Clinicopathological characteristics and diagnostic accuracy of BRAF mutations in ameloblastoma: A Bayesian network analysis.

OBJECTIVE: This Bayesian network meta-analysis was performed to analyze the associations between clinicopathological characteristics and BRAF mutations in ameloblastoma (AM) patients and to evaluate the diagnostic accuracy. MATERIALS AND METHODS: Four electronic databases were searched from 2010 to 2024. The search terms used were specific to BRAF and AM. Observational studies or randomized controlled trials were considered eligible. The incidence of BRAF mutation and corresponding clinicopathological features in AM patients were subjected to Bayesian network analyses and diagnostic accuracy evaluation. RESULTS: A total of 937 AM patients from 20 studies were included. The pooled prevalence of BRAF mutations in AM patients was 72%. According to the Bayesian network analysis, BRAF mutations are more likely to occur in younger (odds ratio [OR], 2.3; credible interval [CrI]: 1.2-4.5), mandible site (OR, 3.6; 95% CrI: 2.7-5.2), and unicystic (OR, 1.6; 95% CrI: 1.1-2.4) AM patients. Similarly, higher diagnostic accuracy was found in the younger, mandible, and unicystic AM groups. CONCLUSIONS: The incidence, risk, and diagnostic accuracy of BRAF mutation in AM were greater in younger patients, those with mandible involvement, and those with unicystic AM than in patients with other clinicopathological features. In addition, there was a strong concordance in the diagnostic accuracy between molecular tests and immunohistochemical analysis.

Orthokeratinized odontogenic cysts: A clinicopathologic study of 159 cases and molecular evidence for the absence of PTCH1 mutations.

BACKGROUND: Orthokeratinized odontogenic cyst (OOC), a newly designated entity of odontogenic cysts, is an intraosseous jaw cyst that is entirely or predominantly lined by orthokeratinized squamous epithelium. The aim of this study was to report a large series of OOC to substantiate its clinicopathologic profiles and to investigate PTCH1 mutations in OOCs. METHOD: The clinicopathologic features of 167 OOCs from 159 patients were analyzed and the immunohistochemical expression of markers related to cell differentiation and proliferation was evaluated. Furthermore, PTCH1 mutations were analyzed in 14 fresh samples of OOC. RESULTS: OOCs occurred mostly in the third and fourth decades (60.4%) with a male predilection (66.7%). The lesions developed more often in the mandible than maxilla, primarily in the posterior mandible and ramus. Eight patients (5.0%) showed multiple locations of either bilateral posterior mandible (n = 6) or both the maxilla and mandible. Radiographically, the majority of OOCs (91.2%) showed a well-demarcated, unilocular radiolucency with 14 multilocular cases (8.8%). A follow-up of 131 patients (123 treated by enucleation with or without marsupialization and eight by peripheral ostectomy) revealed no recurrence during an average period of 4.56 years after surgery. Immunohistochemistry indicated lower proliferative activity and a varying epithelial differentiation pattern in OOC compared with odontogenic keratocysts (OKC). No PTCH1 mutation was detected, except for three known single nucleotide polymorphisms. CONCLUSION: The clinicopathological and molecular differences between OOC and OKC justified their separation, and unlike OKCs, OOCs did not harbor PTCH1 mutations, suggesting different pathogenesis underlying these two jaw cysts.

Salivary gland papillary adenocarcinoma with intestinal-like features: Clinicopathologic, immunohistochemical, and genetic study of six cases.

