DNA deacetylation by histone deacetylase (HDAC) is an important mechanism involved in the oncogenic tumorigenesis of breast cancer. Previous studies have reported an association of the estrogen receptor (ER) with HDACs and demonstrated the efficacy of HDAC inhibitors for the treatment of breast cancers via in vitro experiments. In this study, we examined the association of HDAC expression with clinicopathological parameters and disease-specific survival.
Immunohistochemical (IHC) analysis of HDAC1, HDAC2, HDAC3, and HDAC6 was performed using tissue microarrays in 300 invasive ductal carcinomas. IHC scoring was determined by multiplication of the intensity (0 to 3) and the proportion (0 to 4) of staining, and we classified tumors into low- and high-HDAC expression groups.
High expression of HDAC1 was correlated with the molecular subtype (p=0.001) and human epidermal growth factor 2 (HER2) amplification (p=0.012). High expression of HDAC6 was correlated with a younger age (p<0.001), ER expression (p=0.025), progesterone receptor expression (p=0.034), molecular subtype (p=0.023), and HER2 amplification (p=0.011). High HDAC1 expression was correlated with luminal A tumors (p=0.001), while high HDAC6 expression was more common in luminal B tumors (p=0.023). Although the expression of HDACs did not exhibit prognostic significance in the entire cohort, high expression of HDAC1 and HDAC6 was associated with improved overall survival (OS) in patients with ER-positive tumors (p=0.017 and p=0.029, respectively), and high expression of HDAC2 was correlated with improved OS in ER-negative tumors (p=0.048) on univariate analysis. Furthermore, high HDAC6 expression was associated with improved disease-free survival (p=0.048) on multivariate analysis.
HDAC1 expression is significantly correlated with the molecular subtypes of tumors, with the highest expression being observed in luminal A tumors. HDAC6 is a significantly correlated with ER expression and the molecular subtype, thereby supporting the estrogen regulatory property of HDAC6. HDAC1 and HDAC6 expression are good prognostic factors for ER-positive tumors.
Breast neoplasms; Histone deacetylases; Immunohistochemistry
Castleman disease is a rare lymphoproliferative lesion that is predominantly found in the mediastinum. Retroperitoneal and pararenal localizations are very rare. We describe a 36-year-old man with a hyaline vascular type of Castleman disease involving renal parenchyma and a paraaortic lymph node. Most reported renal Castleman disease was plasma cell type with systemic symptoms. Herein, we report the first Korean case of the hyaline vascular type of Castleman disease involving the renal parenchyma and the paraaortic lymph node simultaneously.
Kidney; Hyaline vascular type, Multicentric; Giant lymph node hyperplasia
The term solitary fibrous tumor (SFT) is preferred over meningeal hemangiopericytoma (HPC), because NAB2-STAT6 gene fusion has been observed in both intracranial and extracranial HPCs. HPCs are now considered cellular variants of SFTs.
This study analyzes 19 patients with STAT6-confirmed SFTs, who were followed for over 11 years in a single institution. Ten patients (10/19, 56.2%) had extracranial metastases (metastatic group), while the remainder (9/19) did not (non-metastatic group). These two groups were compared clinicopathologically.
In the metastatic group, the primary metastatic sites were the lungs (n = 6), bone (n = 4), and liver (n = 3). There was a mean lag time of 14.2 years between the diagnosis of the initial meningeal tumor to that of systemic metastasis. The median age at initial tumor onset was 37.1 years in the metastatic group and 52.5 in the non-metastatic group. The 10-year survival rates of the metastatic- and non-metastatic groups were 100% and 33%, respectively. The significant prognostic factors for poor outcomes on univariate analysis included advanced age (≥45 years) and large initial tumor size (≥5 cm). In contrast, the patients with higher tumor grade, high mitotic rate (≥5/10 high-power fields), high Ki-67 index (≥5%), and the presence of necrosis or CD34 positivity showed tendency of poor prognosis but these parameters were not statistically significant poor prognostic markers.
Among patients with SFTs, younger patients (<45 years) experienced longer survival times and paradoxically had more frequent extracranial metastases after long latent periods than did older patients. Therefore, young patients with SFTs require careful surveillance and follow-up for early detection of systemic metastases.
Central nervous system; Hemangiopericytoma; Neoplasm metastases; NAB2-STAT6 gene fusion; Solitary fibrous tumors
Bone marrow biopsy is a standard method for the evaluation of bone marrow infiltration by lymphoma; however, it is an invasive and painful procedure. Fluorodeoxyglucose positron emission tomography–computed tomography (FDG PET-CT) is a noninvasive imaging technique with the potential to detect bone marrow involvement by lymphoma.
