primary intraosseous odontogenic carcinoma demonstrated concordant p63+/p40+ immunophenotype. P40, similar to p63, highlighted almost all lesional cells of OTs and, overall, the full thickness of the epithelial lining of the cystic areas of OCs and ameloblastoma. The keratin layer of OKC and the adluminal ductal and mucous cells of GOC were p63-/p40-. CONCLUSIONS: Both ΔNp63 and TAp63 isoforms are present in neoplastic and developmental odontogenic lesions; and p63/p40 immunophenotype is nondiscriminatory pertaining to benign and malignant OTs and OCs.

Clinicopathologic and Molecular Characteristics of Familial Cherubism with Associated Odontogenic Tumorous Proliferations.

Cherubism is a rare autosomal dominant condition affecting the jaws and caused by mutations in the gene encoding for the adapter protein SH3BP2 that maps to chromosome 4p16.3. Cherubism is characterized by symmetrically developing bone lesions in the maxilla and mandible. The lesions have been radiographically and histopathologically well-described. Here, we present a family with cherubism with two of its members featuring odontogenic tumorous proliferations in association with persistent central giant cell lesions (CGCL). Specifically, the proband, a 25-year-old male, developed a radiolucent lesion characterized histologically by central odontogenic fibroma-like proliferation in association with a CGCL component, while his mother, at age 57, was diagnosed with primary intraosseous odontogenic carcinoma with areas of benign fibro-osseous lesions. In both patients the lesions occurred in the anterior mandible and presented with clinical enlargement. The son underwent incisional biopsy and did not have additional treatment. His mother underwent extensive mandibulectomy due to widespread tumor. The son has two affected children with classic cherubism while a third child at age 5, had not shown any features of the disease. Mutation analysis of three affected members resulted in the identification of a heterozygous mutation in SH3BP2 (c.1244G>C; p.Arg415Pro). To the best of our knowledge, association of cherubism with odontogenic neoplastic lesions has hitherto not been reported in the literature, thus suggesting a relationship between cherubism with disturbed odontogenesis.