Stiffness as measured with strain elastography is a prognostic factor for pT1/T2 tongue squamous cell carcinoma with muscle-layer invasion.

OBJECTIVE: The objective was to evaluate stiffness as a prognostic factor for tongue squamous cell carcinoma (TSCC). STUDY DESIGN: This retrospective study included 55 patients with pathologic stage pT1 or T2 TSCC with muscle-layer invasion who underwent preoperative strain elastography of the tongue, followed by surgery, as the primary treatment modality at our cancer center. The stiffness of TSCC was semi-quantified as the ratio of the strain value of a non-tumor site to the strain value of the tumor site (strain ratio [SR]) using ultrasound strain elastography findings. RESULTS: SR cutoff values that maximized the significance of the difference for prognosis of delayed cervical lymph node metastasis (DCLNM) and overall survival (OS) were 7.10 and 7.49, respectively. In univariate analysis, SR, age, depth of invasion, pT stage, and perineural invasion were significant risk factors for DCLNM, whereas SR, sex, and DCLNM were identified as having an association with OS. In multivariate analysis, SR was a significant risk factor for DCLNM (hazard ratio [HR] = 3.102; P = .021) and a non-significant but relevant risk factor for OS (HR = 8.774; P = .073). Age also had an association with OS (HR = 0.382; 95% CI 0.127-1.152; P = .088). CONCLUSION: Tongue stiffness is a prognostic factor in patients with pT1/T2 TSCC with muscle-layer invasion. SR values >7.10 indicate a poor prognosis, thereby warranting a strict follow-up regimen in these cases.

Stiffness of tongue squamous cell carcinoma measured using strain elastography correlates with the amount of collagen fibers in the tumor.

OBJECTIVES: To evaluate the stiffness of tongue squamous cell carcinoma (TSCC) using ultrasound strain elastography, a relatively new sonographic imaging technique, and to identify the factors that affect this stiffness. METHODS: We treated 62 patients diagnosed with muscle invasive TSCC, who were treated at the department of oral surgery of our institution. Each patient's tumor stiffness was semi-quantified according to the ratio of cancer to tongue muscle strain measured using ultrasound strain elastography (the strain ratio). Histopathological diagnosis was made on the same section as the ultrasound strain elastography. We set the following histopathological parameters: cancer cell content in the tumor area (%CCC), collagen fiber content in the tumor area (%CFC), and tumor-infiltrating inflammatory cell content in the stromal compartment (%TIIC). Spearman's rank correlation (rs) was used to assess correlations, and P values < 0.05 were considered significant. RESULTS: The mean strain ratio was 9.7 ± 9.8. The mean %CCC was 38.4 ± 11.3%, and % CFC was 31.1 ± 7.8%, % TIICs was 19.9 ± 8.9%. Log (strain ratio) by ultrasound strain elastography was positively correlated with %CFC (rs = 0.379, P = 0.024). %CFC was negatively correlated with %TIICs (rs = - 0.318, P = 0.012). No correlations were observed between other clinico-histopathological factors and either strain ratio, or %CFC. CONCLUSION: The strain ratio of the cancer to the strain of the tongue muscle measured through ultrasound strain elastography positively correlates with the collagen fiber content of the tumor area.

Appropriate surgical margin for odontogenic myxoma: a review of 12 cases.

OBJECTIVE: Odontogenic myxoma (OM) is a rare benign tumor that is frequently nonencapsulated and invades the surrounding bone, resulting in a high risk of recurrence. However, the optimal surgical technique and appropriate surgical margin remains controversial. Here, we report our clinical investigation of 12 patients with OM diagnosed histopathologically. STUDY DESIGN: We retrospectively reviewed the records of 12 patients treated at our institution. Osteotomy or bone shaving with enucleation was generally performed with 5-mm bony margins from the radiologic extent of the tumor. RESULTS: One half of the cases occurred in the maxilla and the other half in the mandible. Treatment for maxillary OM was enucleation in 2 patients and maxillectomy in 4 patients. Treatment for mandibular OM was enucleation with shaving of the surrounding bone in 1 patient and segmental mandibulectomy in 5 patients. Radiographs of surgical specimen removed by segmental mandibulectomy indicated that the mean distance between the tumor and the margin was 5.4 (range 3.4-7.0) mm. Tumor recurrence was noted in 1 patient who had undergone enucleation alone. CONCLUSION: The 1-cm surgical margin for OM, as reported conventionally, might not be necessary. A prospective study is needed to determine the appropriate surgical margin for OM.

