Odontogenic Carcinosarcoma: Clinicopathologic and Molecular Features of Three Cases, a Literature Review and Nomenclature Proposal.

BACKGROUND: Odontogenic carcinosarcoma (OCS) is a rare odontogenic malignancy with limited characterization and unexplored molecular features. We report clinicopathologic and molecular findings in 3 additional OCS and review the literature. METHODS: 3 OCS (5.1%) were identified among 59 malignant odontogenic tumors (in our archives from 1992 to 2022). Clinical, radiologic, histopathologic, immunophenotypic, and molecular findings were reviewed. Data from prior case reports and systematic or non-systematic reviews were extracted for analysis. RESULTS: Three mandibular OCS (age range: 66 to 72 years; 1 male, 2 females) were identified. Case 1 had novel clear-cell morphology, multiple recurrences, and a lethal outcome 28 months after resection. EWSR1 rearrangements were negative, but the tumor showed focal nuclear ß-catenin and strong LEF-1 immunoreactivity. Case 2 demonstrated ameloblastic and sclerosing features and encased the inferior alveolar nerve; the patient was disease-free 22 months after resection with adjuvant chemoradiation therapy. LEF-1 was again strongly positive, and next-generation sequencing demonstrated 9p region-(CDKN2A, CDKN2B) copy number loss, and 12q region-(MDM2, CDK4) copy number gain. Case 3 showed clear-cell and markedly sclerosing features; no follow-up information was available. Literature review along with the current cases yielded 20 cases. OCS showed a male predilection (1.5:1), mandibular predominance (80%, typically posterior), and a bimodal age distribution (modes: 27.7 years, 62.7 years). OCS presented as masses (100%), often with pain (55%), and paresthesia (45%). Tumors were typically radiolucent (88.9%), with bone destruction (61.1%), and/or tooth effacement (27.8%). Preoperative biopsy was sensitive for malignancy (85.7%). At least 45% show evidence for a precursor lesion. 3-year DSS and DFS were 58% and 35%, respectively. Regional and distant (usually lung) metastatic rates were 25% and 31.3%, respectively. Increased mitotic rates and presence of tumor necrosis trended toward worse DSS and DFS. CONCLUSION: OCS is a rare but aggressive malignancy, often arising from precursor tumors and may represent a terminal phenotype rather than a distinct entity. We describe novel clear-cell and sclerosing morphologies. Wnt pathway alterations appear important. Mitotic rates and necrosis may be adverse prognosticators. In keeping with nomenclature trends in other sites, OCS may be more appropriately designated as "biphasic sarcomatoid odontogenic carcinomas."

Microsecretory Adenocarcinoma of Salivary Glands: An Expanded Series of 24 Cases.

Microsecretory adenocarcinoma (MSA) is a recently described salivary gland tumor with a characteristic histologic and immunophenotypic profile and recurrent MEF2C-SS18 fusions. Because only six cases of MSA have been published, its complete clinicopathologic spectrum is unclear, and its biologic behavior has not been documented. Here, we present an updated and expanded experience of 24 MSA cases. All cases of MSA were obtained from the authors' files. Immunohistochemistry for S100, SOX10, p63, p40, SMA, calponin, and mammaglobin was performed. Molecular analysis was performed by targeted RNA sequencing, SS18 break apart fluorescence in situ hybridization, and/or reverse transcriptase polymerase chain reaction for MEF2C-SS18 fusion. Clinical follow-up was obtained from medical records. A total of 24 MSA cases were collected, from 13 women and 11 men, ranging from 17 to 83 years (mean 49.5 years). The vast majority (23 of 24) arose in the oral cavity, with the palate (n = 14) and buccal mucosa (n = 6) as the most frequent subsites. Tumors showed consistent histologic features including: (1) microcystic tubules, (2) flattened intercalated duct-like cells, (3) monotonous oval hyperchromatic nuclei, (4) abundant basophilic luminal secretions, (5) fibromyxoid stroma, and (6) circumscribed borders with subtle infiltration. The tumors were very consistently positive for S100 (24 of 24), p63 (24 of 24), and SOX10 (14 of 14) and negative for p40 (0 of 21), calponin (0 of 12) and mammaglobin (0 of 16), while SMA (4 of 20) was variable. MEF2C-SS18 fusion was demonstrated in 21 of 24 cases; in the remaining 3 cases with insufficient RNA, SS18 break apart FISH was positive. Treatment information was available in 17 cases, all of which were managed with surgery only. In 14 cases with follow-up (1-216 months, mean 30), no cases recurred or metastasized. MSA is a distinct salivary gland neoplasm with remarkably consistent clinical, histologic, immunophenotypic, and genetic features that generally behaves in an indolent manner following surgery alone. These observations solidify MSA as a unique, low-grade salivary gland carcinoma that warrants inclusion in the next version of the WHO classification of head and neck tumors.

