Sclerosing Dermatofibrosarcoma Protuberans: A Possible Diagnosis When a Small Biopsy Shows Sclerotic Fibroma-Like Features.

ABSTRACT: Dermatofibrosarcoma protuberans (DFSP) is a neoplasm of intermediate malignancy with high local recurrence rates. The sclerosing variant is characterized by the presence of sclerotic areas in more than 50% of tumors and is rarely reported. In this report, we describe a case of sclerosing DFSP with areas histopathologically resembling sclerotic fibroma, where the initial biopsy tissue presented a diagnostic challenge. A 77-year-old man presented with a 2-cm firm, erythematous nodule on the chest. A punch biopsy revealed plywood-like sclerosis and spindle cells with a vaguely storiform pattern. The tumor cells were positive for CD34. Sclerotic fibroma and DFSP were considered differential diagnoses. Subsequent excisional biopsy revealed that the tumor comprised 3 different histopathological areas: classic DFSP, sclerotic fibroma-like, and giant cell fibroblastoma-like. This report highlights the importance of reevaluating the clinical context and excision for further characterization.

Spindle-nucleated cells in cervical liquid-based cytology: Difficulties in distinguishing between epithelial and non-epithelial tumours based on morphology.

Uterine tumours resembling ovarian sex cord tumours of the uterine cervix are highly sporadic. Cervical liquid-based cytology revealed two cell patterns: spindle-nucleated cells and polygonal cells.

Chronic active EBV infection in refractory enteritis with longitudinal ulcers with a cobblestone appearance: an autopsied case report.

BACKGROUND: Chronic active Epstein-Barr virus infection (CAEBV) is defined as Epstein-Barr virus (EBV)-positive T/NK cell-related neoplasia, and its major clinical symptom is systemic inflammation presenting as infectious mononucleocytosis, whereas enteritis and diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes of EBV-positive cells and physical symptoms of systemic inflammatory disease constitutes the varied phenotypes of CAEBV. Herein, we describe a case of CAEBV that was initially diagnosed as Crohn's disease (CD) based on ileal ulcers and clinical symptoms of enteritis. CASE PRESENTATION: A 19-year-old woman complained of abdominal pain and fever. Blood examination showed normal blood cell counts without atypical lymphocyte but detected modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection. The esophagogastroduodenoscopic findings were normal. However, colonoscopy revealed a few small ulcers in the terminal ileum. The jejunum and ileum also exhibited various forms of ulcers, exhibiting a cobblestone appearance, on capsule endoscopy. Based on these clinical findings, she was strongly suspected with CD. In the course of treatment by steroid and biologics for refractory enteritis, skin ulcers appeared about 50 months after her initial hospital visit. Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes. We retrospectively assessed her previous ileal ulcer biopsy before treatment and found many EBER-positive lymphocytes. Blood EBV DNA was also positive. Therefore, she was diagnosed with extranodal NK/T-cell lymphoma with CAEBV-related enteritis rather than CD. She was treated with cyclosporine and prednisolone combination therapy for CAEBV-related systemic inflammation and chemotherapy for malignant lymphoma. Unfortunately, her disease continued to progress, leading to multiple organ failure and death at the age of 23 years. CONCLUSION: Clinicians need to remember the possibility of CAEBV as a differential diagnosis of refractory enteritis. Enteritis with intestinal ulcer is a rare symptom of CAEBV, and it is impossible to acquire a definitive diagnosis by ulcer morphology only. In cases where the possibility of CAEBV remains, tissue EBVR expression should be checked by in situ hybridization and blood EBV DNA.

Computer-assisted three-dimensional analysis of multifocal/multicentric prostate cancer.

In order to study multiple contiguous prostate cancer lesions, we constructed computer-assisted, three-dimensional models of multifocal prostate cancer specimens obtained by radical prostatectomy. We then examined the genetic heterogeneity among the specimens by DNA microarray analysis. Cancer foci with high Gleason patterns were found to occur de novo, whereas those with low Gleason patterns occurred contiguously with cancers of low Gleason patterns. Three-dimensional analysis showed that distinct, noncontiguous cancerous foci were genetically independent and multicentric. In contrast some contiguous multifocal lesions had the same genetic origin.