Oral carcinoma: Clinical evaluation using diffusion kurtosis imaging and its correlation with histopathologic findings.

PURPOSE: In this study, we aimed to determine the usefulness of diffusion kurtosis imaging (DKI) as a noninvasive method for evaluation of the histologic grade and lymph node metastasis in patients with oral carcinoma. MATERIALS AND METHODS: Twenty-seven patients with oral carcinoma were examined with a 3-T MR system and 16-channel coil. DKI data were obtained by a single-shot echo-planar imaging sequence with repetition time, 10,000 ms; echo time, 94 ms; field of view, 250 × 204.25 ms; matrix, 120 × 98; section thickness, 4 mm; four b values of 0, 500, 1000, and 2000 s/mm2; and motion-probing gradients in three orthogonal directions. Diffusivity (D) and kurtosis (K) were calculated using the equation: S = S0 ∙ exp(-b ∙ D + b2 ∙ D2 ∙ K/6). Conventional apparent diffusion coefficient (ADC) was also calculated. The MR images were compared with the histopathologic findings. RESULTS: Relative to the histologic grades (Grades 1, 2, and 3) of the 27 oral carcinomas, D values showed a significant inverse correlation (r = -0.885; P < 0.001) and K values showed a significant positive correlation (r = 0.869; P < 0.001), whereas ADC values showed no significant correlation (r = -0.311; P = 0.115). When comparing between metastatic and non-metastatic lymph nodes, significant differences in the D values (P < 0.001) and K values (P < 0.001), but not the ADC values (P = 0.110) became apparent. CONCLUSIONS: In patients with oral carcinoma, DKI seems to be clinically useful for the evaluation of histologic grades and lymph node metastasis.

The Imaging Diagnosis of Less Advanced Cases of Cardiac Amyloidosis: The Relative Apical Sparing Pattern.

An early diagnosis is important for improving the prognosis of cardiac amyloidosis (CA). We herein describe the utility of two-dimensional speckle tracking echocardiography (2-D STE) in diagnosing CA at a less advanced stage. A 63-year-old woman with exertional dyspnea was suspected of having CA based on her echocardiographic and electrocardiographic findings. A myocardial biopsy was negative for amyloid deposits, while the relative apical sparing pattern was detected on 2-D STE, which was highly suggestive of CA. Chemotherapy was initiated as a treatment for CA, and the patient's symptoms were immediately relieved. Thereafter, amyloid deposits were detected in a skin biopsy specimen.

LAMC2 is a predictive marker for the malignant progression of leukoplakia.

BACKGROUND: LAMC2 plays an important role in cancer invasion. The aim of this study was to (i) compare the immunoexpression of LAMC2 in different stages of oral squamous cell carcinoma (OSCC), early and advanced, and (ii) to evaluate LAMC2 as a marker of malignant transformation in leukoplakia. MATERIALS AND METHODS: The expression of LAMC2 was examined by immunohistochemistry in 50 surgical specimens of advanced OSCC assembled as tissue microarrays, and by cDNA microarray in 43 surgical specimens of advanced OSCC. LAMC2 expression was further examined in 39 surgical specimens of early OSCC and in 93 incisional biopsy specimens of leukoplakia of the tongue, which exhibited epithelial dysplasia. The relationship of LAMC2 expression score with clinico-pathological characteristics was analyzed. RESULTS: LAMC2 was remarkably upregulated in OSCC at the cancer-stroma interface. The grade of LAMC2 expression was significantly associated with the pattern and depth of invasion of OSCC. Foci of LAMC2-positive cells were observed in some cases of leukoplakia. The number and size of LAMC2-positive foci were significantly associated with the grade of dysplasia. The presence of LAMC2-positive foci was a significant predictive factor for the malignant progression of leukoplakia. LAMC2-positive leukoplakia had an approximately 11-fold increased risk of malignancy compared with LAMC2-negative leukoplakia. CONCLUSIONS: The results of this study highlight the value of LAMC2 as a marker of cancer invasion. LAMC2-positive foci in leukoplakia suggest an imminent risk of cancer. LAMC2 immunostaining is expected to contribute to a more precise assessment of the malignancy of leukoplakia.

