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We investigated whether the malignant switch of intraductal papillary mucinous neoplasm (IPMN) of the pancreas can be predicted by using the T1ϱ, T2, and apparent diffusion coefficient (ADC) values of cyst fluid.We retrospectively analyzed the magnetic resonance (MR) images of 60 patients (26 males, 34 females, mean age 61 years) with branch-duct type and mixed-type IPMNs. The IPMNs were diagnosed clinically in 39 patients and histologically in 21 patients. The malignant potential was classified by MR imaging based on the international consensus guidelines for the management of IPMN established in 2017. Morphologically, 42 patients had "worrisome features" and three had "high-risk stigmata." Histologically, 14 lesions were diagnosed as low-grade dysplasia and seven as intermediate-grade dysplasia. The T1ϱ, T2, and ADC values of cyst fluid in each patient's largest cyst were measured on the same slice, avoiding solid components. Spearman's rank correlation test was used to determine the correlation between the morphological malignancy and the T1ϱ, T2, and ADC values. These values were also compared between the low-grade and intermediate-grade groups by Mann-Whitney U-test.There was a significant rank-correlation between the morphological classification and T2 value (p=0.04). The T2 value of the intermediate-grade group was significantly higher than that of the low-grade group (p=0.03). No significant correlations were morphologically or histologically obtained regarding T1ϱ and ADC.The T2 value of cyst fluid together with other MR-signs may be useful for predicting the malignant switch in IPMN of the pancreas.

Background: Neuroendocrine neoplasms of the ampulla of Vater (ampullary NEN) have features of both gastrointestinal and pancreato-biliary (PB) NEN. However, the limited number of studies examining ampullary NEN makes it difficult to clarify their unique characteristics. This study aimed to elucidate the clinical characteristics of ampullary NEN. Methods: We enrolled 162 patients with PB-NEN diagnosed at Kyushu University Hospital between 2011 and 2020. Clinical features, pathological diagnoses, treatments, and prognoses were retrospectively analyzed. We also compared ampullary NEN with pancreatic NEN (PanNEN). Results: We analyzed 10 ampullary NEN cases and 149 PanNEN cases. The ampullary NEN cases consisted of 4 cases of neuroendocrine tumor Grade 1 (NET G1), 1 NET G2 (Grade 2), and 5 neuroendocrine carcinomas (NECs). The incidences of NEC and cholangitis were significantly higher in ampullary NEN than in PanNEN. All ampullary NETs had a submucosal tumor-like appearance, as identified by endoscopic ultrasound-guided fine needle aspiration. We treated small NET G1 (Conclusions: Endoscopic findings showed identifiable distinctions between ampullary NETs and NECs.

Pancreatic undifferentiated carcinoma (UDC) is a rare tumor with a worse prognosis than pancreatic ductal adenocarcinoma (PDAC). Recent study showed that UDC exhibits loss of SMARCB1, which is one of the subunits of the SWI/SNF complex. However, whether there are abnormalities of other SWI/SNF complex subunits in UDC has remained unknown. In this study, we attempted to clarify whether the loss of SWI/SNF complex subunits is related to the pathogenesis of UDC by comparing undifferentiated component (UC) and ductal adenocarcinoma component (DAC). Genetic analysis of the ten UCs and six DACs was performed. The expression of ARID1A, SMARCA2, SMARCA4, SMARCB1, SMARCC1, and SMARCC2 in formalin-fixed, paraffin-embedded tumor tissues collected by surgical resection from 18 UDC patients was evaluated immunohistochemically. Moreover, two pancreatic cell lines were evaluated for the effects of siARID1A on the mRNA and protein expression of E-cadherin, vimentin, and epithelial-mesenchymal transition (EMT)-related markers by qRT-PCR, western blotting, and immunofluorescence staining. UCs tended to have a higher frequency of mutation in ARID1A, SMARCA4, and SMARCC2 than DACs. Immunohistochemically, UCs revealed reduced/lost expression of ARID1A (72%), SMARCB1 (44%), SMARCC1 (31%), and SMARCC2 (67%). Reduced/lost expression of ARID1A, SMARCB1, and SMARCC2 was significantly more frequently observed in UCs than in DACs. In the pancreatic cell lines, western blotting and qRT-PCR showed that the downregulation of ARID1A increased the expression of vimentin and EMT-related markers. Our results suggest that the abnormality of SWI/SNF complex subunits, especially ARID1A, is one of the factors behind the morphological change of UDC.