BACKGROUND: Salivary gland tumors with papillary architecture and intestinal-like mucinous cytologic features are rare. Their clinicopathologic and genetic features are not fully understood, and whether they represent one separate entity remains unclear. METHODS: Six salivary adenocarcinomas with papillary architecture and intestinal-like mucinous cytologic features were reported. Immunostaining was done for CK7, CK20, CDX2, SOX10, S100, MUC1, MUC2, and MUC5AC. Tumor DNA samples were extracted for Sanger sequencing. Previously reported morphology-analogous cases were reviewed. RESULTS: Six cases involved the palate (2), retromolar region (1), submandibular region (1), tongue (1), and mandible (1). Five cases were followed up, with one case of recurrence 1 year after surgery, one death from cerebral infarction 7 days after surgery, and three cases without signs of recurrence or metastasis over 5 years. All cases had abundant mucinous production and presented a typical immunophenotype common to salivary primaries, CK7 & MUC1 positive, CK20 & CDX2 negative. Sanger sequencing demonstrated recurrent AKT1 E17K mutations in four cases (4/6, 66.7%). A review of reported salivary intestinal-like tumors revealed 3 out of 13 cases presented with papillary morphology and CDX2 negative. Some salivary papillary neoplasms with mucinous cytologic features termed as intraductal papillary neoplasms or mucinous adenocarcinomas were also reported with AKT1 E17K mutations. CONCLUSION: We describe 6 cases of salivary gland papillary adenocarcinoma with intestinal-like mucinous cytologic features, which are different from conventional intestinal-type adenocarcinoma, presenting a consistent immunophenotype of CK7 & MUC1 positive, CK20 & CDX2 negative and exhibiting recurrent AKT1 E17K mutations.

GNAS mutational analysis in differentiating fibrous dysplasia and ossifying fibroma of the jaw.

Differential diagnosis of fibrous dysplasia and ossifying fibroma may often pose problems for pathologists. The purpose of this study was to evaluate the value of mutational analysis of the GNAS gene in differentiating these two conditions. DNA samples from patients with fibrous dysplasia (n=30) and ossifying fibroma (n=21) were collected to analyze the presence of GNAS mutations at exons 8 and 9, the two previously reported hotspot regions, using polymerase chain reaction and direct sequencing. In all, 90% (27/30) of cases with fibrous dysplasia showed missense mutations of codon 201 at exon 8, with a predilection of arginine-to-histidine substitution (p.R201H, 70%) as opposed to arginine-to-cysteine substitution (p.R201C, 30%), whereas no mutation was detected at exon 9. No mutation was found in all 21 cases with ossifying fibroma. In addition, a meta-analysis of previously published reports on GNAS mutations in fibrous dysplasia and ossifying fibroma was performed to substantiate our findings. A total of 24 reports including 307 cases of fibrous dysplasia and 23 cases of ossifying fibroma were reviewed. The overall incidence of GNAS mutations in fibrous dysplasia was 86% (264/307), and the major types of mutations were also R201H (53%) and R201C (45%). No GNAS mutation was detected in all patients with ossifying fibroma. We also reported one case with uncertain diagnosis due to overlapping clinicopathological features of fibrous dysplasia and ossifying fibroma. An R201H mutation was detected in this case, thus confirming a diagnosis of fibrous dysplasia. Taken together, our findings indicate that mutational analysis of GNAS gene is a reliable adjunct to differentiate ossifying fibroma and fibrous dysplasia of the jaws.

Head and neck carcinoma in children: A clinicopathological study of 42 cases.

Background/purpose: Cancer is an important part of the global burden of childhood diseases. Head and neck carcinoma in children is rare and related research is limited. This study aimed to investigate the clinicopathological features of childhood head and neck carcinoma. Materials and methods: Forty-two cases of childhood head and neck carcinoma treated in our institution were reviewed and analyzed. Results: Median age overall was 11 years. Twenty-three patients (54.8%) were male and 19 (45.2%) were female. Parotid gland location was most common (54.8%). Mucoepidermoid carcinoma and squamous cell carcinoma were the most common histological types (57.1% and 11.9%, respectively). Two patients had a history of bone marrow transplantation and two had a history of odontogenic keratocyst. The recurrence rate after treatment was 8.6%. Conclusion: Early diagnosis and treatment and close follow-up of childhood head and neck carcinoma are warranted to prevent recurrence and improve clinical outcome.

[Recurrence and malignant transformation of intraosseous dentinogenic ghost cell tumor].

