PIK3CA Hotspot Mutations in Saliva as a Diagnostic Marker in Oral Squamous Cell Carcinoma Patients.

BACKGROUND/AIM: This study aimed at the analogous detection of PIK3CA mutations, common in oral squamous cell carcinoma (OSCC), in matched tumor and saliva samples. PATIENTS AND METHODS: Tissue and saliva samples were obtained from 29 patients diagnosed with primary OSCC. Saliva samples were obtained preoperatively; tissue specimens were acquired during tumor resection. Tumor DNA was extracted from both tissue and saliva samples. All samples were controlled for DNA quantity and quality and genetic matching of sample pairs was confirmed using the iPlex Pro Exome QC Panel. Variant detection was performed using the MassARRAY® System, a mass-spectrometry based detection system. Mutational analysis in tissue tumor DNA was made using the multiplexed ClearSEEK™ PIK3CA v1.0 Panel covering 20 hotspot mutations in PIK3CA. In saliva samples, variants were analyzed using both the ClearSEEK™ and the UltraSEEK® Lung v1.1 Panel, with a higher limit of detection but covering less PIK3CA variants. RESULTS: Overall, a PIK3CA variant was found in seven of the 29 tumor tissue samples (24%) by ClearSEEK™; UltraSEEK® additionally confirmed the variant in four of these seven positive samples. Of the three variants not detected by UltraSEEK®, two were not included in the panel and one was included but not detected. Of the seven variants found in tissue, five could also be detected in the matching saliva samples (71%), either by utilizing ClearSEEK™ or UltraSEEK® Conclusion: The detection of PIK3CA hotspot mutations in OSCC and their simultaneous occurrence in saliva underline the potential benefit of liquid biopsies for non-invasive cancer detection and follow-up care of OSCC patients.

Retracing RAS signaling by correlating protein expression in different subtypes of neurofibromatosis 1-associated nerve sheath tumors.

AIMS: Expression patterns of key proteins involved in RAS signaling and connected pathways were determined and correlated to possibly provide information for therapeutic application of RAS inhibitors in neurofibromatosis type 1 (NF1)-associated peripheral nerve sheath tumors (PNST). MATERIALS AND METHODS: Clinical variables (age, sex), histological parameters (cell density, mitoses), and expression of immunohistochemically evaluated ligand and receptor proteins (neuregulin 1 (NRG1), ErbB2, ErbB3), RAS pathway proteins (mTor, Rho, phosphorylated MEK), transcription factors (Pax7, Sox9), and proliferation marker Ki-67, were correlated in cutaneous (CNF, n = 136), diffuse (DNF, n = 123)/diffuse plexiform (DPNF, n = 113), and plexiform neurofibroma (PNF, n = 126), and in malignant PNST (MPNST, n = 22). RESULTS: In CNF, NRG1 correlated with Ki-67 and Pax7. Further, mTOR correlated with ErbB3, Sox9, Pax7, and Ki-67. In DNF/DPNF, expression of NRG1 correlated with pMEK and Pax7. mTOR correlated with pMEK, Sox9, and Pax7. Noteworthy, pMEK was weakly expressed in some DNF but not in DPNF. ErbB3 correlated with mTor and Ki-67. Furthermore, Rho correlated with Pax7 and Ki-67. In PNF, ErbB3 expression was associated with Sox9, mTOR, pMEK, and Pax7 as well as mTOR with Sox9 and Pax7, Rho with pMEK and Pax7, and pMEK with Pax7 and Sox9. In MPNST, only few correlations were observed, ErbB2 correlated with Ki-67, and Rho with pMEK. CONCLUSION: Signaling networks of the RAS pathway could be retraced by correlation analysis of protein expression in subgroups of NF1 associated benign PNST. In regard to treatment of PNST, MEK inhibitors, which are presently evaluated for PNF, may possibly also be effective to some extent in DNF.

Dental Developmental Stages and Decayed, Missing, and Restored Teeth in Neurofibromatosis Type 1-affected Children and Adolescents.

Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited tumor predisposition disease with a highly variable phenotype. The influence of the characteristic NF1 tumors (neurofibromas) on dentition has not yet been examined in detail. The aim of the study was to assess the dentition of NF1 children and adolescents, considering the symmetry of tooth development. Material and Methods: The panoramic radiographs of 59 patients with a confirmed NF1 diagnosis were compared with 59 age-and-sex-matched controls. The stages of tooth development on the sides of the jaw, added to a score, were assessed. In addition, the number of filled or decayed teeth, and the number of retained or missing teeth were assessed. Results: The tooth development of both study groups is symmetrical for almost all parameters and in the same developmental stage according to the sum score of the tooth development stages. Discrete developmental delays of teeth, in particular in the oral area of facial plexiform neurofibroma (PNF) are noticeable. NF1 patients' teeth showed less decay and more restorations than that of the control group. The facial PNF (FPNF) does not impair emergence of deciduous teeth. Conclusions: Development of dentition of NF1 patients does not differ from the general population. However, FPNF with oral tumor components often prevent mesial movement of permanent molars and premolars, so these teeth do not develop contact (spacing), hardly emerge or may stay retained in bone. Oral PNF may have a low-retarding effect on some tooth root development (e.g., wisdom teeth). This effect is negligible when comparing the affected and unaffected sides of the jaw and is probably non-specific. Key words:Neurofibromatosis type 1, plexiform neurofibroma, dentition, mixed dentition, symmetry, oral health, tooth development.

Raman difference spectroscopy and U-Net convolutional neural network for molecular analysis of cutaneous neurofibroma.

In Neurofibromatosis type 1 (NF1), peripheral nerve sheaths tumors are common, with cutaneous neurofibromas resulting in significant aesthetic, painful and functional problems requiring surgical removal. To date, determination of adequate surgical resection margins-complete tumor removal while attempting to preserve viable tissue-remains largely subjective. Thus, residual tumor extension beyond surgical margins or recurrence of the disease may frequently be observed. Here, we introduce Shifted-Excitation Raman Spectroscopy in combination with deep neural networks for the future perspective of objective, real-time diagnosis, and guided surgical ablation. The obtained results are validated through established histological methods. In this study, we evaluated the discrimination between cutaneous neurofibroma (n = 9) and adjacent physiological tissues (n = 25) in 34 surgical pathological specimens ex vivo at a total of 82 distinct measurement loci. Based on a convolutional neural network (U-Net), the mean raw Raman spectra (n = 8,200) were processed and refined, and afterwards the spectral peaks were assigned to their respective molecular origin. Principal component and linear discriminant analysis was used to discriminate cutaneous neurofibromas from physiological tissues with a sensitivity of 100%, specificity of 97.3%, and overall classification accuracy of 97.6%. The results enable the presented optical, non-invasive technique in combination with artificial intelligence as a promising candidate to ameliorate both, diagnosis and treatment of patients affected by cutaneous neurofibroma and NF1.

Multiple central giant cell granuloma of the jaws: diagnostic signposts of Noonan syndrome and RASopathy.

Noonan syndrome (NS) is a phenotypically variable inherited multi-system disorder. Maxillofacial findings can be diagnostic, especially in the evaluation of discrete facial dysmorphia. Diagnostic landmark findings of therapeutic relevance for the jaws such as central giant cell granuloma (CGCG) are rare in NS. However, recent molecular genetic studies indicate that these rare, benign lesions are neoplasms and more common in specific syndromes grouped under the umbrella term RASopathies. A specialist surgical diagnosis can be helpful in identifying the underlying disease. This report outlines diagnosis and treatment of a case of CGCG for which jaw diagnosis became the key to identifying a syndromic disease.

Neurofibromatosis type 1-associated plexiform neurofibromas of the neck: topography of lesions and surgical treatment data of 69 patients.