Treatment of Intra-Articular Lesions After Posterior Inferior Tibiofibular Ligament Injury: A Case Series of Elite Rugby Players.

Background: Surgical intervention is not typically used to treat symptoms after mild tibiofibular ligament injuries without ankle dislocation or subluxation. Purpose: To describe outcomes in patients arthroscopically treated for unique intra-articular lesions after sustaining syndesmosis injury of the ankle. Study Design: Case series; Level of evidence, 4. Methods: A total of 11 elite male rugby players with a mean age of 21.0 years (range, 17-28 years) were referred to our hospital for prolonged posterior ankle pain after a high ankle sprain during rugby football. The patients were examined using standing view radiography, computed tomography (CT) and magnetic resonance imaging (MRI) to determine the extent of ligament damage. Posterior ankle arthroscopy was performed to examine intra-articular lesions. The patients were evaluated using the American Orthopaedic Foot and Ankle Society (AOFAS) ankle/hindfoot rating scale and sports activity score of the Self-Administered Foot Evaluation Questionnaire (SAFE-Q). Results: The average reduced tibiofibular overlap on the standing mortise view was 1.2 mm (range, 0.5-2.0 mm) compared with the opposite ankles. Mason type 1 fracture was detected on CT in 6 patients, and ossification of the interosseous membrane was detected in 2 patients. A bone bruise in the posterior malleolus was observed on MRI in all but 1 patient. Intra-articular fragments located in the posterior ankle were observed and removed arthroscopically. Symptoms improved rapidly after arthroscopic treatment in all patients. All patients returned to rugby games at a median of 11 weeks postoperatively. The median AOFAS scores improved from 77 preoperatively to 100 postoperatively (P < .01), and the median SAFE-Q sports activity subscale score improved from 49.4 to 100 (P < .01). Conclusion: All unique intra-articular lesions that developed in rugby football players after syndesmosis injury were able to be treated arthroscopically. Patients returned to playing rugby football without syndesmosis reduction. Posterior ankle arthroscopy was effective in patients with residual symptoms after syndesmosis injury.

Preference of grade and lymphovascular invasion over invasive size measurement in stage I lung adenocarcinoma.

AIMS: Although it is necessary to measure the invasive size of lung adenocarcinoma with a lepidic component, it is not uncommon to have trouble in measuring the invasive size of lung adenocarcinoma. This study examined whether there were other stronger prognostic factors than invasive size. METHODS: We characterised the clinicopathological features associated with recurrence-free survival (RFS) of 686 patients with the pathological stage (p-Stage) I lung adenocarcinoma. Moreover, we compared the area under the curve (AUC) values for recurrence between various combinations of pathological-baseline (age & sex & p-Stage based on invasive size) (B(i)) and several prognostic factors, and various combinations of p-baseline based on total tumour size (B(t)) and several prognostic factors. RESULTS: AUC showed no significant differences between B(i) & new International Association for the Study of Lung Cancer grade (G) or vascular invasion (V), and B(t) & G or V. AUC was the highest in B & G & lymphatic invasion (L) & V. RFS was significantly shorter in patients with G3 OR L(+) OR V(+) than in those with G≤2 AND L(-) AND V(-) in each p-Stage based on invasive size (p-Stage(i)) and p-Stage based on total tumour size (p-Stage(t)) (p<0.05), and there were no significant differences in RFS between each p-Stage(i) and p-Stage(t). CONCLUSIONS: In any invasive size or total tumour size of p-Stage I lung adenocarcinoma, G, L and V are more powerful prognostic factors than the size criteria of p-Stage. Therefore, pathologists should focus on these pathological findings.