Disordered arrangements of basal cells as a prognostic factor for oral epithelial dysplasia: a morphometric study of 96 cases.

OBJECTIVE: The aim of this study was to assess objectively the predictive value of the atypical appearance of the basal layer of oral epithelial dysplasia (OED) for development into invasive carcinoma. STUDY DESIGN: Ninety-six OED cases were examined. These cases were divided into 2 groups: 38 cases that developed into invasive carcinoma and 58 cases that did not. Furthermore, 12 histopathological factors were quantified morphometrically in each case and assessed by Cox's proportional hazards model. RESULTS: The standard deviation of the length between the apical membrane of the basal cells and the basement membrane was significantly associated with development of OED into invasive carcinoma (P < .001; hazard ratio, 3.124). CONCLUSION: We provided novel, objective data demonstrating that an atypical appearance, especially the disordered arrangement of the basal cells representing loss of polarity, may be useful for predicting the development of OED into invasive carcinoma of the tongue.

Characterizing Genetic Transitions of Copy Number Alterations and Allelic Imbalances in Oral Tongue Carcinoma Metastasis.

Primary tumor (PT) heterogeneity can significantly affect the genetic profile of clones at metastatic sites. To understand the mechanisms underlying metastasis, we compared the genetic profile of paired PT and metastatic lymph node (MLN) samples obtained from patients with oral tongue squamous cell carcinoma (OTSCC). Large-scale genetic profiling was performed on paired PT-MLN samples obtained from 10 OTSCC patients using high-density single-nucleotide polymorphism microarrays. We compared the genetic profile of PT and MLN OTSCC samples to identify common and specific copy number alterations and copy-neutral loss-of-heterozygosity (CN-LOH). Unsupervised hierarchical clustering analysis indicated that 8 of the 10 PT-MLN sample pairs formed clusters, indicating that the primary and metastatic tumors were composed of predominantly genetically similar tumor cells. In 6 of the 10 pairs, 8q11.21, 8q12.2-3, and 8q21.3 gains, and 22q11.23 loss were detected in both the PT and MLN. In addition, 16p11.2 CN-LOH was identified in 9 of the 10 pairs. Conversely, 20q11.2 gain was only observed in the MLNs of 5 of the 10 sample pairs, indicating that genes in this chromosomal region may play a significant role in OTSCC lymph node metastasis. To confirm this, we investigated the expression of two candidate 20q11.2 genes in a separate patient cohort. The expression of one of these genes, E2F1, was significantly increased during the process of metastasis. This study indicates that additional genetic changes, such as 20q11.2 gain, which encodes the E2F1 gene, can be acquired through clonal evolution, and may be required for the metastatic process. © 2016 Wiley Periodicals, Inc.

Primary intraosseous squamous cell carcinoma derived from a maxillary cyst: A case report and literature review.

Primary intraosseous squamous cell carcinoma (PIOSCC) is a rare malignant central jaw tumor derived from odontogenic epithelial remnants. PIOSCC predominantly affects the mandible, although both jawbones may be involved. This case report describes a PIOSCC type 2 of the maxilla in a 37-year-old man, treated by partial maxillectomy. Histopathologically, the tumor was diagnosed as PIOSCC derived from an odontogenic cyst. Postoperatively, the patient has been followed up for 53 months, with no recurrence of the disease. We herein describe the clinical details, treatment results and histopathological characteristics of a rare case of PIOSCC derived from a maxillary odontogenic cyst with reference to the relevant literature.