Odontogenic and Developmental Oral Lesions in Pediatric Patients.

This article reviews odontogenic and developmental oral lesions encountered in the gnathic region of pediatric patients. The process of odontogenesis is discussed as it is essential to understanding the pathogenesis of odontogenic tumors. The clinical presentation, microscopic features, and prognosis are addressed for odontogenic lesions in the neonate (dental lamina cysts/gingival cysts of the newborn, congenital (granular cell) epulis of the newborn, melanotic neuroectodermal tumor, choristoma/heterotopia, cysts of foregut origin), lesions associated with unerupted/erupting teeth (hyperplastic dental follicle, eruption cyst, dentigerous cyst, odontogenic keratocyst/keratocystic odonogenic tumor, buccal bifurcation cyst/inflammatory collateral cyst) and pediatric odontogenic hamartomas and tumors (odontoma, ameloblastic fibroma, ameloblastoma, adenomatoid odontogenic tumor, primordial odontogenic tumor). Pediatric odontogenic and developmental oral lesions range from common to rare, but familiarity with these entities is essential due to the varying management implications of these diagnoses.

Proliferative Verrucous Leukoplakia: An Expert Consensus Guideline for Standardized Assessment and Reporting.

The many diverse terms used to describe the wide spectrum of changes seen in proliferative verrucous leukoplakia (PVL) have resulted in disparate clinical management. The objective of this study was to produce an expert consensus guideline for standardized assessment and reporting by pathologists diagnosing PVL related lesions. 299 biopsies from 84 PVL patients from six institutions were selected from patients who had multifocal oral leukoplakic lesions identified over several years (a minimum follow-up period of 36 months). The lesions demonstrated the spectrum of histologic features described in PVL, and in some cases, patients developed oral cavity squamous cell carcinoma (SCC). An expert working group of oral and maxillofacial and head and neck pathologists reviewed microscopic features in a rigorous fashion, in combination with review of clinical photographs when available. The working group then selected 43 single slide biopsy cases for whole slide digital imaging (WSI) review by members of the consensus conference. The digital images were then reviewed in two surveys separated by a washout period of at least 90 days. Five non-PVL histologic mimics were included as controls. Cases were re-evaluated during a consensus conference with 19 members reporting on the cases. The best inter-observer diagnostic agreement relative to PVL lesions were classified as "corrugated ortho(para)hyperkeratotic lesion, not reactive" and "SCC" (chi-square p = 0.015). There was less than moderate agreement (kappa < 0.60) for lesions in the "Bulky hyperkeratotic epithelial proliferation, not reactive" category. There was ≥ moderate agreement (> 0.41 kappa) for 35 of 48 cases. This expert consensus guideline has been developed with support and endorsement from the leadership of the American Academy of Oral and Maxillofacial Pathology and the North American Society of Head and Neck Pathologists to recommend the use of standardized histopathologic criteria and descriptive terminology to indicate three categories of lesions within PVL: (1) "corrugated ortho(para)hyperkeratotic lesion, not reactive;" (2) "bulky hyperkeratotic epithelial proliferation, not reactive;" and (3) "suspicious for," or "squamous cell carcinoma." Classification of PVL lesions based on a combination of clinical findings and these histologic descriptive categories is encouraged in order to standardize reporting, aid in future research and potentially guide clinical management.