Clinicopathological and genetic analyses of pulmonary enteric adenocarcinoma.

AIMS: Pulmonary enteric adenocarcinoma (PEAC) is a rare variant of pulmonary adenocarcinoma. Due to its rarity, few pathological and molecular studies have been performed on PEAC. We herein conducted clinicopathological, immunohistochemical and molecular analyses of PEAC with a focus on its differentiation from invasive mucinous adenocarcinoma (IMA). METHODS: We examined the clinicopathological features of 16 cases of PEAC and performed a genetic analysis using next-generation sequencing (NGS). The results obtained were compared with those for IMA. RESULTS: The average age of patients with PEAC (seven men and nine women) was 72.9 years. A comparison of clinical data on PEAC and IMA revealed no significant differences in age, sex or smoking history. Fifteen PEAC cases had dirty necrosis. Immunohistochemically, the positive rates for each antibody in PEAC were as follows: CK7, 88% (14/16); CK20, 81% (13/16); CDX2, 88% (14/16); p53, 69% (11/16); MUC1, 100% (16/16); MUC2, 19% (3/16); MUC5AC, 69% (11/16); MUC6, 19% (3/16). The positive rates for these antibodies in IMA were 100%, 87%, 0%, 7%, 93%, 0%, 100% and 80%, respectively. EGFR mutations, the MET exon 14 skipping mutation, BRAF mutations, the ALK fusion gene and ROS-1 fusion gene were not detected in any cases of PEAC or IMA. Among PEAC cases, NGS identified KRAS mutations in seven (44%, 7/16) and TP53 mutations in nine (56%, 9/16). Among IMA cases, the most commonly mutated gene was KRAS (90%). CONCLUSIONS: The rates of dirty necrosis, immunopositivity for CDX2 and TP53 mutations were significantly higher, while that of KRAS mutations was significantly lower in PEAC cases than in IMA cases.

Immunohistochemical analysis of neuroendocrine differentiation in prostate cancer.

OBJECTIVE: To clarify the significance of neuroendocrine differentiation in prostate cancer. METHODS: We immunohistochemically examined 96 samples of prostatic cancers obtained from radical prostatectomies using a specific neuroendocrine marker and various neuropeptides, as well as markers for cell proliferation, angiogenesis and androgen-receptor expression. RESULTS: We frequently found neuroendocrine cells in atrophic glands with or without chronic inflammation in nontumorous tissues. Neuroendocrine cells were detected in 36.5% of prostate cancer samples overall, but had no significant correlation to angiogenesis, cell proliferation or biochemical recurrence. However, patients with a high frequency of neuroendocrine cells (9.4%) tended to undergo preoperative hormonal therapy (p = 0.060), which led to their cancers being atrophic with inflammation. The neuroendocrine cells in these patients contained calcitonin-positive cells (p

Function of JunB in transient amplifying cell senescence and progression of human prostate cancer.

PURPOSE: Replicative senescence in cells acts as a barrier against excessive proliferation and carcinogenesis. Transient amplifying cells (TAC) are a subset of basal cell populations within the prostate from which cancers are thought to originate; therefore, we focused on prostate TAC to investigate the molecular mechanisms by which the TAC may be able to evade senescence. EXPERIMENTAL DESIGN: TAC clones were isolated from each zone within the whole prostate and analyzed in flow cytometry. Prostate cancer cells were transfected with junB small interfering RNA (siRNA) and examined by chorioallantoic membrane assay for cancer invasion. Immunohistochemical analysis was done in primary and metastatic prostate cancer specimens. RESULTS: TAC populations showed increased expression of p53, p21, p16, and pRb, resulting in senescence. TAC clones with reduced p16 expression successfully bypassed this phase. We further found close correlation between the levels of junB and p16 expression. Repeated transfection of junB siRNA in prostatic TAC allowed the cells to escape senescence presumably through inactivation of p16/pRb. The chorioallantoic membrane invasion assay showed much lower in invasive cancer cells with high expression of junB; conversely, silencing of junB by transfection with junB siRNA promoted invasion. We also found that metastatic prostate cancers, as well as cancers with high Gleason scores, showed significantly low junB immunopositivity. CONCLUSIONS: JunB is an essential upstream regulator of p16 and contributes to maintain cell senescence that blocks malignant transformation of TAC. JunB thus apparently plays an important role in controlling prostate carcinogenesis and may be a new target for cancer prevention and therapy.