PURPOSE: Plexiform neurofibromas (PNF) are rare tumors arising from peripheral nerve sheath cells. PNF are a hallmark in patients with neurofibromatosis type 1 (NF1), a tumor predisposition syndrome. PNF often grow invasively and destructively, what may complicate surgical treatment. Data on frequency, location, and surgical procedures of patients with NF1-associated FPNF are scarce. This study provides treatment data of NF1 patients. METHODS: Localization and treatment data of 69 NF1 patients with neck PNF were analyzed. Frequency of lesions was recorded in coded colors on schematic neck drawings. RESULTS: The tumors showed no side preference, were located in the entire area under investigation, and did not respect anatomical units/dermatomes. However, the sternocleidomastoid region was particularly frequently affected. The mean number of surgical measures per patient was 1.33. Complications were extensive swelling, hematoma, and bleeding. Histological assessment usually confirmed the clinical assessment of neoplasm. However, histologic differentiation of PNST reveals differences in between tumors that have been unified in clinical assessment as PNF. CONCLUSION: The color-coded, schematic overview of the frequency distribution of surgical neck interventions in NF1 patients with PNF proved a useful tool to gain assessment of preferred treatment needs. The imaging procedure may be suitable for controlling the external aspect of natural tumor development (growth, effects of aging) in the same way as the documentation of the post-surgical course. Treatment plans for patients with these tumors should consider that repeated interventions may be necessary to achieve a longer-term stable result.

Mandibular symmetry on posterior-anterior cephalograms of neurofibromatosis type 1 patients with facial plexiform neurofibroma.

Introduction: Neurofibromatosis type 1 (NF1) is an is an autosomal dominant heritable tumor predisposition syndrome.. Peripheral nerve sheath tumors (PNST) are a hallmark of NF1. Plexiform neurofibromas (PNF) are neoplasms that are characteristic of NF1, often causing disfiguring effects (e.g., on the face), and are considered precancerous lesions. Previous studies have shown that facial PNF (FPNF) have an impact on the shape of facial bones. This study examines deviations of mandibular symmetry from cephalometric reference planes considering the topography of FPNF. Material and methods: The posterior-anterior (PA) cephalograms of 168 patients with NF1 were examined. We compared three groups: patients with FPNF (n=74), with disseminated cutaneous neurofibroma (DNF (n=94)), and control subjects without NF1 (n=23). The PNF group was subtyped with respect to facial PNST type and location. Typical mandibular cephalometric reference points were determined (condyle, antegonion, and menton). Results: The skeletal measurement points of the mandible in FPNF patients often differ significantly from those of the DNF group. It has been proven that typical asymmetries of the median-sagittal measurement points are indicators of PNF. Differences within the trigeminal tumor spread patterns are indicated in the measured values. A local tumor effect (PNF) on the relation of the measurement points to the reference planes is made plausible by the study results. The investigations prove that tumor type (FPNF) and the number of FPNF affected branches of the trigeminal nerve may correlate with significant deviations of mandible from symmetry on PA projections. Conclusion: The presented study shows that characteristic patterns of mandibular deformity can be measured on standardized radiographs in NF1 patients with FPNF. Mandibular deformities imaged on standardized radiographs may be initial indicators of a previously unrecognized NF1. Tumor-associated alterations of the mandible should be considered in the classification systems of pathognomonic, diagnostically pioneering osseous findings in NF1. The radiological findings provide clues for planning mandibular osteotomies in NF1 patients, especially for assessing facial regions typically highly vascularized by tumor spread. Furthermore, the radiological findings are an indication of a tumor potentially invading and destroying adjacent masticatory and mimic muscle, findings that may have an influence on surgical measures (function, aesthetics, and wound healing).

Neurofibromatosis Type 1-Associated Plexiform Neurofibromas of the Face and Adjacent Head Regions: Topography of Lesions and Surgical Treatment Data of 179 Patients.

Introduction: Facial plexiform neurofibromas (FPNF) are rare tumors frequently diagnosed in patients with neurofibromatosis type 1 (NF1), a tumor predisposition syndrome. FPNF often grows invasively and destructively, which may complicate surgical treatment. Data on the frequency, location, and surgical procedures of patients with NF1-associated FPNF are scarce. This study provides treatment data from a nationally networked reference center for the treatment of NF1 patients. Material and Methods: The localization and treatment data of 179 NF1 patients with FPNF were analyzed. Photographically documented tumors of the study area, further determined by imaging, were manually transferred to a facial scheme and digitized. The digitized registrations of the facial extensions of the tumors of each patient were overlaid in a single image (Photoshop™), so that the file of the facial scheme contained the sum of the tumor localization. Finally, the frequency of tumor localization was indicated with a color code. The frequency of tumor extension-related coded colors was applied to outline the lesions' topography on schematic face drawings (heat map). Results: The distribution of the tumors showed no side preference. The need for the treatment of patients with orbital/periorbital manifestations became evident in the graphic representations. Tumors do not respect anatomical units. However, the classification of the face according to dermatomes, especially the trigeminal nerve, offers indications of tumor spread and guides treatment planning. The mean number of surgical measures per patient was 2.21 (median: 1). Extensive swelling, hematoma, and delayed wound healing were all common postoperative complications. Conclusion: The color-coded, schematic overview of the frequency distribution of cutaneous tumor spread in NF1 patients with FPNF illustrates the importance of orbital/periorbital and cheek tumor manifestations in patients' treatment needs. The imaging procedure is suitable for controlling natural tumor growth in the same way as the documentation of the post-surgical course. Repeated interventions in the region are included in surgical planning of the progressing tumor disease.

