Search

Low-grade, low-stage endometrioid carcinomas (LGLS EC) demonstrate 5-yr survival rates up to 95%. However, a small subset of these tumors recur, and little is known about prognostic markers or established mutation profiles associated with recurrence. The goal of the current study was to identify the molecular profiles of the primary carcinomas and the genomic differences between primary tumors and subsequent recurrences. Four cases of LGLS EC with recurrence and 8 cases without recurrence were evaluated via whole-exome sequencing. Three of the 4 recurrent tumors were evaluated via Oncomine Comprehensive Assay. The resulting molecular profiles of the primary and recurrent tumors were compared. Two of the 3 recurrent cases showed additional mutations in the recurrence. One recurrent tumor included an additional TP53 mutation and the other recurrent tumor showed POLE and DDR2 kinase gene mutation. The POLE mutation occurred outside the exonuclease domain. PIK3CA mutations were detected in 4 of 4 primary LGLS EC with recurrence and in 3 of 8 disease-free cases. LGLS EC with recurrence showed higher MSIsensor scores compared with LGLS without recurrence. The level of copy number gains in LGLS EC with recurrence was larger than LGLS EC without recurrence. This pilot study showed 1 of 3 recurrent cases gained a mutation associated with genetic instability (TP53) and 1 of them also acquired a mutation in the DDR2 kinase, a potential therapeutic target. We also noted a higher level of copy number gains, MSIsensor scores and PIK3CA mutations in the primary tumors that later recurred., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Adenomyoepitheliomas (AMEs) of the breast are uncommon and span the morphologic spectrum of benign, atypical, in situ, and invasive forms. In exceptionally rare cases, these tumors metastasize to regional lymph nodes or distant sites. In the era of genomic characterization, data is limited regarding AMEs. The aim of this study was to provide insight into the molecular underpinnings of a spectrum of AMEs. Seven cases of AMEs of the breast (benign-1, atypical-2, in situ-1, invasive-3) were identified in our files. The seven samples were interrogated using the Oncomine Comprehensive Assay v3 (ThermoFisher). Two atypical AMEs and the malignant in situ AME harbored the same gain-of-function PIK3CA mutation. The malignant in situ AME also showed EGFR amplification, not described previously. Both a benign AME and a malignant invasive AME shared the same gain-of-function AKT1 variant. The benign AME also showed a GNAS mutation. Moreover, the same gain-of-function HRAS mutation was present in an atypical AME and a malignant invasive AME. We also identified co-occurring HRAS and PIK3CA mutations in an ER-positive atypical AME, which has not been previously described. No fusion drivers were detected. We describe the molecular characteristics of the spectrum of AME tumors of the breast, which harbor alterations in the PI3K/AKT pathway. Our findings are clinically relevant with respect to the current options of targeted therapy in the rare instances where malignant AME tumors of the breast progress.

Mixed endometrial carcinomas are defined as a combination of 2 or more distinct histologic subtypes, one of which must be a type II tumor comprising at least 5% of the tumor volume. The oncogenesis of these tumors remains unclear, particularly in light of the increasingly appreciated morphologic overlap among subtypes, as well as evolving molecular data. We evaluated 8 cases of mixed endometrial carcinoma, including 4 endometrioid (EC)/serous (SC), 1 SC/clear cell (CC), and 3 EC/CC cases, to study the underlying molecular features and oncogenic mechanisms at play. Each component was analyzed by a targeted next-generation sequencing assay. All tumors shared mutations in both components. In 6 cases, one component showed additional mutations. Two EC/SC cases showed shared mutations and mutations unique to each component. When present, unique mutations were typically seen in the SC component, including variants in POLE and TP53, as well as potentially targetable genes DDR2, MAP2K1, and CCNE1. In EC/SC tumors, ERBB2 abnormalities were seen in 2 cases. EC/CC cases showed FGFR2 activating mutations in the EC component only. No fusion drivers were identified. Our data suggest that the majority of these tumors begin as a single clone and diverge along 2 pathways: (1) tumor progression, with one component showing additional mutations, and (2) tumor divergence, in which tumor components have both shared mutations and mutations unique to each component. In addition, the findings suggest a component of morphologic mimicry in these tumors. Our findings are clinically relevant since targetable mutations may be present in only one component of mixed tumors.