OBJECTIVE: To describe the histologic and clinical findings of recurrent intraosseous dentinogenic ghost cell tumor (DGCT) and its malignant transformation. METHODS: The clinical features, treatment, pathology and prognosis of recurrent intraosseous DGCT patients from 53 cases of mixed odontogenic tumors with ghost cells and mesenchymal inductive components were retrospectively reviewed. RESULTS: Ten recurrent cases from 14 DGCT were all male and the age at diagnosis ranged from 18 to 60 years with an average of 32.4 years. The main manifestation was progressive bone bulging. Radiographically the tumor was characterized by ill-defined radiolucency. Most recurrent tumors had entrenched the surrounding tissues. Seven cases occurred in the maxilla among which 2 cases were transformed into ghost cell odontogenic carcinoma and 2 showed features of increased cell proliferation. Three cases occurred in the mandible among which 1 case showed a high proliferative activity. The initial surgery of all recurrent cases was curettage. CONCLUSION: The microscopic findings and prognosis suggested that intraosseous DGCT was locally aggressive. Multiple recurrences increased the risk of malignant transformation. Curettage alone might not be adequate for the management of DGCT. Maxillary cases with ill-defined borders, especially those showing an increased proliferative activity in biopsy or frozen section examination, should be treated more radically.

[In vitro cultivation and identification of epithelial cells of keratocystic odontogenic tumor].

OBJECTIVE: To establish a method of in vitro cultivation of epithelial cells of keratocystic odontogenic tumors (KCOT). METHODS: Tissue block and enzyme digestion techniques were used for primary cultivation of KCOT cells. The cells were grown in keratinocyte-serum free medium (K-SFM). The biological characteristics of the cultivated keratinocytes were identified by phase microscopic observation and by immunohistochemistry of cytokeratin, vimentin, cytokeratin10 and 14. RESULTS: KCOT keratinocytes could survive for 30-50 days in K-SFM after passing 2-4 generations. Cells were polygon and showed typical slabstone-like appearance. Immunostaining showed positive staining for cytokeratin antibody, and negative for vimentin. CONCLUSION: KCOT epithelial cells could be serially cultured in vitro in K-SFM by techniques suggested in this study.

[Studies on keratocystic odontogenic tumors].

Keratocystic odontogenic tumors (KCOTs, previously known as odontogenic keratocysts) are aggressive, noninflammatory jaw lesions with a putative high growth potential and a propensity for recurrence. This article puts together a summary of the serial studies related to KCOTs undertaken by the author's research group in recent years. Intraosseous jaw cysts with a solely orthokeratinized lining epithelium have been suggested to differ from the typical KCOTs. We report 20 cases of such cyst type under the term of 'orthokeratinized odontogenic cyst (OOC)'. Apart from the presence of a keratinizing epithelial lining, the OOC lacks the other histological features of KCOT, exhibits little if any tendency to recur, has no apparent association with NBCCS, may be cured by simple enucleation, and may thus constitute its own clinical entity. Mutations in PTCH1 gene are responsible for NBCCS and are related in tumors associated with this syndrome. We have so far detected 26 PTCH1 mutations (2 mutations occurred twice) in 10 out of 34 (29.4%) sporadic and 14 out of 16 (87.5%) NBCCS-associated KCOTs. The 26 mutations consisted of 10 frameshift, 2 nonsense, 3 aberrant splicing, 4 in-frame insertion/deletion/ duplication and 7 missense mutations. Two missense mutations in PTCH2 were also detected in 2 out of 15 NBCCS related KCOT patients. By contrast, no pathogenic mutation was detected in SMO. Thus, our data, together with reports from other groups, indicate that defects of PTCH1 are involved in the pathogenesis of syndromic as well as sporadic KCOTs. The pathogenic role of PTCH2 requires further investigation. A series of in vitro studies on bone resorption of KCOTs and ameloblastomas were undertaken by this group. The results indicate that odontogenic lesions could promote bone resorption in vitro and it is likely to be related to some of the cytokines secreted by the lesions.

Primary intestinal-type adenocarcinoma of the buccal mucosa: A case report and literature review.

