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.

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.

Signet-ring cell sinus histiocytosis: report of the clinicopathologic characteristics of 4 cases with emphasis on the differential diagnosis of signet-ring cell lesions.

Signet-ring cell sinus histiocytosis (SRCSH) represents a distinctly rare reactive phenomenon predominantly affecting axillary and pelvic lymph nodes (LNs) of individuals with breast or prostatic adenocarcinoma. Reports of SRCSH in the literature are sparse with only 12 previous examples, thus underscoring the rarity of this process. Here, we report 4 additional SRCSH cases affecting 2 women and 2 men (M/F = 1:1; age range: 50-71 years; mean age = 61 years). In the 2 men, pelvic LNs were excised during radical cystoprostatectomy for genitourinary cancer, whereas in one woman, SRCSH was incidentally discovered in axillary LNs during mastectomy for breast adenocarcinoma. The other female patient presented with a history of aortic valve replacement and enlarged supraclavicular LNs. Microscopically, all involved LNs exhibited marked distention with filling of the subcapsular and medullary sinuses by sheets of signet-ring histiocytes containing a singular large, cytoplasmic vacuole and a crescentic nucleus. Overt cytologic atypia, pleomorphism, and mitoses were absent. Erythrophagocytosis and occasional fibrosis were appreciated. None of the LNs with SRCSH showed evidence of metastatic tumor. Immunohistochemically, signet-ring sinus histiocytes were invariably positive for CD68 and CD163 but were negative for pancytokeratins. The histopathologic characteristics of SRCSH, albeit bland, in conjunction with the patient's medical history, may be misinterpreted as metastatic adenocarcinoma with signet-ring cell configuration. Immunohistochemical confirmation of the histiocytic lineage of the lesional cells in SRCSH usually suffices for rendering an accurate diagnosis. The underlying pathogenetic mechanism and possible biologic significance of SRCSH remain currently unknown.

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.

Primary mucosal melanomas of the head and neck are characterised by overexpression of the DNA mutating enzyme APOBEC3B.

AIMS: Primary head/neck mucosal melanomas (MMs) are rare and exhibit aggressive biologic behaviour and elevated mutational loads. The molecular mechanisms responsible for high genomic instability observed in head/neck MMs remain elusive. The DNA cytosine deaminase APOBEC3B (A3B) constitutes a major endogenous source of mutation in human cancer. A3B-related mutations are identified through C-to-T/-G base substitutions in 5'-TCA/T motifs. Herein, we present immunohistochemical and genomic data supportive of a role for A3B in head/neck MMs. METHODS AND RESULTS: A3B protein levels were assessed in oral (n = 13) and sinonasal (n = 13) melanomas, and oral melanocytic nevi (n = 13) by immunohistochemistry using a custom rabbit α-A3B mAb (5210-87-13). Heterogeneous, selective-to-diffuse, nuclear only, A3B immunopositivity was observed in 12 of 13 (92.3%) oral melanomas (H-score range = 9-72, median = 40) and 8 of 13 (62%) sinonasal melanomas (H-score range = 1-110, median = 24). Two cases negative for A3B showed prominent cytoplasmic staining consistent with A3G. A3B protein levels were significantly higher in oral and sinonasal MMs than intraoral melanocytic nevi (P < 0.0001 and P = 0.0022, respectively), which were A3B-negative (H-score range = 1-8, median = 4). A3B levels, however, did not differ significantly between oral and sinonasal tumours (P > 0.99). NGS performed in 10 sinonasal MMs revealed missense NRAS mutations in 50% of the studied cases and one each KIT and HRAS mutations. Publicly available whole-genome sequencing (WGS) data disclosed that the number of C-to-T mutations and APOBEC3 enrichment score were markedly elevated in head/neck MMs (n = 2). CONCLUSION: The above data strongly indicate a possible role for the mutagenic enzyme A3B in head/neck melanomagenesis, but not benign melanocytic neoplasms.

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.

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

[This corrects the article DOI: 10.1016/j.xhgg.2020.100009.].

Polymorphous Adenocarcinoma, Low Grade Variant, Colliding with a Neurofibroma.