Materials and Methods
We retrospectively reviewed medical records of lymphoma patients. All patients were examined by FDG PET-CT and iliac crest bone marrow biopsy for initial staging work-up.
The study population comprised 94 patients (median age, 60 years; 56 males) with Hodgkin’s lymphoma (n=8) or non-Hodgkin’s lymphoma (n=86). Maximum standardized uptake values on the iliac crest of patients with lymphoma infiltrated bone marrow were significantly higher than those of patients with intact bone marrow (2.2±1.2 g/mL vs. 1.3±0.4 g/mL; p=0.001). The calculated values for FDG PET-CT during evaluation of bone marrow involvement were as follows: sensitivity 50%, specificity 96%, positive predictive value 80%, negative predictive value 85%, and positive likelihood ratio (LR+) 11.7. The value of LR+ was 16.0 in patients with aggressive subtypes of non-Hodgkin’s lymphoma (NHL).
FDG PET-CT could not replace bone marrow biopsy due to the low sensitivity of FDG PET-CT for detection of bone marrow infiltration in lymphoma patients. Conversely, FDG PET-CT had high specificity and LR+; therefore, it could be a useful tool for image-guided biopsy for lymphoma staging, especially for aggressive subtypes of NHL. In addition, unilateral bone marrow biopsy could be substituted for bilateral bone marrow biopsy in lymphoma patients with increased FDG uptake on any iliac crest.
Lymphoma; Positron-emission tomography; Bone marrow examination
The BRAF (V600E) mutation is the most prevalent type of genetic alteration that has been identified in papillary thyroid carcinoma (PTC); in addition, previous immunohistochemical studies have revealed the overexpression of p53 protein in PTC. The aim of the present study was to investigate the prevalence of the BRAF (V600E) mutation and the expression of p53 in PTC, as well as to determine any associations between these two factors and the clinicopathological features of PTC. The study was performed on 66 PTC patients who underwent surgical tumor resection between January and December 2012. Polymerase chain reaction-based DNA amplification was used to analyze extracted DNA from the tumor specimens in order to determine the prevalence of the BRAF (V600E) mutation. In addition, immunohistochemical analysis was employed in order to evaluate the protein expression of p53 in sections of tumor tissue. Furthermore, statistical analysis was performed in order to determine any associations among the BRAF (V600E) mutation prevalence, p53 overexpression and the clinicopathological features of PTC patients, including age, gender, tumor size, multiplicity, lymph node metastasis and extrathyroidal extension. The results revealed that the BRAF (V600E) mutation was observed in 50 (75.8%) of the 66 PTC patients and overexpression of p53 was found in 52 (78.8%) of 66 cases. No significant correlations were observed between the BRAF (V600E) mutation or p53 protein overexpression and the clinicopathological features of patients. However, the BRAF (V600E) mutation demonstrated noteworthy, but non-significant, correlations with the overexpression of p53 (P=0.0854) and extrathyroidal extension (P=0.0661). In addition, a significant correlation was observed between lymph node metastasis and bilaterality (P=0.0280). In conclusion, the present study demonstrated that the BRAF (V600E) mutation and overexpression of p53 were not significantly correlated with clinicopathological features of PTC, although notable associations were identified between BRAF (V600E) mutation and overexpression of p53 as well as extrathyroidal extension. In addition, lymph node metastasis was significantly associated with bilaterality.
BRAF (V600E) mutation; p53 protein; clinicopathologic features; papillary thyroid carcinoma
Previously, cutaneous lymphomas were classified according to either the European Organization for the Research and Treatment of Cancer (EORTC) or the World Health Organization (WHO) classification paradigms. The aim of this study was to determine the relative frequency of Korean cutaneous lymphoma according to the new WHO-EORTC classification system.
A total of 517 patients were recruited during a recent 5 year-period (2006-2010) from 21 institutes and classified according to the WHO-EORTC criteria.
The patients included 298 males and 219 females, and the mean age at diagnosis was 49 years. The lesions preferentially affected the trunk area (40.2%). The most frequent subtypes in order of decreasing prevalence were mycosis fungoides (22.2%), peripheral T-cell lymphoma (17.2%), CD30+ T-cell lymphoproliferative disorder (13.7%), and extranodal natural killer/T (NK/T) cell lymphoma, nasal type (12.0%). Diffuse large B-cell lymphoma accounted for 11.2% of cases, half of which were secondary cutaneous involvement; other types of B-cell lymphoma accounted for less than 1% of cases.