Inter-observer Variability in the Diagnosis of Proliferative Verrucous Leukoplakia: Clinical Implications for Oral and Maxillofacial Surgeon Understanding: A Collaborative Pilot Study.

The use of diverse terminology may lead to inconsistent diagnosis and subsequent mistreatment of lesions within the proliferative verrucous leukoplakia (PVL) spectrum. The objectives of this study were: (a) to measure inter-observer variability between a variety of pathologists diagnosing PVL lesions; and (b) to evaluate the impact of diverse terminologies on understanding, interpretation, and subsequent treatment planning by oral and maxillofacial surgeons (OMFS). Six oral pathologists (OP) and six head and neck pathologists (HNP) reviewed 40 digitally scanned slides of PVL-type lesions. Inter-observer agreement on diagnoses was evaluated by Fleiss' kappa analysis. The most commonly used diagnostic terminologies were sent to ten OMFS to evaluate their resulting interpretations and potential follow-up treatment approaches. The overall means of the surgeons' responses were compared by Student t test. There was poor inter-observer agreement between pathologists on the diagnosis of PVL lesions (κ = 0.270), although there was good agreement (κ = 0.650) when diagnosing frankly malignant lesions. The lowest agreement was in diagnosing verrucous hyperplasia (VH) with/without dysplasia, atypical epithelial proliferation (AEP), and verrucous carcinoma (VC). The OMFS showed the lowest agreement on identical categories of non-malignant diagnoses, specifically VH and AEP. This study demonstrates a lack of standardized terminology and diagnostic criteria for the spectrum of PVL lesions. We recommend adopting standardized criteria and terminology, proposed and established by an expert panel white paper, to assist pathologists and clinicians in uniformly diagnosing and managing PVL spectrum lesions.

Recurrent oral ulceration: Etiology, classification, management, and diagnostic algorithm.

Recurrent oral ulcerations are manifestations of a heterogeneous set of both general and more-or-less specific oral diseases due to numerous potential etiologies, including, but not limited to, infections, medications, autoimmune disease, and other systemic disease. This review discusses the pathogenesis, clinical presentation, diagnosis, and management of the common causes of recurrent oral ulceration. The following types/etiologies of recurrent oral ulceration are covered: traumatic ulceration, chemical ulceration, recurrent aphthous stomatitis, medication-related ulceration, infectious ulceration, mucocutaneous disease, and autoimmune/systemic disease. A diagnostic algorithm for recurrent oral ulceration is also presented.

Reappraising localized juvenile spongiotic gingival hyperplasia.

BACKGROUND: Localized juvenile spongiotic gingival hyperplasia (LJSGH) is a gingival lesion of unknown cause. The purpose of this study is to present a series of LJSGH cases and compare the findings with the literature. METHODS: After obtaining institutional review board approval, cases of biopsy-proven LJSGH from 2008 through 2018 were retrieved from the University of Pittsburgh Oral Pathology Biopsy Service archives and reviewed. In addition, a comprehensive review of the literature was performed. RESULTS: Twenty-eight cases were identified. No significant sex predilection was noted (male-female ratio, 1.25:1). The age range was from 3 through 64 years (median, 14.5 years). Twenty-six cases (92.9%) affected the anterior facial gingiva, and 27 cases (96.4%) occurred in the maxilla. The most common clinical impression was pyogenic granuloma (55.6%). All cases presented with the same histopathology regardless of patient age. Cytokeratin 19 immunohistochemistry was used to confirm the diagnosis in cases that occurred in patients outside the typically affected demographic. CONCLUSIONS: Our results are in concordance with the literature, with most cases localized to the anterior maxillary gingiva of children and young adults. However, 5 of our cases occurred in adults. Cytokeratin 19 is of diagnostic utility in these cases. PRACTICAL IMPLICATIONS: Although LJSGH is most commonly seen in children and young adults, we present cases occurring in adults. Our series and the literature found that LJSGH is not restricted to juveniles and that it can be multifocal. Dentists should be aware of this when formulating a differential diagnosis. Therefore, the nomenclature may not represent the disease spectrum of these gingival lesions.

Ectomesenchymal Chondromyxoid Tumor: A Neoplasm Characterized by Recurrent RREB1-MKL2 Fusions.

