Summary Intraductal papillary mucinous neoplasm is characterized by cystically dilated main and/or branch pancreatic duct with mucus. According to the degree of atypia, intraductal papillary mucinous ...neoplasm is classified into 3 groups: adenoma, borderline, and carcinoma. Furthermore, intraductal papillary mucinous neoplasm is considered to progress through an adenoma-carcinoma sequence like colorectal carcinoma. Programmed cell death 4 is a recently identified tumor suppressor that was found to inhibit translation. Programmed cell death 4 has been reported to inhibit tumorigenesis, tumor progression, proliferation, invasion, and metastasis in several human malignancies. We examined 108 cases of intraductal papillary mucinous neoplasm by immunohistochemistry and revealed that programmed cell death 4 expression was recognized in both the nucleus and cytoplasm in intraductal papillary mucinous neoplasm. The positive rate of programmed cell death 4 was 79%, 43%, and 10% in adenoma, borderline, and carcinoma, respectively. The positive rate of programmed cell death 4 decreased from adenoma to carcinoma ( P < .0001, both adenoma versus borderline and borderline versus carcinoma), indicating that programmed cell death 4 might inhibit tumor progression in intraductal papillary mucinous neoplasm. Programmed cell death 4 expression had a strong relationship with p21 expression ( P < .0001) and an inverse correlation with Ki-67 labeling index ( r = −0.6255, P < .0001). Thus, programmed cell death 4 might inhibit the proliferation of intraductal papillary mucinous neoplasm; and its inhibition might partly result from cell cycle arrest caused by the up-regulation of p21. In conclusion, programmed cell death 4 may inhibit tumor progression in intraductal papillary mucinous neoplasm; and the loss of programmed cell death 4 expression is representative of the malignant potential of intraductal papillary mucinous neoplasm including the proliferative activity. Therefore, programmed cell death 4 can be an important biomarker for intraductal papillary mucinous neoplasm.
Purpose
Transferrin receptor (TFR), a membrane protein that has a critical role in the transport of iron into cells, is known to be a ferroptosis-related marker. Although TFR is reported to be ...abundantly expressed in tumor cells, its relationship with ferroptosis inducers in hepatocellular carcinoma (HCC) remains unclear.
Methods
The authors performed immunohistochemical staining of TFR and divided 350 HCC patients into two groups according to its expression. They analyzed the association between TFR expression and prognosis or clinicopathologic factors. In addition, the regulation of malignant activity and its effect on the efficacy of ferroptosis inducers were investigated in vitro.
Results
For this study, 350 patients were divided into TFR-positive (
n
=180, 51.4%) and TFR-negative (
n
= 170, 48.6%) groups. The TFR-positive group had more hepatitis B surface antigen (HBs-Ag) (
p
= 0.0230), higher α-fetoprotein (AFP) levels (
p
= 0.0023), higher des-gamma-carboxyprothrombin (DCP) levels (
p
= 0.0327), a larger tumor size (
p
= 0.0090), greater proportions of Barcelona Clinic Liver Cancer (BCLC) stage B or C (
p
= 0.0005), poor differentiation (
p
< 0.0001), and microscopic intrahepatic metastasis (
p
= 0.0066). In the multivariate analyses, TFR expression was an independent prognostic factor in disease-free survival (
p
= 0.0315). In vitro,
TFRC
knockdown decreased cell motility. In addition,
TFRC
knockdown abolished artesunate (AS)-, lenvatinib-, and sorafenib-induced ferroptosis in HCC cell lines. The study demonstrated that simultaneous treatment of AS with multi-kinase inhibitor augmented the ferroptosis-inducing effects of AS in HCC cell lines.
Conclusion
TFR expression is a poor prognostic factor in HCC, but its expression increases sensitivity to ferroptosis-inducing agents.
Background
In liver transplantation (LT) for adult biliary atresia (BA), we often encounter a cirrhotic deformation of the native liver. We aimed to investigate a morphological study of the removed ...livers and the patient’s clinical status.
Methods
We examined 8 BA patients who had undergone LT in adulthood at our hospital. The presence of hypertrophic or atrophic areas of the removed liver was recorded macroscopically. We graded the microscopic findings in the porta hepatis area, a hypertrophic area, and an atrophic area, respectively. Moreover, we investigated the relationship between these morphological findings and the pre-transplant clinical status (MELD score).
Results
Macroscopically, a hypertrophic area existed in central liver in all cases (8/8 cases), while an atrophic area was existed in peripheral liver (7/8 cases). Microscopically, an atrophic area was the most severely impaired, while the porta hepatis and hypertrophic area were relatively intact. The pathological score in a compensatory hypertrophic area was strongly correlated with the MELD score.