Invasive gallbladder carcinoma (GBC) is preceded by two main types of precursor lesions: intracholecystic papillary-tubular neoplasms (ICPNs) and biliary intraepithelial neoplasias (BilINs). Invasive GBCs with an ICPN component have more favorable prognoses than those without an ICPN component. Some BilINs show a relatively exophytic papillary pattern but do not meet the ICPN criteria; at our institution, we call these papillary neoplasias. To clarify the clinical significance of papillary neoplasia, we herein examined 80 invasive GBCs and classified them into three groups based on the type of preinvasive lesions: those with ICPN (ICPN group, n = 35), those with papillary neoplasia (pap-neoplasia group, n = 13), and those without ICPN/papillary neoplasia (group without ICPN/pap-neoplasia, n = 32). We then compared the prognostic differences and characterized the tumors of each group by determining the immunohistochemical expressions of various biomarkers. The overall survival periods of the ICPN and pap-neoplasia groups were significantly longer than that of the group without ICPN/pap-neoplasia (P 0.0001, P = 0.0036, respectively). Multivariate analysis revealed that lacking ICPN/papillary neoplasia was independently associated with poor prognosis (P = 0.0007), as were poor differentiation (P = 0.0395), presence of preoperative symptoms (P = 0.0488), and advanced stage (P = 0.0234). Invasive components of the ICPN and pap-neoplasia groups were characterized by higher expressions of p16 and p53 compared with those of the group without ICPN/pap-neoplasia. The prognoses of the invasive GBCs with either papillary neoplasia or ICPN were thus more favorable than those of the invasive GBCs without ICPN/pap-neoplasia. Invasive GBCs with exophytic papillary preinvasive lesions (ICPN and papillary neoplasia) may be biologically different from those without such lesions.

AimsDedifferentiation is a histological phenomenon characterised by abrupt transition of histology to a sarcomatous component with high-grade malignant potential in solitary fibrous tumour (SFT). The authors histologically reviewed SFT cases to reveal the histological background of dedifferentiated SFTs.MethodsClinicopathological and histopathological findings of 145 SFT cases were reviewed. Immunohistochemical staining and genetic analysis were also performed.ResultsThe non-dedifferentiated components showed a cellular component in 45 of 145 (31%), high mitotic rate (≥4/10 high-powered field) in 12 of 145 (8.2%) tumours, necrosis in 7 of 145 (4.8%) tumours, multinodular growth pattern in 39 of 132 (29.5%) available tumours and intratumoural fibrous septa in 37 of 131 (28.2%). Immunohistochemically, the non-dedifferentiated components were positive for CD34 in 128 of 141 (90.7%), bcl-2 in 101 of 133 (75.9%), nuclear pattern of β-catenin in 64 of 127 (50.3%) and p16 in 22 of 140 (15.7%). Loss of Rb protein expression was detected in 17 of 110 (15.4%) cases. Statistically, cellular component, multinodular structure, p16 overexpression and Rb protein loss were significantly associated with dedifferentiation. Moreover, cellular component and multinodular structure were significantly associated with p16 overexpression and Rb protein loss. All the non-deddifferentiated components showed wild type of p53 expression. The dedifferentiated components of all 10 dedifferentiated tumours presented positivity for p16 in 9 of 10 (90%) and mutational type of p53 in 5 of 10 (50%). Loss of Rb protein expression was detected in 6 of 10 (60%).ConclusionsThe authors propose that cellular or multinodular transformation may be associated with dedifferentiation. They also suggest that cellular and multinodular transformation may be associated with p16 overexpression and Rb downregulation.

Background Metastatic cancer to the stomach is relatively rare. Prostate-specific antigen (PSA) is a reliable biomarker used in the screening and management of patients with prostate cancer. However, it is difficult to definitively diagnose a PSA-negative metastatic gastric tumor of prostate cancer because the cancer sometimes resembles primary gastric cancer in clinical images. It is also difficult to distinguish metastatic cancer from primary cancer even in the pathological examination of biopsy samples when the lesion is poorly differentiated adenocarcinoma. There is a possibility that the characteristics of the cancer are changed during treatment such as chemotherapy or radiation therapy. Therefore, careful consideration is required for surgical indication. Case presentation A 60-year-old male underwent radical prostatectomy and subsequent radiation therapy for advanced prostate cancer (pT3N1M0) 10 years previously, and hormone therapy was started for metachronous multiple bone metastasis 10 months before. Upper gastrointestinal endoscopy revealed an irregular depressed lesion with a convergence of folds at the greater curvature of the upper gastric body. Biopsy showed poorly differentiated adenocarcinoma that was negative for PSA upon immunohistochemistry. He had high serum carcinoembryonic antigen (CEA) (946.1 ng/ml) and carbohydrate antigen 19-9 (CA19-9) (465.1 U/ml) levels with no elevation of PSA (0.152 ng/ml). The tumor was diagnosed as primary gastric cancer based on the clinical imaging and pathological examination of the biopsy sample including the PSA staining. Based on the diagnosis, laparoscopic proximal gastrectomy with lymphadenectomy was performed. However, pathological examination of the resected specimen revealed poorly differentiated adenocarcinoma that was positive for other prostate markers such as androgen receptor. Thus, the patient was diagnosed with metastasized prostate cancer to the stomach. Conclusions We report a case of metastatic gastric cancer of prostate cancer 10 years after radical prostatectomy. In the present case, it was difficult to diagnose a metastatic gastric tumor of prostate cancer preoperatively, because of its resemblance to primary gastric cancer without PSA expression and no serum PSA elevation. Although a rare case entity, it is important to consider the possibility of a metastatic gastric tumor when the surgical indication is determined in cases with another co-existing cancer.