Intestinal-type adenocarcinoma of the primary salivary glands is extremely rare. So far, only 11 cases of primary intestinal-type adenocarcinoma of the oral cavity and major salivary glands have been reported. Two of those tumors arose in the floor of mouth, 7 in the tongue, and 2 in the major salivary glands. However, it has remained unclear whether these tumors are derived from mature salivary glands, and primary intestinal-type adenocarcinoma of the buccal mucosa has not been reported previously. Here, we present the first documented case of primary intestinal-type adenocarcinoma arising in a minor salivary gland of the buccal mucosa. Histopathologically, the tumor resembled a well-differentiated or mucinous colonic adenocarcinoma. Immunohistochemically, the tumor cells were diffusely positive for AE1/AE3, CAM5.2, CK7, SATB2, ß-catenin, p53, Ki-67, MUC2, and MUC5 AC. CK14 and CK20 were positive in some of the tumor cells. CDX2, CA19-9, SP-A, TTF-1, PSA, SMA, p63, and cyclin D1 were negative in the tumor cells. The tumor in the present case may have originated from salivary gland duct epithelium that underwent transformation to phenotypic intestinal-type epithelium. In this very rare case of primary intestinal-type adenocarcinoma of the buccal mucosa, we considered diagnostic markers that could be indicative of mature salivary gland origin.

Palatal Polymorphous Adenocarcinoma with High-Grade Transformation: A Case Report and Literature Review.

Polymorphous adenocarcinoma (PAC) is the second most common intraoral malignant neoplasm of the minor salivary glands. However, it is very rare for PAC to show high-grade transformation (HGT) and to our knowledge, the English literature only seven reported cases. HGT tends to be observed when PAC recurs, and it is extremely rare to be seen at initial presentation. Here we report a 43-year-old Japanese male patient with PAC of the right palate showing HGT at initial presentation. Histopathologically, the tumor was characterized by a prominent solid and papillary-cystic growth pattern, with nuclear atypia and necrosis in area of HGT. The immunohistochemical staining pattern was consistent with PAC, as the tumor cells showed diffuse positivity for cytokeratin, vimentin and S-100, and focal positivity for bcl-2, ɑ-SMA and EMA. The tumor cells in HGT areas were markedly positive for AR and Ki-67 (about 40%/HPF), and also focally positive for cyclin D1 and p53, whereas HER2/neu, ER, PgR, p63, D2-40, GCDFP-15, and mitochondria were negative. Here we present a very rare case of palatal PAC with HGT at initial presentation.

[PTCH2 gene alterations in keratocystic odontogenic tumors associated with nevoid basal cell carcinoma syndrome].

OBJECTIVE: To investigate alterations in PTCH2 in keratocystic odontogenic tumors (KCOT) associated with nevoid basal cell carcinoma syndrome (NBCCS). METHODS: Genomic DNA was extracted from samples of frozen lesion tissues and peripheral blood of 15 NBCCS patients with multiple KCOTs. PTCH2 mutations were detected by PCR-direct sequencing. RESULTS: 2 novel missence mutations(c.323 T>C,c.1319 C>T)of PTCH2 were identified and 9 polymorphisms (3 of which were novel) were determined in the present series. CONCLUSION: Although not as frequent as PTCH1 mutations, PTCH2 germline mutations were detectable in a subset of NBCCS patients with KCOTs. The pathogenetic role of these PTCH2 mutations is yet to be clarified.

[Diagnosis and management of oral melanotic neuroectodermal tumor of infancy].

OBJECTIVE: To investigate the clinicopathological features of oral melanotic neuroectodermal tumor of infancy (MNTI). METHODS: We retrospectively reviewed the clinical and pathological data of 13 cases of oral MNTI treated in Peking University School and Hospital of Stomatology from 1980 to 2007. RESULTS: The age of patients ranged from 2 to 7 months old. Nine lesions occurred in the maxilla, 3 in the mandible and 1 in the cheek. The most common symptom of the disease was swelling. Five tumors were found purple-reddish or blue-blackish. The neoplasm grew rapidly. Only 1 case was diagnosed as MNTI and 3 cases were diagnosed as malignant tumor before biopsy. Two of 9 cases with follow-up information recurred in one month after surgery and 1 case dead of the tumor. One case with remnants of tumor did not recur after 19 years postoperatively. CONCLUSION: Oral MNTIs appear to occur in certain locations and people of certain age. Special attention should be paid to the color of the tumor during intra-oral examination. This tumor grew rapidly and invasively and the patients require close follow-up within the first 6 months postoperatively. The pathologic differential diagnosis of MNTI should include other pediatric "small round cell" neoplasms. Conservative excision is the preferred treatment choice.