Conclusions
This study suggests that the partial shrinking is not uncommon in BA cirrhotic liver. It may be due to the imbalance of bile drainage by the different segment. The patient’s pre-transplant status depends on the compensatory hypertrophic liver.
Programmed cell death‐1 (PD‐1) and programmed cell death‐ligand 1 (PD‐L1) have been identified as novel targets of immunotherapy of lung cancer. In present study, we evaluated the metabolic ...characteristics of lung cancer by using 18F‐fluorodeoxyglucose positron emission tomography/computed tomography (18F‐FDG PET/CT) with regard to PD‐L1 protein expression. PD‐L1 protein expression was evaluated by immunohistochemistry with the antibody clone SP142 in 579 surgically resected primary lung cancer patients. Cases with less than 5% tumor membrane staining were considered negative. We examined the association between the frequency of PD‐L1 protein expression and the maximum standardized uptake value (SUVmax) in preoperative 18F‐FDG PET/CT. The cut‐off values for SUVmax were determined by receiver operating characteristic curve analyses. The SUVmax was significantly higher in nonsmall cell lung cancer (NSCLC) patients with PD‐L1 protein expression compared with those without PD‐L1 protein expression (P < 0.0001). However, there was no correlation between SUVmax and PD‐L1 protein expression in patients with neuroendocrine tumors (P = 0.6545). Multivariate analysis revealed that smoking, the presence of pleural invasion, and high SUVmax were independent predictors of PD‐L1 positivity. PD‐L1‐expressing NSCLC had a high glucose metabolism. The SUVmax in preoperative 18F‐FDG PET/CT was a predictor of PD‐L1 protein expression in patients with NSCLC.
PD‐L1‐expressing NSCLC had a high glucose metabolism. The SUVmax in preoperative 18F‐FDG PET/CT was a predictor of PD‐L1 protein expression in patients with NSCLC.
Summary Mullerian mucinous borderline tumor and gastrointestinal mucinous borderline tumor are considered mucinous tumor subtypes. However, it has been reported that mullerian mucinous borderline ...tumor shares many clinicopathologic features with serous borderline tumor. Furthermore, some investigators have explained the histogenesis of mullerian mucinous borderline tumor by metaplastic and hyperplastic transformation of endometriosis (Fukunaga M, Ushigome S. Epithelial metaplastic changes in ovarian endometriosis. Mod Pathol. 1998;11:784-788). The purpose of this study is to substantiate the concept that mullerian mucinous borderline tumor is histogenetically closer to serous borderline tumor or low-grade endometrioid tumor than to gastrointestinal mucinous borderline tumor by directly comparing their immunophenotype. A total of 80 cases of low-grade ovarian tumors composed of 20 mullerian mucinous borderline tumors, 20 gastrointestinal mucinous borderline tumors, 20 serous borderline tumors, and 20 low-grade endometrioid tumors were immunohistochemically evaluated for the expression of estrogen receptor, progesterone receptor, vimentin, WT-1, β -catenin, and PTEN. Almost all cases of mullerian mucinous borderline tumor, serous borderline tumor, and low-grade endometrioid tumor showed diffuse and strong nuclear expression of estrogen receptor and progesterone receptor. In addition, about half of the mullerian mucinous borderline tumor, serous borderline tumor, and low-grade endometrioid tumor cases showed focal but strong vimentin cytoplasmic expression. In contrast, gastrointestinal mucinous borderline tumor showed no expression of estrogen receptor, progesterone receptor, or vimentin, except for 1 case in which estrogen receptor expression was very focally and weakly observed. WT-1 nuclear expression was observed in most serous borderline tumors and only 15% of low-grade endometrioid tumor, but mullerian and gastrointestinal mucinous borderline tumor cases were completely negative. β -Catenin nuclear expression was significantly more frequent in low-grade endometrioid tumor than in mullerian mucinous borderline tumor, gastrointestinal mucinous borderline tumor, or serous borderline tumor. PTEN expression was significantly lower in low-grade endometrioid tumor than in mullerian mucinous borderline tumor, gastrointestinal mucinous borderline tumor, and serous borderline tumor. Multiple comparisons of quantitative immunoreactivities of estrogen receptor, progesterone receptor, and vimentin revealed that the gastrointestinal mucinous borderline tumor expression profiles were significantly different from those of mullerian mucinous borderline tumors, serous borderline tumors, and low-grade endometrioid tumors. The immunohistochemical expression profiles of estrogen receptor, progesterone receptor, and vimentin substantiate the concept that the histogenesis of mullerian mucinous borderline tumor is closer to those of serous borderline tumor and low-grade endometrioid tumor than to that of gastrointestinal mucinous borderline tumor. However, aberrant β -catenin and PTEN protein expression, both of which are known to contribute to the tumorigenesis of low-grade endometrioid tumor, appeared to be less important for the tumorigenesis of mullerian mucinous borderline tumor.