Ectomesenchymal chondromyxoid tumor is a rare and benign neoplasm with a predilection for the anterior dorsal tongue. Despite morphologic heterogeneity, most cases are characterized by a proliferation of bland spindle cells with a distinctive reticular growth pattern and myxoid stroma. The immunophenotype of these neoplasms is likewise variable; most cases express glial fibrillary acid protein and S100 protein, with inconsistent reports of keratin and myoid marker expression. The molecular pathogenesis is poorly understood; however, a subset of cases has been reported to harbor EWSR1 gene rearrangement. Following identification of an RREB1-MKL2 fusion gene by RNA Sequencing in an index patient, a retrospective review of additional cases of ectomesenchymal chondromyxoid tumors was performed to better characterize the clinical, immunohistochemical, and molecular attributes of this neoplasm. A total of 21 cases were included in this series. A marked predisposition for the dorsal tongue was confirmed. Most cases conformed to prior morphologic descriptions; however, hypercellularity, hyalinized stroma, and necrosis were rare attributes not previously emphasized. The neoplastic cells frequently coexpressed glial fibrillary acid protein, S100 protein, keratin, smooth muscle actin, and/or desmin; a single case was found to contain significant myogenin expression. An RREB1-MKL2 fusion product was identified in 19 tumors (90%), a single tumor (5%) had an EWSR1-CREM fusion product, and the remaining case lacked any known fusion gene by RNA Sequencing. The latter 2 cases subtly differed morphologically from many in the cohort. This series illustrates that recurrent RREB1-MKL2 fusions occur in most, perhaps all, cases of ectomesenchymal chondromyxoid tumor.

Analytic survey of 57 cases of oral metastases.

BACKGROUND: Oral lesions have been reported among the first signs of an undiagnosed metastatic disease. Accurate diagnosis of an occult metastasis remains critical in determining the treatment course. Previous studies regarding oral metastatic tumors present varied data regarding the most frequent metastases to the oral cavity. These discrepancies echo the changes in incidence rates for certain malignancies over time and demonstrate the need for periodic updates in oral metastasis studies. METHODS: Using Text Information Extraction System, a de-identified pathology database, we compiled 57 cases over a period of 19 years using key terms to search for oral metastases. RESULTS: For both males and females, the most common primary sites were lung (21.1%), liver (12.3%), breast (10.5%), kidney (10.5%), and colorectal (8.8%). We found an equal number of lung and breast metastases in females and metastases from the liver to be the most prevalent for males. In most of our cases (54.9%), the patient had no history of the primary malignancy and the oral lesion preceded awareness of the widespread cancer. CONCLUSIONS: As a departure from many previous case series, we found lung and breast metastases to be equally numerous in women and liver as the most common oral metastasis in men. Also, we identified a tendency for the patient to present with a previous history in certain malignancies, such as breast cancer, whereas in other malignancies, such as renal cell carcinoma, our data demonstrated a propensity to present in the oral cavity without history of a primary tumor.

Relevance of smoking interventions for dental clinic patients with smoking-related disease.

OBJECTIVES: Despite a decline in cigarette smoking in the United States, high rates persist among the socioeconomically underserved who consequently are at risk for smoking-related disease (SRD). Since academically affiliated dental clinics are more likely to encounter underserved patients, smoking interventions could address both the oral and systemic risks of continued smoking. To determine the relevance of providing smoking counseling in the context of SRD, this study examined the prevalence of smoking and its associations with socioeconomic status (SES), SRD and its sequela, and medication use. METHODS: Socioeconomic and smoking status was determined from 1,797 electronic health records of a sample of patients at a Pennsylvania dental clinic in 2010. Low SES included patients who were covered by a Medicaid program (MA) or "self-payers." High SES encompassed those with an employment-based commercial dental insurance (COM). Self-reported smoking rates were compared with patients' SES, SRDs or sequela, and medications being used for the management of their SRDs. RESULTS: Overall, 41.7 percent of these patients were smoking. Smoking was related to SES with the highest rate (52.7 percent) among MA patients compared with 31.5 percent in patients with COM. In addition, 37 percent of patients with SRD or sequela and 33 percent who were taking medications for their management were smoking. CONCLUSIONS: Academically affiliated dental clinics are more likely to encounter underserved patients who smoke and have SRD. For greater patient impact and receptivity, it is essential that tobacco cessation interventions emphasize the risks of smoking on systemic as well as oral health.