A clinicopathologic study on central odontogenic fibroma: with special reference to amyloid variant.

OBJECTIVE: The aim of this study was to clarify the clinicopathologic features of central odontogenic fibroma (OF), especially the amyloid variant, and to discuss its association with the Langerhans cell variant of calcifying epithelial odontogenic tumor (CEOT). STUDY DESIGN: The clinicopathologic features and immunophenotypes of 17 OFs, including 6 amyloid variants, were analyzed. The Langerhans cell variant of CEOT is reviewed, and its relationship with OF is discussed. RESULTS: Most OFs (13 of 17) were located at the anterior region of the jaws, often with root resorption. The amyloid variant exhibited the typical clinicopathologic features of OFs, characterized by dispersed small epithelial nests embedded in a fibrous stroma. Immunohistochemically, the epithelial component in all central OFs, including the amyloid variants, exhibited dispersed staining for CK10/13 but was negative for CK7 and CK8/18. Langerhans cells were positive for S-100 and Langerin in the epithelium of OFs, including the amyloid variants. CONCLUSIONS: The amyloid variant of OF is a rare benign tumor exhibiting the typical clinicopathologic features of conventional OFs and should not be diagnosed as CEOT even in the presence of amyloid deposits. Previously reported cases described as "Langerhans cell variant of CEOT" should be classified as the "amyloid variant of OF," given that it shares features more in common with OFs than with CEOTs.

Initial-Stage Primary Intraosseous Squamous Cell Carcinoma Derived from Odontogenic Keratocyst with Unusual Keratoameloblastomatous Change of the Maxilla: A Case Report and Literature Discussion.

Primary intraosseous squamous cell carcinoma (PIOSCC) is a rare malignant neoplasm derived from odontogenic epithelial remnants in the central jaw bone. Most PIOSCCs originate from odontogenic cysts with a nonkeratinized epithelial lining, especially from radicular/residual and dentigerous cysts. There have been few reports of PIOSCCs derived from the odontogenic keratocyst (OKC), particularly those describing pathological features at the initial stage. The diagnosis of PIOSCC is difficult and based on exclusion of other carcinomas, including metastatic tumors from other primary sites. Here, we report an extremely rare case of initial-stage PIOSCC derived from the OKC with unusual keratoameloblastomatous change of the maxilla.

Ameloblastic fibroma: a review of published studies with special reference to its nature and biological behavior.

To further elucidate confusions with respect to the nature and biological behavior of ameloblastic fibroma (AF), available English-language literature since its first description in 1891 was reviewed. A total number of 123 cases with well-documented follow-up data were retrieved to evaluate various clinical, pathological and behavioral aspects of this tumor. AF tends to occur in the first two decades (89/123; 72.4%), but patients older than 22 years are not uncommon (30 cases). An overall recurrence rate of 33.3% (41 cases) is identified in reported cases who were treated by conservative (91.5%) and radical (8.5%) methods. Malignant transformation is evident in 14 recurrent tumors with an overall transformation rate of 11.4%. These data support the view that majority of AFs are true neoplasms. However, a small number of AFs occurring in childhood may represent the primitive stage of a developing odontoma, as three of the reported recurrent AFs do show further maturation with formation of dental hard tissues. A significantly longer recurrence-free survival was noted in patients treated by radical procedures in comparison to those treated by conservative methods and the age of patients at the first presentation was significantly related to malignant transformation of AF. As we are unable, at present, to differentiate a hamartomatous lesion from a neoplasm among this group of lesions merely on histologic grounds, age of the patients should be an important consideration when choosing therapeutic methods. Radical surgery should not be employed for the treatment of AFs in young people.

CDC73 gene mutations in sporadic ossifying fibroma of the jaws.