Objectives: In this study, the effects of ozonetherapy on secondary wound healing were evaluated histologically and immuno-histochemically., Material and Methods: Material and Methods: 8 healthy pigs were used in this study. Six wounds with 10 mm in diameter were created through the punch technique on the palatinal gingiva of each pig. Ozone gas was applied on only 3 wounds (test group) and the remaining 3 were left to natural healing (control group). Biopsy samples were taken from one of the wounds in each group on the third day, from another wound of each group on the seventh day, and from another one on the tenth day. Routine histological analysis and immuno-histochemical staining were performed to investigate transforming growth factor-beta (TGF-β) and (VEGF) expressions., Results: Results: No statistical difference was found between the test and control groups in terms of collagen fibers, epithelial formation and inflammation scores. A VEGF expression found in the test group was statistically higher than control group samples taken on the 3rd and 7th day. There was no statistical difference between the test and control groups in terms of TGF-β expression on any of the sampling days., Conclusions: Conclusion: The topical application of ozone gas could be effective in the early stages of wound healing by increasing the amount of VEGF expression. Clinical Relevance: Topical application of ozone gas may be effective in the early stages of oral wound healing.

Purpose: Platelet-rich plasma (PRP) is a novel method for transferring autogenous growth factors to the wound area. The aim of this study was to evaluate the efficacy of double-application of PRP (DA-PRP) on bone healing in rabbit cranial defects by examining osteonectin (ON) and osteocalcin (OC) expression., Materials and Methods: Twenty-eight rabbits, each with two surgically prepared calvarial bone defects, were included in this study and divided into six groups: The defects (N=56) were treated with either a single-application of PRP (SA-PRP) (n=10), a combination of SA-PRP and betatricalciumphosphate (SA-PRP+β-TCP) (n=10), only DAPRP (n=8), both DA-PRP and beta-tricalciumphosphate (DA-PRP+β-TCP) (n=8), only beta-tricalciumphosphate (β-TCP) (n=10), or controls (n=10). The animals were sacrificed at 30th day postoperatively and samples were immunohistochemically examined for ON and OC expressions., Results: It was determined that DA-PRP did not significantly improve the ON and OC percentages achieved by SA-PRP or the controls. The three groups treated with β-TCP showed a higher percentage of ON than those treated without β-TCP (p<0.05). The β-TCP treated groups and SA-PRP group demonstrated higher OC percentage than DA-PRP and control groups (p<0.05)., Conclusion: The present findings suggest that DAPRP did not have a significant effect on the healing of non-critical size rabbit cranial bone defects., Competing Interests: Conflict of interest: None declared.

Increased telomerase activity is associated with almost all types of advanced human cancers with unknown molecular mechanism(s). Two recurrent point mutations in the promoter region of telomerase reverse transcriptase (TERT)--the key subunit of telomerase--have recently been identified in melanoma as well as a small sample of bladder cancer cell lines. However, the incidence and clinical-pathological significance of these mutations in urothelial carcinoma have not been well established yet. We collected 86 specimens of urothelial carcinoma including upper and lower urinary tract: high grade and low grade, invasive and noninvasive, and primary and metastatic. We also included some matched benign urothelium and common benign bladder lesions: cystitis, nephrogenic adenoma, and inverted papilloma. In addition, we collected urine samples for urothelial carcinoma workup; blood samples from patients underwent cystectomy with extensive lymphovascular invasion. All specimens were subject to polymerase chain reaction amplification and bidirectional Sanger sequencing for the TERT promoter mutations: C228T and C250T. We found that 64 (74%) of 86 carcinoma samples harbored 1 of the 2 TERT promoter mutations (C228T, n = 54; C250T, n = 10); the incidences were roughly equal regardless of site of origin, histologic grade, and invasive status. All matched benign and benign lesion samples showed wild-type sequence. These TERT promoter mutations are the most common genetic alterations in urothelial carcinoma and are not associated with tumor locations, grade, or invasiveness. Importantly, the feasibility of detecting these mutations in urine samples may provide a novel method to detect urothelial carcinoma in urine., (Copyright © 2015 Elsevier Inc. All rights reserved.)