Intraoral Pseudo-Onion Bulb Intraneural Proliferations in a Patient with Hemimandibular Hyperplasia: A Case Report and Review of the Literature.

This report and review of the literature describes a case of benign intraoral lesions of perineurial origin in a patient with symptomatic hemimandibular hyperplasia causing partial denture soreness. Perineuriomas are a benign peripheral nerve sheath tumor composed of perineurial cells. Intraoral perineuriomas are an extremely rare entity. Two main types of perineuriomas have been described: intraneural and extraneural perineuriomas. A third, similar entity, called an intraneural pseudoperineuriomatous proliferation, has recently been proposed in the literature as a separate and distinctive diagnosis. This report describes the histologic and clinical presentation of intraneural pseudoperineuriomatous proliferations in a patient with hemimandibular hyperplasia.

Cervicofacial subcutaneous emphysema: a clinical case and review of the literature.

Cervicofacial subcutaneous emphysema is a known, rare complication of both dental and surgical procedures. Cervicofacial subcutaneous emphysema arises when air is forced beneath the tissues, leading to swelling, crepitus on palpation, and the potential of the air to spread along the fascial planes. This report presents a case of cervicofacial subcutaneous emphysema in a patient who had undergone surgical extraction of the mandibular right first molar. The dentist in this case used a compressed air-driven handpiece to section the tooth. This forced air, under high pressure, into the subcutaneous tissue spaces. The patient presented with severe hemifacial swelling and crepitus on palpation. Computed tomographic examination revealed air subcutaneously, and a diagnosis of cervicofacial subcutaneous emphysema was made.

A subset of ectomesenchymal chondromyxoid tumours of the tongue show EWSR1 rearrangements and are genetically linked to soft tissue myoepithelial neoplasms: a study of 11 cases.

AIMS: Ectomesenchymal chondromyxoid tumour (ECT) is a rare, benign intraoral neoplasm showing a predilection for the anterior dorsum of the tongue. The World Health Organization includes ECT in the pathological spectrum of soft tissue myoepithelioma. EWS RNA-binding protein 1 gene (EWSR1) rearrangement is found in 45% of cutaneous, soft tissue and bone myoepithelial neoplasms, and pleomorphic adenoma gene 1 (PLAG1) aberrations are found in 37% of EWSR1-negative soft tissue myoepitheliomas. The aim of this study was to evaluate the presence of EWSR1 and PLAG1 rearrangements in ECTs. METHODS AND RESULTS: Eleven formalin-fixed, paraffin-embedded ECTs were evaluated with fluorescence in-situ hybridization probes for EWSR1 (22q12) and PLAG1 (8q12). Among the 11 ECTs tested, three (27.3%) showed EWSR1 rearrangement in >15% of tumour cells, whereas eight (72.7%) cases did not show EWSR1 rearrangement. Eight of nine (89%) ECTs showed gain of EWSR1, probably representing gain of all or part of chromosome 22, in a varying proportion of neoplastic cells ranging between 1.4% and 27.9%. PLAG1 rearrangement was not detected in the successfully hybridized tissue sections (7/11). No correlation was observed between the molecular and histopathological findings, such as morphology of the neoplastic cells, the presence of atypia, and matrical type. CONCLUSIONS: We identified EWSR1 rearrangement in >25% of ECTs. These results suggest that some ECTs are at least genetically related to myoepithelioma of the soft parts. Finally, PLAG1 aberrations do not appear to be critical in the pathogenesis of ECT of the tongue.

Hyalinizing clear cell carcinoma of the head and neck: Case series and update.