Prostate cancer antigen-1 contributes to cell survival and invasion though discoidin receptor 1 in human prostate cancer.

A novel gene, prostate cancer antigen (PCA)-1, was recently reported to be expressed in the prostate; however, its biological roles remain unclear. Knockdown of the PCA-1 gene by small interfering RNA transfection induced apoptosis through reducing the expression of the anti-apoptotic molecule Bcl-xl and cytoplasmic release of cytochrome c in the androgen-independent prostate cancer cell line PC3. Moreover, in vitro matrigel and in vivo chorioallantoic membrane assays showed that silencing of PCA-1 significantly downregulated discoidin receptor (DDR)-1 expression, resulting in suppression of cancer-cell invasion. Transfection with PCA-1 increased the levels of both Bcl-xl and DDR1, which made the cells more invasive through the upregulation of matrix metalloproteinase 9 in DU145. Interestingly, long-term culture using androgen-free medium increased the level of PCA-1 and the related expression of Bcl-xl and DDR-1 in the androgen-sensitive cancer cell line LNCaP, suggesting that PCA-1 signaling is associated with androgen independence. Immunohistochemical analysis in a series of 169 prostate carcinomas showed that PCA-1 and DDR1 were strongly expressed in prostate cancer cells, including preneoplastic lesions, but there was little or no expression in normal epithelium. Moreover, the expression of PCA-1 and DDR-1 was associated with a hormone-independent state of prostate cancer. Taken together, we propose that PCA-1-DDR-1 signaling is a new important axis involved in malignant potential prostate cancer associated with hormone-refractory status.

Postoperative cytological findings from the use of the Integran microfibrillar collagen hemostatic matrix in conization.

The Integran microfibrillar collagen hemostatic matrix is one form of microfibrillar collagen hemostat. This form has a sheet-type structure and has explicitly been used in Japan. In gynecology, this sheet-type matrix has helped effect uterine surface hemostasis, especially in myomectomy and cervical conization. However, cytotechnologists and pathologists have overlooked the foreign materials used for conization in postoperative cervical cytology. We report two cases describing the characteristic cervical cytology findings when Integran was used in conization. The first case was a 67-year-old woman who underwent conization because of cervical intraepithelial neoplasia (CIN) 3. Thirty-six days after the surgery, many cylindrical fragments of glossy acellular materials appeared in the cervical cytology. Fortunately, the content did not impede the diagnosis of NILM. The patient then underwent hysterectomy two months after conization. Surgical specimen revealed a high degree of inflammation and granulation without malignancy. Following surgery, the cylindrical fragments disappeared from microscopic findings. The second case was a 45-year-old woman who underwent conization because of CIN3. Thirty-four days after the surgery, many tubular pieces of glossy acellular materials appeared in cervical cytology, as seen in the first case. The cytological diagnosis was NILM. One hundred days after surgery, cervical cytology revealed many clue cells but no cylindrical fragments. These clusters of cylindrical fragments of glossy acellular materials in cervical cytology after conization might induce a delay in diagnosing the persistence and recurrence of cervical cancer. This article is the first report describing cervical cytology findings associated with Integran use.

Molecular pathogenesis of pediatric astrocytic tumors.