Expression of CD90 decreases with progression of synovial chondromatosis in the temporomandibular joint.

OBJECTIVES: The aim of the present study was to investigate the factors that contribute to the progression of synovial chondromatosis in the temporomandibular joint (TMJ). METHODS: The authors investigated the expression of CD105 and CD90 in specimens from 17 patients with synovial chondromatosis in the TMJ, using immunohistochemical staining, and expression of CD105 and CD90 in cartilaginous nodules was scored semiquantitatively. RESULTS: The expression of CD105 and CD90 was found in almost all the cases. In particular, the expression of CD90 in cartilaginous nodules significantly decreased with the progression of synovial chondromatosis. DISCUSSION: The factors that determine progression of synovial chondromatosis are not fully understood. The results of this study suggest that CD90 may play an important role in the progression of synovial chondromatosis in the TMJ.

Primary ameloblastic carcinoma of the maxilla: A case report and literature review.

Ameloblastic carcinoma (AC) is a rare malignant odontogenic neoplasm that tends to occur in the mandible rather than in the maxilla. This malignancy is classified as a tumor that combines the morphological features of ameloblastoma and carcinoma, regardless of the presence or absence of metastasis. In addition, AC has been classified into two types, primary and secondary. The former develops de novo and the latter develops by malignant transformation of a pre-existing benign ameloblastoma. The present study describes the case of a 22-year-old patient with primary AC of the maxilla. A review of the literature focusing on the clinical details, treatment results and histopathological and phenotypic information available for ameloblastic carcinoma of the maxilla from a 60-year period was also performed. As a result, it was found that primary AC is dominant in the maxilla and does not exhibit an aggressive phenotype compared with secondary AC. In addition, the presence of recurrence was found to correlate with mortality, indicating that early, aggressive and complete removal of the tumor is the best treatment for survival.

Adenocarcinoma arising from an anal gland-Report of a case.

INTRODUCTION: Adenocarcinoma arising from an anal gland is extremely rare. Most anal canal cancers are squamous cell carcinoma, and adenocarcinoma is infrequently diagnosed. Diagnostic criteria and the standard treatment for adenocarcinoma of the anal canal have not been clearly defined, in part because of the rarity of this lesion. PRESENTATION OF CASE: An 84-year-old man who presented with a piece of tissue prolapsing from the anus. An incisional biopsy showed adenocarcinoma, and an abdomino-perineal resection was then performed. Cytokeratin 7 (CK7), cytokeratin 19 (CK19) stained positive in the specimen, suggesting that the tumor developed from an anal gland. The patient was discharged after surgery without any complications. DISCUSSION: Exact diagnostic criteria for adenocarcinoma of the anal canal have not been previously described. In the present case, CK7 and CK19 were stained, and the tumor showed positivity for both of these markers, which is compatible with the staining patterns of anal gland origin cancer. Radical resection is recommended rather than local resection, because of the tumor's high recurrence rate. Some authors recommend combined modality treatment with preoperative or postoperative chemoradiotherapy because of the high rate of distant recurrence. CONCLUSION: The preoperative diagnosis of adenocarcinoma arising from an anal gland is not easily established. However, it may be possible to suspect an anal glandular adenocarcinoma based on a meticulous physical examination, appropriate diagnostic studies and pathological findings on biopsy.

Peripheral odontogenic keratocyst associated with nevoid basal cell carcinoma syndrome: a case report.