Association between C-Reactive protein and periodontitis in an obese population from the NHANES 2009-2010.

BACKGROUND: Various data have been obtained on the relationship between body mass index (BMI) and C-reactive protein (CRP) and periodontitis. The aim of this study was to determine whether CRP/BMI are associated with periodontitis using data from the National Health and Nutrition Examination Survey (NHANES) database. METHODS: A cross-sectional analysis of data from 3602 participants in the 2009-2010 NHANES cycle was performed. The definition of periodontitis was used to divide participants into four groups according to the criteria of Eke. Correlations between CRP/BMI and periodontitis were tested for statistical significance by means of descriptive statistics, multivariate regression, and subgroup-stratified analyses, with and without adjustments for confounders (such as age and sex). RESULTS: There were no statistically significant differences (p > 0.05) regarding BMI and the development of periodontitis. After adjustment for age, sex, race, marital status, annual family income, alcohol consumption, hypertension, smoking, chronic pulmonary disease, cardiovascular disease, diabetes, flossing, and arthritis, CRP correlated significantly with the development of periodontitis in the subgroups stratified by obesity, with an odds ratio (OR) of 1.2 (95% CI, 1.0 to 1.5). CONCLUSION: Through data analysis, we found an association between CRP levels and periodontitis prevalence in the American population, although this association was only present in the obese population. While there are several hypotheses about the underlying mechanism, further studies are needed to validate these findings.

Expression of Ras signaling pathway proteins and developmental factors in peripheral nerve sheath tumors of patients with neurofibromatosis type 1.

PURPOSE: To characterize expression of factors relevant for Ras signaling and developmental factors in a large series of peripheral nerve sheath tumors (PNST) obtained from patients with neurofibromatosis type 1 (NF1). MATERIALS AND METHODS: Tissue micro-array technique was applied to study 520 PNST of 385 NF1 patients by immunohistochemistry for mTor, Rho, phosphorylated MEK, Pax7, Sox9, and periaxin expression. PNST comprised cutaneous neurofibroma (CNF) (n = 114), diffuse neurofibroma (DNF) (n = 109), diffuse plexiform neurofibroma (DPNF) (n = 108), plexiform neurofibroma (PNF) (n = 110), and malignant PNST (MPNST) (n = 22). RESULTS: All proteins examined showed highest expression levels/highest frequency of expression in MPNST. Benign PNF with potential for malignant dedifferentiation expressed mTor, phosphorylated MEK, Sox9, and periaxin significantly higher/more frequently than other benign neurofibroma subtypes. CONCLUSION: In NF1-associated PNST, expression of proteins involved in Ras-signaling and development is upregulated not only in MPNST, but also in benign PNF with the potential for malignant dedifferentiation. The differences in protein expression may provide clues for understanding the therapeutic effects of substances applied for reduction of PNST in NF1.

Atypical neurofibromas reveal distinct epigenetic features with proximity to benign peripheral nerve sheath tumor entities.