RadioGraphics continues to publish radiologic-pathologic case material selected from the American Institute for Radiologic Pathology (AIRP) "best case" presentations. The AIRP conducts a 4-week Radiologic Pathology Correlation Course, which is offered five times per year. On the penultimate day of the course, the best case presentation is held at the American Film Institute Silver Theater and Cultural Center in Silver Spring, Md. The AIRP faculty identifies the best cases, from each organ system, brought by the resident attendees. One or more of the best cases from each of the five courses are then solicited for publication in RadioGraphics. These cases emphasize the importance of radiologic-pathologic correlation in the imaging evaluation and diagnosis of diseases encountered at the institute and its predecessor, the Armed Forces Institute of Pathology (AFIP).

Squamous cell carcinoma (SCC) can arise from different anatomical sites including the skin, head and neck, lung, esophagus, genital area, and so on. Despite the same histopathologic features and immunohistochemistry profile, the SCCs of different body sites can show tremendous differences in their presenting symptoms, risk factor associations, natural history, prognosis, and response to treatment. This may reflect the fact that SCCs are heterogenous and likely have unique molecular characteristics at different anatomical sites. Recurrent somatic mutations in the TERT promoter region were first reported in human melanomas. Subsequently, other tumors including cutaneous SCC were found to demonstrate high frequencies of the same mutations. However, the incidences of TERT promoter mutation in noncutaneous SCCs have not been systemically studied. We investigated the TERT promoter mutation status among SCCs from different sites. We collected 84 cases of SCC from the skin (27), head and neck (12), lung (25), and cervix (10), as well as 10 cases of urothelial carcinoma with squamous differentiation (UC-SqD). We found that the frequencies of TERT promoter mutation among SCC of different sits are quite heterogenous: ~70% in skin SCC and UC-SqD, 16.67% in head and neck SCC, and 0% in lung and cervix SCC. These results may support the hypothesis of different carcinogenesis mechanisms of SCC in different sites. It also indicates that TERT promoter mutation could be a biomarker for distinguishing skin SCC or UC-SqD vs pulmonary SCC., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Upper urinary tract urothelial cell carcinomas (UUT-UCs) are uncommon and are defined as urothelial carcinoma involving the urinary tract from the renal calyces, renal pelvis to the distal ureter. One well-known an peculiar histopathological finding in UUT-UC is urothelial carcinoma with intratubular spread (retrograde spread within renal tubules). However, this special feature has not been systematically studied. We therefore collected a total of 53 consecutive cases of upper urinary tract urothelial carcinomas (UUT-UCs), and studied the clinical and pathological features of intratubular spread (IS). A cocktail stain comprised of antibodies PAX8 and p63 together with PAS was validated and employed to facilitate the study of intratubular spread. Seventeen cases (31.5%) showed intratubular spread demonstrated by either H&E stain and/or the cocktail stain. All of the 17 cases wit intratubular spread had tumor involvement of the renal calyx; the majority of these (14/17, 82.4%) were high grade urothelial carcinoma and the remainder (3/17, 17.6%) were low grade. 4 of 17cases (23.5%) were non-invasive. We classified intratubular spread into 4 different types, based on histopathological patterns: pagetoid, typical, florid, and secondary invasion from intratubular spread. In conclusion, study shows intratubular spread of urothelial carcinoma is fairly common phenomenon in UUT-UC and is associated with a variety of clinical-pathological features. High grade UUT-UC tends to have more extensive intratubular spread and secondary invasion into renal parenchyma. Distinct morphological characteristics as well as the staining pattern from a unique cocktail stain help to identify and evaluate intratubular spread of urothelial carcinoma. Recognizing these different types of intratubular spreading (IS) is crucial for accurate staging of some upper urinary tract urothelial carcinomas (UUT-UCs).