Collision tumors, composed of two distinct benign or malignant neoplasms, are rarely reported in the oral cavity. We present a case of a 61-year-old female with an asymptomatic non-demarcated lump on the soft palate of unknown duration. An incisional biopsy revealed the presence of two neoplastic populations, a neurofibroma that was partially infiltrated by a polymorphous adenocarcinoma, low-grade variant. Total surgical excision was performed, with uneventful follow-up period. The development of collision tumors may be incidental, although molecular events may influence the pathogenetic mechanism of the phenomenon.

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.

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.

Salivary Mucinous Adenocarcinoma Is a Histologically Diverse Single Entity With Recurrent AKT1 E17K Mutations: Clinicopathologic and Molecular Characterization With Proposal for a Unified Classification.

Mucin-producing salivary adenocarcinomas were historically divided into separate colloid carcinoma, papillary cystadenocarcinoma, and signet ring cell carcinoma diagnoses based on histologic pattern, but have recently been grouped together in the adenocarcinoma not otherwise specified category. It is currently unclear if these tumors represent 1 or more distinct entities and how they are related to well-circumscribed papillary mucinous lesions with recurrent AKT1 E17K mutations that were recently described as salivary intraductal papillary mucinous neoplasm. Here, we sought to evaluate the clinicopathologic and molecular features of salivary mucinous adenocarcinomas to clarify their classification. We identified 17 invasive mucin-producing salivary adenocarcinomas, 10 with a single histologic pattern, and 7 with mixed patterns. While most tumors demonstrated papillary growth (n=15), it was frequently intermixed with colloid (n=6) and signet ring (n=3) architecture with obvious transitions between patterns. All were cytokeratin 7 positive (100%) and cytokeratin 20 negative (0%). Next-generation sequencing performed on a subset demonstrated recurrent AKT1 E17K mutations in 8 cases (100%) and TP53 alterations in 7 cases (88%). Of 12 cases with clinical follow-up (median: 17 mo), 4 developed cervical lymph node metastases, all of which had colloid or signet ring components. Overall, overlapping histologic and immunohistochemical features coupled with recurrent AKT1 E17K mutations across patterns suggests that mucin-producing salivary adenocarcinomas represent a histologically diverse single entity that is closely related to tumors described as salivary intraductal papillary mucinous neoplasm. We propose a unified mucinous adenocarcinoma category subdivided into papillary, colloid, signet ring, and mixed subtypes to facilitate better recognition and classification of these tumors.

Endogenous APOBEC3B overexpression characterizes HPV-positive and HPV-negative oral epithelial dysplasias and head and neck cancers.

The DNA cytosine deaminase APOBEC3B (A3B) is a newly recognized endogenous source of mutations in a range of human tumors, including head/neck cancer. A3B inflicts C-to-T and C-to-G base substitutions in 5'-TCA/T trinucleotide motifs, contributes to accelerated rates of tumor development, and affects clinical outcomes in a variety of cancer types. High-risk human papillomavirus (HPV) infection causes A3B overexpression, and HPV-positive cervical and head/neck cancers are among tumor types with the highest degree of APOBEC signature mutations. A3B overexpression in HPV-positive tumor types is caused by the viral E6/E7 oncoproteins and may be an early off-to-on switch in tumorigenesis. In comparison, less is known about the molecular mechanisms responsible for A3B overexpression in HPV-negative head/neck cancers. Here, we utilize an immunohistochemical approach to determine whether A3B is turned from off-to-on or if it undergoes a more gradual transition to overexpression in HPV-negative head/neck cancers. As positive controls, almost all HPV-positive oral epithelial dysplasias and oropharyngeal cancers showed high levels of nuclear A3B staining regardless of diagnosis. As negative controls, A3B levels were low in phenotypically normal epithelium adjacent to cancer and oral epithelial hyperplasias. Interestingly, HPV-negative and low-grade oral epithelial dysplasias showed intermediate A3B levels, while high-grade oral dysplasias showed high A3B levels similar to oral squamous cell carcinomas. A3B levels were highest in grade 2 and grade 3 oral squamous cell carcinomas. In addition, a strong positive association was found between nuclear A3B and Ki67 scores suggesting a linkage to the cell cycle. Overall, these results support a model in which gradual activation of A3B expression occurs during HPV-negative tumor development and suggest that A3B overexpression may provide a marker for advanced grade oral dysplasia and cancer.

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.

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.

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.

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.