BACKGROUND: Plexiform neurofibromas can transform into atypical neurofibromas (ANF) and then further progress to aggressive malignant peripheral nerve sheath tumors (MPNST). ANF have been described to harbor distinct histological features and frequent loss of CDKN2A/B. However, histological evaluation may be rater-dependent, and detailed knowledge about the molecular mechanisms of malignant transformation is scarce. In general, malignant transformation can be accompanied by significant epigenetic changes, and global DNA methylation profiling is able to differentiate relevant tumor subgroups. Therefore, epigenetic profiling might provide a valuable tool to distinguish and characterize ANF with differing extent of histopathological atypia from neurofibromas and MPNST. METHODS: We investigated 40 tumors histologically diagnosed as ANF and compared their global methylation profile to other peripheral nerve sheath tumors. RESULTS: Unsupervised class discovery and t-SNE analysis indicated that 36/40 ANF cluster with benign peripheral nerve sheath tumors with clear separation from MPNST. 21 ANF formed a molecularly distinct cluster in proximity to schwannomas. Tumors in this cluster had a frequent heterozygous or homozygous loss of CDKN2A/B and significantly more lymphocyte infiltration than MPNST, schwannomas, and NF. Few ANF clustered closely with neurofibromas, schwannomas, or MPNST, raising the question, whether diagnosis based on histological features alone might pose a risk to both over- and underestimate the aggressiveness of these lesions. CONCLUSIONS: Our data suggest that ANF with varying histological morphology show distinct epigenetic similarities and cluster in proximity to benign peripheral nerve sheath tumor entities. Future investigations should pay special respect to correlating this methylation pattern to clinical outcomes.

Characterization of Dental Pulp Stem Cell Populations in the Teeth of Patients With Neurofibromatosis Type 1 - Therapeutic Potential for Bone Tissue Engineering.

BACKGROUND/AIM: Neurofibromas (NF) are the most common benign nerve sheath tumors in the tongue, gingiva, major salivary glands, and jaw bones. Nowadays, tissue engineering is a revolutionary technique for reconstructing tissues. To explore the feasibility of using stem cells derived from NF teeth to treat orofacial bone defects, the differences in cell biological properties between an NF teeth group and Normal teeth group. PATIENTS AND METHODS: The intra-dental pulp tissues from each tooth were extracted. The cell survival rates, morphology, proliferation rates, cell activity, and differentiation abilities were contrastively analyzed between the NF teeth group and Normal teeth group. RESULTS: Between the two groups, there were no differences in the primary generation (P0) cells (p>0.05), the cell yield, and the time required for the cells to grow out of the pulp tissue and attach to the culture plate. Furthermore, no differences were found at the first generation (passage) between the two groups in colony formation rate and cell survival rate. The proliferation capacity, cell growth curve, and surface marker expression of dental pulp cells was not altered in the third generation (p>0.05). CONCLUSION: Dental pulp stem cells from NF teeth were successfully obtained and were not different from normal dental pulp stem cells. Although, clinical research using tissue-engineered bone to repair bone defects is still in its infancy, it will eventually enter the clinic and become a routine means of bone defect reconstruction treatment as related disciplines and technologies develop.

ERN GENTURIS tumour surveillance guidelines for individuals with neurofibromatosis type 1.

Background: Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder, predisposing development of benign and malignant tumours. Given the oncogenic potential, long-term surveillance is important in patients with NF1. Proposals for NF1 care and its specific manifestations have been developed, but lack integration within routine care. This guideline aims to assimilate available information on NF1 associated tumours (based on evidence and/or expert opinion) to assist healthcare professionals in undertaking tumour surveillance of NF1 individuals. Methods: By comprehensive literature review, performed March 18th 2020, guidelines were developed by a NF1 expert group and patient representatives, conversant with clinical care of the wide NF1 disease spectrum. We used a modified Delphi procedure to overcome issues of variability in recommendations for specific (national) health care settings, and to deal with recommendations based on indirect (scarce) evidence. Findings: We defined proposals for personalised and targeted tumour management in NF1, ensuring appropriate care for those in need, whilst reducing unnecessary intervention. We also incorporated the tumour-related psychosocial and quality of life impact of NF1. Interpretation: The guideline reflects the current care for NF1 in Europe. They are not meant to be prescriptive and may be adjusted to local available resources at the treating centre, both within and outside EU countries. Funding: This guideline has been supported by the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS). ERN GENTURIS is funded by the European Union. DGE is supported by the Manchester NIHRBiomedical Research Centre (IS-BRC-1215-20007).

Unusual Findings in a Patient With Carney Complex due to a Novel PRKAR1A Mutation.