Various studies have shown biostimulation effects of laser irradiation by producing metabolic changes within the cells. Little is known about the biological effect of laser irradiation on the oral tissues. Among the many physiological effects, it is important to recognize that low-level laser therapy (LLLT) may affect release of growth factors from fibroblasts. Therefore, the aim of the present study was to determine whether the laser irradiation can enhance the release of basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), and receptor of IGF-1 (IGFBP3) from human gingival fibroblasts (HGF). The number of all samples in the study were 30, and the samples were randomly divided into three equal groups; In the first group (single dose group), HGF were irradiated with laser energy of 685 nm, for 140 s, 2 J/cm(2) for one time, and in the second group, energy at the same dose was applied for two consecutive days (double dose group). The third group served as nonirradiated control group. Proliferation, viability, and bFGF, IGF-1, IGFBP3 analysis of control and irradiated cultures were compared with each other. Both of the irradiated groups revealed higher proliferation and viability in comparison to the control group. Comparison of the single-dose group with the control group revealed statistically significant increases in bFGF (p < 0.01) and IGF-1 (p < 0.01), but IGFBP3 increased insignificantly (p > 0.05). When the double dose group was compared with the control group, significant increases were determined in all of the parameters (p < 0.01). In the comparison of the differences between the two irradiated groups (one dose and two doses), none of the parameters displayed any statistically significant difference (p > 0.05). In both of the laser groups, LLLT increased the cell proliferation and cell viability. The results of this study showed that LLLT increased the proliferation of HGF cells and release of bFGF, IGF-1, and IGFBP3 from these cells. LLLT may play an important role in periodontal wound healing and regeneration by enhancing the production of the growth factors.

Background: Most studies have evaluated serum C-reactive protein (CRP) levels in chronic periodontitis (CP) patients, and a few investigations have examined gingival crevicular fluid (GCF) CRP levels. The aims of this study were to determine GCF and serum levels of high-sensitivity CRP (HsCRP) in CP patients with or without coronary artery disease (CAD) and to investigate the relationship between the GCF and serum HsCRP levels in CP patients with and without CAD., Methods: Thirty CP patients with angiographically proven CAD, 20 CP patients, and 17 healthy individuals were included in the study. Clinical parameters were recorded, and serum and GCF samples were collected. The level of HsCRP in GCF was assayed by a high-sensitivity enzyme-linked immunosorbent assay. The HsCRP level was assayed in the plasma on a nephelometer., Results: The serum HsCRP levels were significantly higher in CP patients with or without CAD than in the control group, and there was a correlation between serum HsCRP levels and clinical parameters and between serum HsCRP levels and GCF volume. There was no statistically significant difference in GCF HsCRP levels between the groups. There was no correlation between GCF HsCRP levels and clinical parameters, GCF volume, or serum HsCRP levels., Conclusions: Patients with CP and CP + CAD had statistically significant elevations in serum HsCRP levels compared to healthy subjects. However, HsCRP levels of GCF did not differ from those of the control and CP groups or the control and CP + CAD groups. Further studies are needed to clarify the relationship between GCF CRP levels and periodontal diseases.

Background: Cigarette smoking has been identified as an important risk factor for the initiation and progression of chronic periodontitis (CP). The aim of this study was to investigate the effects of phase I periodontal therapy and adjunctive flurbiprofen administration on matrix metalloproteinase (MMP)-8 levels in gingival crevicular fluid (GCF) samples from smoking and non-smoking patients with CP., Methods: Twenty-nine non-smoking and 29 smoking patients with CP were divided into four groups according to periodontal treatment modalities. Group 1 (non-smokers with CP) and group 3 (smokers with CP) patients received daily 100-mg flurbiprofen tablets in a 2 x 1 regimen for 10 days together with scaling and root planing (SRP). Patients in group 2 (non-smokers with CP) and group 4 (smokers with CP) received placebo tablets in a 2 x 1 regimen for 10 days together with SRP. Plaque index (PI), gingival index (GI), probing depth (PD), and clinical attachment level (CAL) measurements were recorded; GCF samples were collected from each sampling area at baseline and after the 10-day period of drug intake by a single examiner who was unaware of the treatment modality. Assays for GCF MMP-8 were carried out by an enzyme-linked immunosorbent assay., Results: All groups showed statistically significant reductions in PI and GI scores following the phase I periodontal treatment (P < 0.05), but no statistical differences were observed in PD and CAL scores after therapy. In all groups, the reduction of GCF MMP-8 levels after therapy was statistically significant compared to baseline levels (P < 0.001). When groups 1 and 3 and 2 and 4 were compared according to GCF MMP-8 levels after the therapy, no statistically significant differences were observed (P = 0.117 and P = 0.485, respectively)., Conclusion: Flurbiprofen administration had no additional inhibitory effect over SRP alone on GCF levels of MMP-8 in smokers compared to non-smokers with CP.

Calcium-channel blockers (CCB), including verapamil, nifedipine, and diltiazem, are one of the most widely prescribed class of drugs in the treatment of cardiovascular disease. In the last several years, CCBs have been linked with a distinct cutaneous subset in the lupus spectrum, subacute cutaneous lupus erythematosus (SCLE), and we describe a case induced by verapamil.