In comparison with data from Western countries, this study revealed relatively lower rates of mycosis fungoides and B-cell lymphoma in Korean patients, as well as higher rates of subcutaneous panniculitis-like T-cell lymphoma and NK/T cell lymphoma.
Cutaneous lymphoma; World Health Organization; EORTC; Classification
Human papillomavirus (HPV) infection has been demonstrated in some of the nonmelanoma skin cancers as well as in precancerous lesions. Multiple infections of mucosal high-risk HPV may contribute to the onset of digital Bowen's disease through, if any, digital-genital transmission. We screened for the presence of the mucosal HPV DNA in patients with extragenital Bowen's disease (n = 30), squamous cell carcinoma (n = 11), bowenoid papulosis (n = 9), verrucous carcinoma (n = 1), actinic keratosis (n = 5), and basal cell carcinoma (n = 5). We used a PANArray HPV Genotyping Chip for high-risk and low-risk mucosal types. Genotyping data was confirmed using a conventional direct DNA sequencing method. Two cases of extragenital Bowen's disease were positive for types 16 and 33 of mucosal HPV, respectively. None of the squamous cell carcinoma cases were positive. Neither patients with digital Bowen's disease (n = 5) nor those with squamous cell carcinoma (n = 3) showed any mucosal high-risk HPV. Mucosal high-risk HPV DNA was confirmed in 5 (55.6%) of the 9 patients with bowenoid papulosis. HPV 16 was most prevalent (n = 3), while the DNA of HPVs 35 and 67 was detected in one sample for each of the two types. Our study demonstrated that two (6.7%) of the patients with 30 extragenital Bowen's disease were positive for types 16 and 33 of mucosal HPV, respectively. HPVs belonging to the mucosal high-risk group may participate in the development of extragenital Bowen's disease. However, we could not find any relationship between the mucosal high-risk HPV and Bowen's disease or squamous cell carcinoma in the fingers.
Heterotopic gastrointestinal cysts are rarely found in the oral cavity. Most of these cysts are lined with gastric mucosa and involve the tongue. There have been no reported heterotopic intestinal cysts of the submandibular gland that are completely lined with colonic mucosa. An 8-year-old girl presented with an enlarging swelling in the left submandibular area, and a 4-cm unilocular cyst was fully excised. The cyst was completely lined with colonic mucosa that was surrounded by smooth muscle layer, and the lining cells were positive for CDX-2, an intestinal marker, indicating a high degree of differentiation. The pathogenesis remains unclear, but it may be related to the misplacement of embryonic rests within the oral cavity during early fetal development. Although heterotopic intestinal cysts rarely occur in the submandibular gland, they should be considered in the differential diagnosis of facial swellings in the pediatric population.
Submandibular gland; Cysts; Heterotopia; Intestines
It has generally been proven that histone acetylation and deacetylation are involved in the malignant transformation. To date, however, this has rarely been studied in cases of malignant lymphoma.
We studied nine cases of reactive lymphoid hyperplasia, 78 cases of diffuse large B-cell lymphoma (DLBCL), 13 cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and 13 cases of extranodal NK/T-cell lymphoma, nasal type (NKTCL). Thus, we attempted to elucidate the associations of the degree of the expression of histone acetyltransferase 1 (HAT1), histone deacetylase (HDAC) 1, HDAC2, and HDAC3 with the clinical behaviors of above malignant lymphomas using the immunohistochemistry and a western blot analysis.
The degree of the expression of HAT1 was higher in cases of DLBCL, PTCL-NOS or NKTCL as compared with reactive lymphoid hyperplasia (p<0.05). The degree of the expression of HAT1 was correlated with that of HDAC1 in cases of DLBCL or NKTCL (p<0.05). The degree of the expression of HAT1 and HDAC1 was correlated with a poor survival in cases of DLBCL or PTCL-NOS (p>0.05).
HAT1, HDAC1, and HDAC2 play a critical role in the development of malignant lymphomas. Both HAT1 and HDAC1 might be indicators for a poor prognosis in cases of DLBCL as cooperating factors.
Acetylation; Deacetylation; Histone deacetylase inhibitors; Lymphoma
To investigate the molecular and cellular pathogenesis underlying myocarditis, we used an experimental autoimmune myocarditis (EAM)-induced heart failure rat model that represents T cell mediated postinflammatory heart disorders.