BACKGROUND/AIM: Carney complex (CNC) is a rare autosomal dominant tumor-predisposition syndrome with variable expression. Its main features are pigmentary skin lesions, soft-tissue myxomas, and endocrine overactivity or tumors. There is occasional overlap with other syndromes, and oligosymptomatic cases may escape diagnosis. This report describes the long journey of a patient until the diagnosis of CNC was finally made after a thorough diagnostic workup. CASE REPORT: The female patient was referred for treatment of a subcutaneous tumor of the lower abdomen. Medical reports detailed previous excisions of fibroma, neurofibroma and myxoma, and a malignant tumor of the cerebellopontine angle. The resected subcutaneous tumor was a myxoma. The identification of a previously unknown frameshift mutation in the gene for protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A) in the patient confirmed the diagnosis of CNC. CONCLUSION: Patients with CNC may have highly variable clinical findings. Some rare lesions in CNC are more commonly recorded in other syndromes, making early diagnosis difficult in some cases. Genetic testing greatly facilitates diagnosis.

Corrigendum: DCBLD1 Overexpression is associated with a poor prognosis in head and neck squamous cell carcinoma.

[This corrects the article DOI: 10.3389/fimmu.2022.939344.].

DCBLD1 Overexpression Is Associated With a Poor Prognosis in Head and Neck Squamous Cell Carcinoma.

Background: DCBLD1 is highly expressed in several kinds of cancer and plays a potential prognostic factor. However, the prognostic value and immune infiltration in head and neck squamous cell carcinoma remain unclear and need further research. Materials and Methods: DCBLD1 expression and clinical information were obtained from the Cancer Genome Atlas (TCGA) database. The mRNA level in cell lines (SCC25 and CAL27) and gingival fibroblasts were detected using quantitative PCR. Cox regression analysis was used to evaluate the prognostic values of DCBLD1 and clinical data in HNSCC. A nomogram was also established to predict the impact of DCBLD1 on prognosis based on Cox multivariate results. The methylation level of DCBLD1 in HNSC and its prognosis were analyzed in UALACN and MethSurv. Finally, the potential biological functions of DCBLD1 were investigated using gene set enrichment analysis (GSEA) and single-sample GSEA (ssGSEA). Results: The mRNA and protein expression levels of DCBLD1 were highly expressed in HNSCC tissue and cell lines. The Cox analyses demonstrate that highly expressed DCBLD1 is an independent prognosis marker (p < 0.05). ROC curve analysis showed the performance of DCBLD1 (area under the ROC curve: 0.948, sensitivity: 93.2%, specificity: 84.7%). The methylation was increased in HNSCC patients compared with normal subjects (p < 0.05) and was associated with poor prognosis at sites cg27642470 and cg21104965. Additionally, DCBLD1 expression is poorly associated with immune cell infiltration and immunological checkpoints PD-L1 and TIM-3. Conclusion: In head and neck squamous cell carcinoma, DCBLD1 is overexpressed, associated with poor patient prognosis. The detailed underlying mechanism merits further research.

Recurrent Mandibular Giant Cell Lesion in Neurofibromatosis Type 1: Second Hit Mutation on the NF1 Gene in the Osseous Lesion.

BACKGROUND/AIM: In the autosomal dominant hereditary disease neurofibromatosis type 1 (NF1), lesions of the jaw develop in isolated cases, which are diagnosed as central giant cell granuloma (CGCG). This study aimed to clarify the genetic basis of a bone lesion in a syndromic patient. CASE REPORT: The NF1 patient had developed a CGCG that recurred after local excision. Blood and tumor tissue were studied for NF1 mutations using advanced molecular genetic methods. Examinations of blood and tumor tissue provided evidence of the constitutive mutation in both samples. A further mutation was detected in the tumor, which was interpreted as a somatic mutation. The detection of somatic mutation in the tissue was successful both on native and routinely fixed material. CONCLUSION: The study supports current assessments of CGCG as a benign neoplasm. In NF1 patients, the phenotype seems to imply bi-allelic loss of the NF1 gene. The detection of both mutations in routinely fixed tissue allows studies of archived tissue samples with this diagnosis.

ERBB2 and ERBB3 Growth Factor Receptors, Neuregulin-1, CD44 and Ki-67 Proliferation Index in Neurofibromatosis Type 1-associated Peripheral Nerve Sheath Tumors.