OBJECTIVE: Peripheral odontogenic keratocyst (POKC) is a rare gingival cyst showing histologic features identical to those of keratocystic odontogenic tumor. A rare case of POKC associated with nevoid basal cell carcinoma syndrome (NBCCS) is presented. STUDY DESIGN: A 24-year-old woman with NBCCS presented with a pigmented papule, 3 mm in size, involving the lingual gingiva of the right canine area of the mandible. Based on a clinical diagnosis of benign pigmentation, an excisional biopsy was performed, and a histopathologic diagnosis of POKC was rendered. RESULTS: The lining cells were positive for the proteins GLI2, BCL2, keratin 8, keratin 17, and mTOR. TP53 and Ber-EP4 were also weakly positive. Gene mutational analysis on a buccal swab sample revealed 2 missense mutations in the PTCH1 gene. CONCLUSIONS: This case is a distinctive example of a genuine soft tissue counterpart of keratocystic odontogenic tumor, in which an aberrant PTCH1-GLI pathway played a considerable role in the pathogenesis.

Three-dimensional reconstruction of oral tongue squamous cell carcinoma at invasion front.

We conducted three-dimensional (3D) reconstruction of oral tongue squamous cell carcinoma (OTSCC) using serial histological sections to visualize the architecture of invasive tumors. Fourteen OTSCC cases were collected from archival paraffin-embedded specimens. Based on a pathodiagnostic survey of whole cancer lesions, a core tissue specimen (3 mm in diameter) was dissected out from the deep invasion front using a paraffin tissue microarray. Serial sections (4 µ m thick) were double immunostained with pan-cytokeratin and Ki67 antibodies and digitized images were acquired using virtual microscopy. For 3D reconstruction, image registration and RGB color segmentation were automated using ImageJ software to avoid operator-dependent subjective errors. Based on the 3D tumor architecture, we classified the mode of invasion into four types: pushing and bulky architecture; trabecular architecture; diffuse spreading; and special forms. Direct visualization and quantitative assessment of the parenchymal-stromal border provide a new dimension in our understanding of OTSCC architecture. These 3D morphometric analyses also ascertained that cell invasion (individually and collectively) occurs at the deep invasive front of the OTSCC. These results demonstrate the advantages of histology-based 3D reconstruction for evaluating tumor architecture and its potential for a wide range of applications.

General rules for clinical and pathological studies on oral cancer: a synopsis.

For the doctors and other medical staff treating oral cancers, it is necessary to standardize basic concepts and rules on oral cancers to progress in the treatment, research and diagnosis. Oral cancers are integrated in head and neck cancers and are applied to the general rules on head and neck cancer, but it is considered that more detailed rules based on the characteristics of oral cancers are essential. The objectives of this 'General Rules for Clinical and Pathological Studies on Oral Cancer' are to contribute to the development of the diagnosis, treatment and research of oral cancers based on the correct and useful medical information of clinical, surgical, pathological and image findings accumulated from individual patients at various institutions.

AMP kinase-related kinase NUAK2 affects tumor growth, migration, and clinical outcome of human melanoma.

The identification of genes that participate in melanomagenesis should suggest strategies for developing therapeutic modalities. We used a public array comparative genomic hybridization (CGH) database and real-time quantitative PCR (qPCR) analyses to identify the AMP kinase (AMPK)-related kinase NUAK2 as a candidate gene for melanomagenesis, and we analyzed its functions in melanoma cells. Our analyses had identified a locus at 1q32 where genomic gain is strongly associated with tumor thickness, and we used real-time qPCR analyses and regression analyses to identify NUAK2 as a candidate gene at that locus. Associations of relapse-free survival and overall survival of 92 primary melanoma patients with NUAK2 expression measured using immunohistochemistry were investigated using Kaplan-Meier curves, log rank tests, and Cox regression models. Knockdown of NUAK2 induces senescence and reduces S-phase, decreases migration, and down-regulates expression of mammalian target of rapamycin (mTOR). In vivo analysis demonstrated that knockdown of NUAK2 suppresses melanoma tumor growth in mice. Survival analysis showed that the risk of relapse is greater in acral melanoma patients with high levels of NUAK2 expression than in acral melanoma patients with low levels of NUAK2 expression (hazard ratio = 3.88; 95% confidence interval = 1.44-10.50; P = 0.0075). These data demonstrate that NUAK2 expression is significantly associated with the oncogenic features of melanoma cells and with the survival of acral melanoma patients. NUAK2 may provide a drug target to suppress melanoma progression. This study further supports the importance of NUAK2 in cancer development and tumor progression, while AMPK has antioncogenic properties.