By performing unbiased 2-dimensional electrophoresis of protein extracts from control rat heart tissues and EAM rat heart tissues, followed by nano-HPLC-ESI-QIT-MS, 67 proteins were identified from 71 spots that exhibited significantly altered expression levels. The majority of up-regulated proteins were confidently associated with unfolded protein responses (UPR), while the majority of down-regulated proteins were involved with the generation of precursor metabolites and energy metabolism in mitochondria. Although there was no difference in AKT signaling between EAM rat heart tissues and control rat heart tissues, the amounts and activities of extracellular signal-regulated kinase (ERK)-1/2 and ribosomal protein S6 (rpS6) were significantly increased. By comparing our data with the previously reported myocardial proteome of the Coxsackie viruses of group B (CVB)-mediated myocarditis model, we found that UPR-related proteins were commonly up-regulated in two murine myocarditis models. Even though only two out of 29 down-regulated proteins in EAM rat heart tissues were also dysregulated in CVB-infected rat heart tissues, other proteins known to be involved with the generation of precursor metabolites and energy metabolism in mitochondria were also dysregulated in CVB-mediated myocarditis rat heart tissues, suggesting that impairment of mitochondrial functions may be a common underlying mechanism of the two murine myocarditis models.
UPR, ERK-1/2 and S6RP signaling were activated in both EAM- and CVB-induced myocarditis murine models. Thus, the conserved components of signaling pathways in two murine models of acute myocarditis could be targets for developing new therapeutic drugs or methods aimed at treating enigmatic myocarditis.
Cutaneous γ/δ T-cell lymphoma is an extremely rare and highly aggressive tumor that is often resistant to treatment, such as polychemotherapy and radiotherapy. Due to the complexity of clinical, pathologic, and immunohistochemical features of this disease entity, the physician should perform a careful evaluation; however, treatment should be rapid and aggressive. We present a case of fatal cutaneous γ/δ T-cell lymphoma of a 55-year old woman who died after recurrence with central nerve system metastasis.
CNS; Cutaneous T cell lymphoma; Gamma delta TCR; Neoplasm metastasis
Bone destruction is primarily mediated by osteoclastic bone resorption, and cancer cells stimulate the formation and activation of osteoclasts next to metastatic foci. Accumulating evidences indicate that receptor activator of NF-kB ligand (RANKL) is the ultimate extracellular mediator that stimulates osteoclast differentiation into mature osteoclasts. In contrast, osteoprotegerin (OPG) inhibits osteoclast development. In order to elucidate a mechanism for cancer-induced osteoclastogenesis, cells from a human breast cancer line, MDA-MB-231, were directly co-cultured with ST2, MC3T3-E1, or with primary mouse calvarial cells. Osteoclast-like cells and tartarate resistant acid phosphatase (TRAP) activities were then quantitated. We examined these cell lines and samples from breast cancer by RT-PCR for the expressions of OPG and RANKL mRNA. Compared to controls, co-culture of MDA-MB-231 cells with stromal or osteoblastic cells induced an increase in number of osteoclasts and TRAP activities. MDA-MB-231 cells alone or breast cancer samples did not express RANKL mRNA. However, co-culture of these cancer cells with stromal or osteoblastic cells induced RANKL mRNA expression and decreased OPG mRNA expression. These experiments demonstrate that direct interactions between breast cancer and stromal or osteoblastic cells induce osteoclastogenesis in vitro through modulating RANKL expression.
Actinomycosis is a slowly progressive infectious disease caused by an anaerobic and microaerophilic bacteria that colonizes the face, neck, lung, pleura and the ileocecal region.
There have been a few cases of this disease which have involved in the lung but one very rare case has been reported. We report a case of foreign body-induced endobronchial actinomycosis mimicking bronchogenic carcinoma in a 69-year-old man. On admission, the patient presented with weight loss, cough and hemoptysis. The fiberoptic bronchoscopy revealed a soft tissue mass, with a partial occlusion of the left upper bronchus, which resembled bronchogenic carcinoma. Contrary to the first impression, the biopsy of the bronchus revealed the mass lesion to be an actinomycotic infection involving the bronchus. After the confirmation of the lesion, treatment with penicillin was initiated. The follow-up bronchoscopy revealed an aspirated fish bone at the site of infection. The foreign body was safely removed.
Actinomycosis; Foreign bodies; Carcinoma; Bronchogenic