BACKGROUND: The tumor suppressor gene CDC73 was found to be associated with hyperparathyroidism-jaw tumor syndrome (HPT-JT), which is characterized by parathyroid adenoma or carcinoma, ossifying fibroma (OF) of the jaws, and renal and uterine lesions. Mutations in CDC73 have also been frequently detected in sporadic parathyroid carcinomas and renal tumors. However, the prevalence and range of CDC73 mutations in sporadic OFs have not been established. METHODS: We directly sequenced coding and flanking splice junctional regions of CDC73 in 40 cases of sporadic OF of the jaws. We also used immunohistochemistry to detect parafibromin, the protein product of CDC73, in those cases. RESULTS: Two novel CDC73 mutations were identified in 2 of the 40 cases (5 %). Both were somatic mutations located in exon 1 of the coding region. Strong parafibromin expression was detected in all 40 cases, irrespective of the presence of CDC73 mutations. CONCLUSIONS: Mutations inCDC73 were rare in sporadic OF of the jaws, but may affect the pathogenesis of a small subset of tumors of this type.

Clinicopathologic spectrum of the so-called calcifying odontogenic cysts: a study of 21 intraosseous cases with reconsideration of the terminology and classification.

The so-called calcifying odontogenic cyst (COC) represents a heterogeneous group of lesions that exhibit a variety of clinicopathologic and behavioral features. Because of this diversity, there has been confusion and disagreement on the terminology and classification of these lesions. We reviewed the clinicopathologic features of 21 intraosseous cases that were previously diagnosed as COC or under related diagnostic terms. Based on the biologic behavior, the lesions of the present series were divided into three subgroups: cyst, benign tumor, and malignant tumor. Sixteen cases (nine men and seven women) proved to be unicystic lesions with (five cases) or without associated odontoma. The lining epithelium of the cystic lesions fulfilled the histologic criteria for COC proposed by the World Health Organization, and their overall clinicopathologic features were consistent with that of developmental odontogenic cysts. The age of patients from the cyst group peaked at the second decade. The maxilla was affected more often (69%) than the mandible, with a predilection for the canine-premolar region (62.5%). Thirteen patients with follow-up information revealed no recurrence following enucleation. The four cases in the benign tumor group had variable clinicopathologic features. Two cases were solid tumors consisting of ameloblastoma-like sheets of odontogenic epithelium that contained ghost cells/calcification foci and juxtaepithelial dentinoid. Both patients experienced multiple recurrences following conservative surgeries. The other two lesions contained typical areas of COC and other types of odontogenic tumors (one ameloblastoma and one odontogenic myxofibroma). All four lesions occurred in the mandible and were relatively large. In the present series one case identified as malignant tumor arose from a previously benign COC. The tumor shared some features of COC (ghost cell foci and dystrophic calcification) but also had prominent mitotic activity, nuclear and cytoplasmic pleomorphism, areas of tumor necrosis, and infiltrative/destructive growth. Recognizing the extreme diversity in clinicopathologic features and biologic behavior among the so-called COCs, we suggest that the term COC should be used to specifically designate the unicystic lesions with or without an associated odontoma, i.e., lesions of the cyst group, and other related lesions identified as benign tumor and malignant tumor should be termed and classified separately. A tentative scheme with respect to the terminology and classification for this group of disparately behaving lesions was herein proposed to reflect the likely difference of their nature.

A clinicopathologic study on calcifying epithelial odontogenic tumor: with special reference to Langerhans cell variant.

BACKGROUND: Calcifying epithelial odontogenic tumour (CEOT) is a rare benign odontogenic tumour, and its Langerhans cell variant is even rarer. Due to the limited number of recorded cases, the biological behaviour and histogenesis of the Langerhans cell variant of CEOT are not yet fully understood. Thus, the correlation between conventional CEOT and the Langerhans cell variant remains to be clarified. MATERIAL (CASES): Eight cases of CEOT including 2 cases of Langerhans cell variant were clinicopathologically studied and the English language literature was reviewed. Langerhans cells were detected in 2 cases of conventional CEOT and in 2 cases of Langerhans cell variant by immunohistochemistry. RESULTS AND FINDINGS: In the 6 cases of conventional CEOT, 5 tumours involved the premolar and molar region and the anterior portion of the mandible was affected in 1 case. Four patients were followed for 2-7 years and did not show any sign of recurrence. A review of the English language literature revealed 5 cases; combined with the present 2 new cases, a total of 7 cases of Langerhans cell variant of CEOT were collected. The patients were all Asian. Six tumours occurred in the maxilla and 1 in mandible; all mainly involved the anterior region of the jaws. Five patients were followed for 2-10 years and did not show any evidence of recurrence. Langerhans cells can be seen in both the conventional and the Langerhans cell variant of CEOT; however, increased numbers of Langerhans cells are seen in the latter. CONCLUSIONS: Although the Langerhans cell variant of CEOT is a rare entity and behaves similarly to the conventional type, it could show unique clinical and histologic features that may pose problems for differential diagnosis. VIRTUAL SLIDES: http://www.diagnosticpathology.diagnomx.eu/vs/1979090740113894.