AIM: To characterize the growth pattern and antigen profile of peripheral nerve sheaths tumors (PNST) in a large series of tumors obtained from patients with neurofibromatosis type 1 (NF1). MATERIALS AND METHODS: Tissue micro-array technique was applied to study 520 PNSTs of 385 patients with NF1 by immunohistochemistry for human epidermal growth factor receptors erb-b2 receptor tyrosine kinase 2 (ERBB2) and ERBB3, CD44, neuroregulin (NRG1) and proliferation index by Ki-67. PNSTs were classified as cutaneous neurofibroma (CNF) in 114 cases, diffuse neurofibroma (DNF) in 109, diffuse plexiform neurofibroma (DPNF) in 108, plexiform neurofibroma (PNF) in 110, and malignant PNST (MPNST) in 22. RESULTS: The Ki-67 proliferation index was significantly higher in MPNST than in benign PNST (p<0.001). ERBB2 expression was significantly lower in PNST with diffuse growth than in PNF and MPNST (p<0.001). ERBB3 expression was also higher in PNF and MPNST (both p<0.001) than in diffuse PNST. NRG1 expression was significantly higher in PNF than in non-encapsulated benign PNST or MPNST (both p<0.001). Co-expression of ERBB2, ERBB3 and ligand NRG1 was rare, mainly observed in PNST with a plexiform component (in four PNFs, nine DPNFs, one CNF, and two MPNSTs). Expression of CD44 in contrast was significantly stronger in diffusely growing PNST than in PNF (p<0.001). CONCLUSION: Growth factor receptors ERBB2 and ERBB3 were significantly up-regulated in PNF and MPNST. The antigen expression pattern of DPNF resembled that of benign PNST with diffuse growth pattern rather than that of encapsulated PNF. Differentiating PNST may be important for the assessment of neurofibroma progression, and for the expected impact of drugs currently used for tumor reduction.

Posterior-Anterior Cephalometric Study of Neurofibromatosis Type 1 Patients With Facial Plexiform Neurofibroma: Analysis of Skeletal Symmetry Concerning Midfacial and Skull Base Reference Points (Zygomatic Arch, Mastoid, and Juga).

BACKGROUND/AIM: Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome that is also characterized by skeletal abnormalities. In the cranial region, skeletal dysplasia is observed that is associated with a characteristic peripheral nerve sheath tumor, the plexiform neurofibroma (PNF). The aim of the study was to determine PNF-associated skeletal asymmetries of the mid-skull and skull base as an indicator of local tumor development. PATIENTS AND METHODS: The distances of the zygomatic arch, mastoid, and juga measurement points from the interorbital horizontal plane and median sagittal plane were examined on anterior-posterior cephalograms of 168 NF1 patients (females: 82, males: 86) and compared with the findings of a control group. A distinction was made as to whether the patients had developed a facial PNF. RESULTS: The distances of the measurement points from the reference planes differed between the patient and control group (p<0.05). Within the NF1 patients, differences between certain distances were noted when comparing patients with PNF and without PNF (p<0.05). In PNF patients, discrete changes in the skull contour were also detectable on the non-affected side (p<0.05). The caudal measurement point of the skull base showed no changes in the group comparison. CONCLUSION: The individually very variable facial PNF in NF1 is associated with deformations and misalignments of midfacial bones that follow a pattern quantifiable with cephalometric analysis.

Sequential Loss of Mandibular Permanent Incisors in Noonan Syndrome.

BACKGROUND: Noonan syndrome (NS) is a multigenic disorder with a highly variable phenotype. Cardiac disorders and a predisposition to neoplasm often require early medical attention. Central giant central lesions (CGCLs) of the jaws are part of the phenotype. CASE REPORT: In a patient with genetically confirmed NS and multiple teeth loss presumably caused by CGCL, careful review of the medical history and radiographic findings made it probable that the cause of tooth loss was cervical root resorption (CRR) of the teeth following long-term orthodontic therapy. CONCLUSION: CRR is a rare dental disease of unknown origin. However, association with prior orthodontic therapy is well documented. In NS, mandibular lesions can occur which, at first glance, might lead the examiner to assume that it is a CGCL, but on closer analysis, obviously are of non-tumorous origin and should be assessed as coincidental. The report adds relevant information to orthodontic treatment of NS patients.