Astrocytomas are the most common pediatric brain tumors, accounting for 7%-8% of all childhood cancers. Relatively few studies have been performed on their molecular properties; therefore, classification of pediatric astrocytic tumors into genetic subtypes similar to that of adult tumors remains to be defined. Here, we report an extensive characterization of 44 pediatric astrocytomas--16 diffuse astrocytomas (WHO grade II), 10 anaplastic astrocytomas (WHO grade III), and 18 glioblastomas (WHO grade IV)--in terms of genetic alterations frequently observed in adult astrocytomas. Some form of p53 mutation was found in three diffuse astrocytomas, in three anaplastic astrocytomas, and in six glioblastomas examined; PTEN mutations were detected only in two glioblastomas. EGFR amplification was detected in only one anaplastic astrocytoma and two glioblastomas, but no amplification was observed for the PDGFR-alpha gene. Loss of heterozygosity (LOH) on 1p/19q and 10p/10q was less common in pediatric astrocytic tumors than in those seen in adults, but the frequency of LOH on 22q was comparable, occurring in 44% of diffuse astrocytomas, 40% of anaplastic astrocytomas, and 61% of glioblastomas. Interestingly, a higher frequency of p53 mutations and LOH on 19q and 22q in tumors from children six or more years of age at diagnosis was found, compared with those from younger children. Our results suggest some differences in children compared to adults in the genetic pathways leading to the formation of de novo astrocytic tumors. In addition, this study suggests potentially distinct developmental pathways in younger versus older children.

DNA hypermethylation status of multiple genes in papillary thyroid carcinomas.

OBJECTIVE: The aim of this study was hypermethylation of multiple genes for papillary thyroid carcinomas (PTCs). METHODS: We examined 39 lesions using methylation-specific PCR to assess hypermethylation in genes, including p16(INK4a), p14(ARF), RB1, p27(Kip1)and 0(6)-MGMT. Homozygous deletions of p16(INK4a) and p14(ARF) were investigated by differential PCR, all with reference to clinicopathological factors. RESULTS: We found methylation of p16(INK4a) in 35.9% (14/39); p14(ARF) in 2.6% (1/39); RB1 in 23.1% (9/39); p27(Kip1) in 15.4% (6/39),and 0(6)-MGMT in 15.4% (6/39). Hypermethylation of at least one of these genes was apparent in 66.7% (26/39). Homozygous deletions of p14(ARF) and p16(INK4a) were detected in 7.7 (3/39) and 2.6% (1/39), respectively. In cases with p16(INK4a) alterations, tumors were significantly increased. A history of chronic thyroid disease and lymphocytic infiltration was significantly associated with p14(ARF) alterations, without regional lymph node metastases. CONCLUSIONS: Our data suggest that alterations in p16(INK4a), mainly hypermethylation, may be linked to tumor growth but not tumor development, while alterations in p14(ARF) may contribute to the induction of chronic inflammation-related PTCs.

High expression of a new marker PCA-1 in human prostate carcinoma.

PURPOSE: Identifying the genetic factors involved in prostate carcinogenesis is critical. Novel cancer-specific markers aid in early detection, in differentiating between cancer and nonmalignant disorders, and in monitoring clinical of prostate disease. We therefore examined differential gene displays in an attempt to identify genes that may be involved in prostate carcinogenesis. EXPERIMENTAL DESIGN: Applying fluorescent differential display analysis to human prostate carcinomas, we have identified and cloned several cDNA transcripts. Antisera were raised against synthetic peptides and used in Western blot and immunohistochemical analyses. The mRNAs were also analyzed by real-time reverse transcription-PCR. For functional analysis, we assessed methylmethane sulfonate (MMS)-induced toxicity in COS-7 cells after cDNA transfection. RESULTS: We identified a gene, designated prostate cancer antigen-1 (pca-1), which shows high mRNA expression in prostate carcinoma. Database analysis of the deduced amino acid sequence of PCA-1 indicated high similarity to Escherichia coli AlkB, a DNA alkylation damage repair enzyme. By immunohistochemical analysis, PCA-1 was expressed in a high number of both prostate carcinoma samples and in the atypical cells within high-grade prostatic intraepithelial neoplasias but not in benign prostatic hyperplasia or normal adjacent tissues. PCA-1-transfected COS-7 cells further showed resistance against MMS-induced cell death. CONCLUSIONS: These findings suggest that PCA-1 could be a useful diagnostic marker. Furthermore, because this human counterpart of AlkB exhibits a protective function against alkylation damage in mammalian cells, PCA-1 may also serve as a therapeutic target molecule for prostate cancer.