The large intracellular loop of ptch1 mediates the non-canonical Hedgehog pathway through cyclin B1 in nevoid basal cell carcinoma syndrome.

Mutations in the transmembrane receptor patched homolog 1 (Homo sapiens) (ptch1) are responsible for nevoid basal cell carcinoma syndrome (NBCCS), an autosomal dominant disorder that causes developmental abnormalities and predisposes the affected individuals to cancer. Many of these mutations, including mutations in the C-terminus of the large intracellular loop (ICL) of ptch1 (p.C727VfsX745 and p.S733IfsX736), result in the premature truncation of the protein. The ptch1­C727VfsX745 and ptch1-S733IfsX736 mutations have been identified in patients with NBCCS­associated keratocystic odontogenic tumors (KCOTs). In the present study, we found that the molecular mechanisms regulated by the non-canonical Hedgehog (Hh) signaling pathway through cyclin B1 are involved in the pathogenesis of NBCCS-associated KCOTs. In contrast to wild-type ptch1, ptch1-C727VfsX745 and ptch1­S733IfsX736 clearly exhibited reduced binding to cyclin B1. Moreover, the cells expressing these two mutations demonstrated an increase in cell cycle progression and these two mutation constructs failed to inhibit cell proliferation. In addition, the mutants enhanced the activity of glioma-associated oncogene family zinc finger 1 (GLI1), a downstream reporter of Hh signaling. Thus, our data suggest that the non-canonical Hh pathway mediated through ptch1 and cyclin B1 is involved in the pathogenesis of NBCCS-associated KCOTs. The C-terminus of ICL in ptch1 may also be a potential therapeutic target in the treatment of this disease.

Two cases of multiple ossifying fibromas in the jaws.

BACKGROUND: The clinicopathologic characteristics of multiple ossifying fibroma (OF) are unclear due to the condition's rarity, making diagnosis challenging. Sporadic multiple OFs must be distinguished from hyperparathyroidism-jaw tumour syndrome (HPT-JT) related OF and other fibro-osseous lesions. METHODS: Multiple OF cases were identified from ossifying fibroma cases. Clinical data including age, sex, anatomic site, radiographic features, clinical impression, treatment and available follow-up data as well as serum calcium, phosphorus, and parathyroid hormone (PTH) were recorded. GNAS and HRPT2 genetic mutations were examined in the two present cases. Case reports of sporadic multiple ossifying fibroma and HPT-JT-related OF were also reviewed. RESULTS: The two present cases were confirmed as sporadic multiple OF, with no genetic GNAS and HRPT2 mutations found. The incidence of sporadic multiple ossifying fibroma was 2.0% (2/102). The total 18 sporadic multiform OF cases were characterized as followed: 13 (72.2%) female; 5 (27.8%) male; mean age 28.6 years; 2/16 (11.1%) cases only in the mandible; 4/18 (22.2%) cases only in the maxilla; and 12/18 (66.7%) cases in both the maxilla and mandible. Radiographically, the lesions were radiolucent in 5/18 (27.8%) cases and mixed density in 13/18 (72.2%) cases. Along with 24 cases of HPT-JT related OF were reviewed, sixteen (66.7%) patients were diagnosed with a single lesion, and 8 patients (33.3%) were diagnosed with multiple jaw lesions. CONCLUSIONS: Sporadic multiple OFs are very rare, but must be distinguished from HPT-JT related OF. We strongly recommend that patients diagnosed with multiple ossifying fibromas receive serum PTH testing and mutation screening of HRPT2. VIRTUAL SLIDES: http://www.diagnosticpathology.diagnomx.eu/vs/1194507146115753.