Gushima M, Hirahashi M, Matsumoto T, Fujita K, Ohuchida K, Oda Y, Yao T, Iida M & Tsuneyoshi M (2011) Histopathology59, 460–469
Expression of activation‐induced cytidine deaminase in ulcerative ...colitis‐associated carcinogenesis
Aims: Activation‐induced cytidine deaminase (AID) is a DNA/RNA‐editing enzyme that is essential for hypermutation and class‐switch recombination in immunoglobulin genes. The aim of this study was to investigate the expression of AID and its association with p53 mutation in ulcerative colitis (UC)‐associated carcinogenesis.
Methods and results: The expression of AID was examined in 25 patients with UC‐associated neoplasia, 20 UC patients without neoplasia, 18 patients with non‐inflamed colorectal mucosa unaffected by UC, and 19 patients with sporadic colorectal cancer, by immunohistochemistry and quantitative reverse transcription polymerase chain reaction analysis. Mutational analysis and immunohistochemistry for p53 were also performed. The degree of AID expression was not different between UC‐associated neoplasia and sporadic colorectal cancer. However, AID was expressed in both UC‐associated neoplasia and UC without neoplasia. Whereas AID expression in UC‐associated neoplasia was not correlated with the grade of dysplasia, expression in non‐neoplastic mucosa of UC was correlated with the histological grade of inflammation. In UC‐associated neoplasia, there was no significant correlation between AID expression and p53 mutation.
Conclusions: AID is associated with inflammation in UC, whereas it may not specifically contribute to carcinogenesis in UC.
Diffuse‐type giant cell tumor (GCT)/pigmented villonodular synovitis (PVNS) in the axial skeleton or spine is rare. Herein is reported a case of diffuse‐type GCT/PVNS involving the sacrum and the ...fifth lumbar vertebra, in which the patient developed regional lymph node swelling after recurrence. The recurrent tumor was found to have atypical histological features such as spindle cell morphology, cytological atypia and high mitotic rate, which are compatible with the diagnostic criteria of secondary malignant diffuse‐type GCT/PVNS. Although the nodal lesions were not sampled histologically, the clinical and histological features indicate that the current case is an example of malignant diffuse‐type GCT/PVNS. This case is considered to be the first case of malignant diffuse‐type GCT/PVNS in the spine, because no such lesions have been previously reported in the axial skeleton or spine. Careful surveillance should be required for diffuse‐type GCT/PVNS arising at unusual site.
The aberrant methylation of promoter CpG islands is known to be a major inactivation mechanism of tumor-related genes. To determine the clinicopathological significance of gene promoter methylation ...in soft tissue sarcomas, we examined the promoter methylation status of 10 tumor-related genes in 65 soft tissue sarcomas and 19 adjacent non-neoplastic tissues by methylation-specific PCR. The methylation frequencies of tumor-related genes tested in soft tissue sarcomas were 17 (26%) for RASSF1A, 11 (17%) for DAP kinase, 10 (15%) for MGMT, nine (14%) for GSTP1, eight (12%) for PTEN, six (9%) for p16 and hMLH1, five (8%) for hMSH2, two (3%) for p14, and one (2%) for RB. Promoter methylation of these genes was not recognized in non-neoplastic tissues. All those cases of soft tissue sarcoma that had MGMT methylation, with the exception of one case of malignant peripheral nerve sheath tumor, showed large tumor size (≥10 cm) or recurrence. Moreover, eight of 10 cases with MGMT methylation revealed high American Joint Committee on Cancer stage. Seven of 10 cases (70%) with MGMT methylation showed a loss of MGMT expression by immunohistochemistry. In addition, MGMT methylation status had a statistically significant correlation with a loss of MGMT expression (P=0.014). In conclusion, although methylation of tumor-related genes was a relatively rare event in soft tissue sarcomas, methylation was tumor-specific. Of 10 tumor-related genes, cases with MGMT methylation had a tendency to be aggressive behavior. Moreover, MGMT methylation was closely associated with a loss of MGMT expression. Although our findings need to be extending to a large series, promoter methylation of tumor-related genes is likely to have an association with the pathogenesis of soft tissue sarcomas. Furthermore, MGMT methylation may be associated with tumor aggressiveness and the inactivation of MGMT gene.
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