Primary cutaneous B-cell lymphoma is an uncommon neoplasm with classification schemes that may be confusing, but with clinical presentations that are relatively consistent. Clinical exam and history can raise the index of suspicion for this condition, although the diagnosis is confirmed only by pathological evaluation. We report such a scenario in the case of a 74-year old male with a slowly expanding oval plaque on his right upper arm.

This study was undertaken to evaluate the biocompatibility, cellular reaction and resorption characteristics of a type I bovine collagen membrane material either enriched with or without fibronectin solution in vivo using light (LM) and transmission electron microscopy (TEM). Experimental osseous dehiscence defects were surgically produced bilaterally on the labial aspect of the mandibular 2nd, 3rd, and 4th premolar teeth in four mongrel dogs. Collagen membranes rehydrated with fibronectin solution (group FM) and membranes rehydrated with saline (group M) were placed over the bony defects. The third premolar teeth on which the flap operation was performed served as control (group C), with no membrane placed. Flaps were positioned slightly coronally and sutured. Gingival tissue samples and block biopsies were obtained from all experimental and control sites for LM and TEM evaluation at 7 days. For each group, morphometric analysis was performed and the numbers of macrophages in the most coronal area of the free gingiva were counted. Postoperative healing was uneventful during the experimental period, and all membranes remained covered. Light microscopic evaluation revealed similar resorption patterns in the most coronal area of the membranes both enriched with and without fibronectin solution within the first 7 days. The mean numbers of macrophages were higher in experimental groups than in the control group. In TEM evaluation, more excessive intracellular macrophage activity was observed in group M than group FM. As a result of these observations it may be concluded that similar resorption characteristics existed in the most coronal area in both experimental groups with LM evaluation, but with TEM it was observed that the membranes enriched with fibronectin solution were resorbed more slowly at the ultrastructural level.

The present study was planned to assess the capacity of a resorbable collagen membrane enriched with fibronectin to prevent the apical migration of epithelium and to facilitate new attachment and new bone. Experimental osseous dehiscence defects were produced on the bilateral labial aspect of mandibular 2nd, 3rd and 4th premolar teeth in six mongrel dogs. Guided tissue regeneration therapy using collagen membranes, which were rehydrated with fibronectin solution, was performed on one quadrant (group A). In the contralateral quadrant, the same collagen membranes, but rehydrated only with saline (group B), were placed over the bony defects. The third premolar teeth, which were treated by open-flap debridement, served as control (group C). Flaps were positioned slightly coronally and sutured; sutures were removed 10 days later. The dogs were killed 30 days after reconstructive therapy. Tissue blocks containing the experimental and control teeth were excised, demineralized in EDTA, and embedded in paraffin. Histological and histometric evaluation revealed that all groups demonstrated similar effects on preventing the down-growth of epithelium and formation of new cementum and new bone. Collagen membranes were tolerated well within the tissues, and membrane remnants were identified at 30 days. In summary, this study indicated that in this dog model similar healing results could be achieved with a bovine type I collagen membrane with or without fibronectin solution and open-flap debridement.

Intralesional injection of 5-fluorouracil has recently been reported as a possible method of treatment for an assortment of benign and malignant cutaneous neoplasms. We report the development of squamous-cell carcinoma within a basal-cell epithelioma that was treated with intralesional injections of 5-FU.

Five different cases of verrucous proliferative lesions of skin are described and discussed. One of each developed in a chronic ulcer on a heel, in a scar on a lower leg, and on the penis, and two appeared in the region of the buttock in relation to chronic inflammatory sinuses. All these lesions showed morphological and clinical features of verrucous carcinoma which are described. It has been concluded that the variously named verrucous lesions in the literature (epithelioma cuniculatum, florid papillomatosis, giant cutaneous papilloma and papillomatosis cutis carcinoides), as well as our five cases represent a verrucous carcinoma which is a particular type of squamous cell carcinoma. This tumor develops typically in moist areas which are frequently sites of chronic inflammation. Despite the favorable prognosis, it is a potentially invasive tumor.

Successful management of keratoacanthomas and basal-cell epitheliomas by intralesional injections of 5-fluorouracil is reported.