BACKGROUND: Hyalinizing clear cell carcinoma (HCCC) is a rare neoplasm of salivary gland origin which is low-grade in nature. In this series, we report on 9 cases of HCCC and update the literature. METHODS: A comprehensive literature search was performed. Our institutional database was queried for cases of HCCC. Pathology reports and slides were reviewed. Data was extracted, including demographics, staging, primary treatment, histopathologic findings, recurrence, and disease status. Statistical analysis was performed using a Pearson's chi-square test. RESULTS: One hundred thirty-six total cases were included for analysis. The overall recurrence rate was 19.8%. Necrosis was associated with risk of recurrence (p = .003). Positive margins and lymph node status were associated with risk of recurrence. Prognosis was good with only 3 of 82 patients reported dying with disease. CONCLUSION: HCCC has an overall good prognosis with potential for aggressive behavior. The presence of necrosis, locoregional disease, or positive margins is associated with risk for recurrence.

Mixed radiopaque and radiolucent lesion of the maxillary sinus: a radiographic challenge.

This article describes 3 patients, each of whom presented with an asymptomatic mixed radiopaque and radiolucent lesion of the maxillary sinus associated with a nonvital tooth. Based on the radiographic findings, a diagnosis of a collapsed (ruptured) radicular cyst was rendered in each case. A tissue biopsy was performed in 1 case, and the results supported the diagnosis. The radiographic and histopathological features, etiology, pathophysiology, and radiographic differential diagnosis of this condition are discussed.

Seven Cases of Proliferative Verrucous Leukoplakia: The Need for a High Clinical Suspicion Among Dental Practitioners.

Proliferative verrucous leukoplakia is a distinct precancerous condition with a high rate of recurrence and malignant transformation over time. Proliferative verrucous leukoplakia has no specific histopathologic presentation; therefore, emphases must be on clinical presentation and history to make a diagnosis giving the need for a high clinical suspicion. This condition is very important for the general dentist to recognize. Here we describe the clinical and microscopic features of seven cases of proliferative verrucous leukoplakia, with two cases which demonstrated malignant transformation (hybrid carcinoma and squamous cell carcinoma).

An in vivo model to assess magnesium alloys and their biological effect on human bone marrow stromal cells.

Magnesium (Mg) alloys have many unique qualities which make them ideal candidates for bone fixation devices, including biocompatibility and degradation in vivo. Despite a rise in Mg alloy production and research, there remains no standardized system to assess their degradation or biological effect on human stem cells in vivo. In this study, we developed a novel in vivo model to assess Mg alloys for craniofacial and orthopedic applications. Our model consists of a collagen sponge seeded with human bone marrow stromal cells (hBMSCs) around a central Mg alloy rod. These scaffolds were implanted subcutaneously in mice and analyzed after eight weeks. Alloy degradation and biological effect were determined by microcomputed tomography (microCT), histological staining, and immunohistochemistry (IHC). MicroCT showed greater volume loss for pure Mg compared to AZ31 after eight weeks in vivo. Histological analysis showed that hBMSCs were retained around the Mg implants after 8 weeks. Furthermore, immunohistochemistry showed the expression of dentin matrix protein 1 and osteopontin around both pure Mg and AZ31 with implanted hBMSCs. In addition, histological sections showed a thin mineral layer around all degrading alloys at the alloy-tissue interface. In conclusion, our data show that degrading pure Mg and AZ31 implants are cytocompatible and do not inhibit the osteogenic property of hBMSCs in vivo. These results demonstrate that this model can be used to efficiently assess the biological effect of corroding Mg alloys in vivo. Importantly, this model may be modified to accommodate additional cell types and clinical applications. STATEMENT OF SIGNIFICANCE: Magnesium (Mg) alloys have been investigated as ideal candidates for bone fixation devices due to high biocompatibility and degradation in vivo, and there is a growing need of establishing an efficient in vivo material screening system. In this study, we assessed degradation rate and biological effect of Mg alloys by transplanting Mg alloy rod with human bone marrow stromal cells seeded on collagen sponge subcutaneously in mice. After 8 weeks, samples were analyzed by microcomputed tomography and histological staining. Our data show that degrading Mg alloys are cytocompatible and do not inhibit the osteogenic property of hBMSCs in vivo. These results demonstrate that this model can be used to efficiently assess the biological effect of corroding Mg alloys in vivo.