Oral premalignant lesions: from the pathological viewpoint.

Under the widely used World Health Organization (WHO) classification for the pathological diagnosis of oral premalignant lesions, dysplasia, which is graded as mild, moderate or severe, and carcinoma in situ (CIS), which is a non-invasive carcinoma, are classified as precursor lesions of oral squamous cell carcinoma. Since the first edition (Wahi et al. International histological classification of tumours no. 4, WHO, Geneva, 1971), the criterion for CIS--that all epithelial layers are replaced by atypical cells--has remained unchanged. However, this dysplasia-carcinoma sequence theory was introduced from the viewpoint of pathological changes in the uterine cervix: in contrast, almost all premalignant lesions and CIS of the oral mucosa show superficial maturation and differentiation. Based on this recognition, the squamous intraepithelial neoplasia (SIN) classification and Ljubljana classification were included in WHO's latest edition published in 2005. Although the WHO classification is commonly used in Japan, recent developments in oral oncology have promoted modifications of the classification used in this country. In 2005, the Working Group of the Japan Society for Oral Tumours advocated iodine staining and proposed a modified SIN system, and in 2007, the Working Committee of the Japanese Society for Oral Pathology (JSOP) reported a new CIS (JSOP) definition that included differentiated-type CIS. In 2010, based on these studies, a new entity--oral intraepithelial neoplasia (OIN)--was included in the first edition of General Rules for Clinical and Pathological Studies on Oral Cancer. In this review, we focus on the OIN/CIS (JSOP) new classification of premalignant lesions in oral mucosa, which further advances the concept of SIN.

FGFR4 polymorphism, TP53 mutation, and their combinations are prognostic factors for oral squamous cell carcinoma.

The genotype of the fibroblast growth factor receptor 4 (FGFR4) gene and TP53 mutation have been reported as prognostic factors for cancers of the head and neck, bladder, breast and colon. To determine whether they are applicable for oral squamous cell carcinoma (OSCC), we investigated these two genes in OSCC samples from 150 patients who had undergone radical surgery and in 100 cancer-free individuals. In OSCC, the FGFR4 Gly388Arg polymorphism and the presence or absence of mutation in TP53 did not show a significant association with the clinicopathological features of the tumors at surgery. However, the FGFR4 Arg388 allele, as well as mutations in TP53, was found to be closely associated with poor prognosis. Moreover, these two parameters synergistically affected the survival of OSCC patients. During 60 months of observation after radical surgery, a majority of patients with homozygous Arg388 FGFR4 plus mutated TP53 died of cancer, whereas >90% patients carrying homozygous Gly388 FGFR4 plus wild-type TP53 survived. Therefore, the FGFR4 Gly388Arg polymorphism and TP53 mutations, as well as their combinations, are excellent predictors of the prognosis for OSCC patients.

Telomere lengths in the oral epithelia with and without carcinoma.

Aging appears to be intrinsically related to carcinogenesis. Genomic instability due to telomere shortening plays an important role in carcinoma development. In order to clarify telomere dysfunction in carcinoma development, we examined the uninvolved epithelium adjacent to carcinoma in situ (CIS), i.e. background of CIS, and CIS itself, compared to control without carcinoma, using an improved quantitative fluorescence in situ hybridization (Q-FISH) method. We also estimated anaphase bridge (AB), which is inferred to be related to chromosomal instability. In all cell types (basal, parabasal, and suprabasal), mean telomere lengths were significantly shorter in the background than in the control. We also demonstrated increased incidences of AB, not only in CIS, but also in the background and control epithelia with excessively shortened telomeres. Thus we have conclusively demonstrated that CIS arises from epithelium with short telomeres.