Novel tumor suppressor loci on 6q22-23 in primary central nervous system lymphomas.

Deletions on the long arm of chromosome 6 (6q) are one of the most common chromosomal alterations in systemic high-grade non-Hodgkin's lymphomas. However, the locations of allelic deletions and their roles have not yet been reported in primary central nervous system lymphomas (PCNSLs), most of which are classed as non-Hodgkin's lymphoma. We thus performed fine loss of heterozygosity (LOH) mapping of 6q in 29 samples of surgically resected PCNSLs using 39 microsatellite markers to identify commonly deleted regions. LOH was found at 1 or more loci at 6q22-23 in 19 samples (66%); furthermore, 18 of these samples shared a deletion in the same small ( approximately 140 kb) region flanked by D6S1030 and D6S1690, a region in which the human R-PTP-kappa gene (PTPRK) is reported to be located. Reverse transcription-PCR analysis of the mRNA from 4 cases with 6q deletions confirmed loss of this gene, and loss of PTPRK expression was observed in 76% (22 of 29) of tumors with immunohistochemistry. In addition, LOH on 6q22-q23 significantly correlated to shorter patient survival (12.8 +/- 4.3 versus 23.4 +/- 3.5 months; P < 0.0001). Our results suggest that a 140-kb deletion located at 6q22-23 may contain the putative tumor suppressor, PTPRK, that appears to be relevant to the pathogenesis and prognosis of PCNSLs.

Promotor hypermethylation of p14ARF is a key alteration for progression of oral squamous cell carcinoma.

We investigated the promotor hypermethylation status of multiple genes in 49 oral squamous cell carcinomas (OSCC), using the methylation-specific PCR (MSP) assay. The genes examined included p16INK4a, p14ARF, RB1, p21Waf1, p27Kip1, PTEN, p73, 0(6)-MGMT, and GST-P. Detailed clinicopathological data, such as patient age, sex, tobacco use, alcohol consumption, lesion site, degree of tumor differentiation, tumor size, presence of lymph node metastasis, and clinical stage, were collected for all 49 samples. Overall, gene methylation was detected in 46.9% (23/49) of samples and was closely correlated with tobacco use or/and alcohol consumption. Of the genes investigated, p16INK4a, p14ARF, 0(6)-MGMT, RB1, PTEN, and p27Kip1 were found to be methylated in 34.7%, 20.4%, 12.2%, 10.2%, 6.1%, and 4.1% of these 49 tumors, respectively, but methylation of p21Waf1, p73, and GST-P was not detected at all. Methylation frequencies were much higher for each gene when computed among informative cases only. Concurrent promotor hypermethylation of p16INK4a and p14ARF correlated significantly with tumor size, lymph node metastasis, and stage III/IV advanced OSCC; p14ARF hypermethylation, in particular, was significantly associated with both lymph node metastasis and late clinical stage. Our results suggest that DNA methylation of multiple genes, especially hypermethylation of the p14ARF promoter, is common in OSCC and is associated with the use of tobacco and/or alcohol consumption. For this type of cancer, the data further implicates gene methylation as playing an important role in tumor progression.

Therapy-related myelodysplastic syndrome: a case study.

We present a case of therapy-related myelodyspastic syndrome in which the t(3;8)(q26;q24) translocation appeared, even though no chromosomal abnormalities were found at the initial diagnosis of acute myeloid leukemia. To the best of our knowledge, there have only been around 20 reported cases of myeloid malignancies involving t(3;8)(q26;q24). We discuss the characteristics of t(3;8)(q26;q24) along with a review of literature.