A 54-year-old man with pancreatic head tumor had undergone pancreaticoduodenectomy and was diagnosed with pancreatic neuroendocrine tumor (P-NET) associated with sporadic multiple endocrine neoplasm type 1. Five years after the resection, P-NET recurred and liver metastases were observed. He was treated with a somatostatin analog. Eleven years after the resection, computed tomography revealed a new pancreatic hypodense and hypovascular mass adjacent to the P-NET that was diagnosed as pancreatic adenocarcinoma via endoscopic ultrasound-guided fine-needle aspiration. He underwent a total remnant pancreatectomy. Pathological examination showed that the lesion was constituted by a pancreatic ductal adenocarcinoma (PDAC) and a neuroendocrine tumor. Additionally, the invasive ductal carcinoma collided with the neuroendocrine tumor. Both PDAC and P-NET cells were observed in the collision area. We could observe the onset of PDAC during the treatment of P-NET. Moreover, we are the first to report the case of a collision of pancreatic endocrine and exocrine tumors diagnosed preoperatively.

Hamartomas in the pancreas are rare and are often histologically and morphologically similar to solitary fibrous tumours (SFTs). We examined the differences between hamartomas and SFTs at the molecular level. METHODS AND RESULTS: Thirteen patients histopathologically diagnosed with pancreatic hamartoma were included in the study. We also performed STAT6 immunohistochemistry (IHC), which is used in the diagnosis of SFT. Furthermore, for the three cases in which RNA was extracted, reverse transcription polymerase chain reaction to search for NAB2::STAT6 fusions was used. Macroscopically, 13 patients had well-demarcated tumour lesions. Histologically, no islets of Langerhans were observed in the lesions, acinar tissue and ducts were unevenly distributed and elastic fibres were not observed around the ducts by Elastica van Gieson staining. One case contained a lipomatous hamartoma composed mainly of adipose tissue. Seven of the 13 cases demonstrated expression of STAT6 in the nuclei of intervening spindle cells. NAB2::STAT6 fusions were observed in two of the three cases in which RNA was extracted. These two cases also demonstrated STAT6 expression in spindle cells using STAT6 IHC. In one case of lipomatous hamartoma, we did not confirm NAB2::STAT6 fusion or STAT6 expression in STAT6 IHC. CONCLUSION: Of the 13 patients histopathologically diagnosed with hamartoma, two demonstrated NAB2::STAT6 fusions, suggesting the existence of pancreatic hamartomas with molecular-level components identical to those of SFT.

Mucinous cystic neoplasm (MCN) of the pancreas rarely progresses to invasive carcinoma, but few studies have analyzed genomic alterations involved in its malignant transformation. The relationships of ring finger protein 43 (RNF43) mutations with cytological atypia, RNF43 protein expression, and Wnt signaling proteins in MCN remain unclear. This study included 106 MCN cases, classified into 89 low-grade dysplasia (LG), 9 high-grade dysplasia (HG), and 8 invasive carcinoma (INV). We analyzed HG/INV and LG lesions of 9 HG/INV cases and LG lesions of 9 LG cases using targeted sequencing and confirmed the protein expression of RNF43 and β-catenin. The frequency of RNF43 mutations was significantly higher in HG/INV cases than in LG cases. Furthermore, HG/INV lesions (56%) and LG lesions (33%) of HG/INV cases possessed RNF43 mutation, whereas no such mutation was detected in any LG cases. The expression of RNF43 was reduced in 71% of HG/INV cases and significantly correlated with histological grade and aberrant expression of β-catenin. In 3 of 5 RNF43-mutated cases, the expression of RNF43 was reduced, but there was no significant correlation between RNF43 mutation and protein expression. MCNs frequently harbored KRAS mutations, at rates of 100% in HG/INV lesions and 50% in LG lesions of HG/INV and LG cases. There was no significant difference in mutation frequency in LG lesions between HG/INV and LG cases. These results suggest that RNF43 mutations may be involved in and predictive of malignant transformation from an early stage of MCN.

ARID1A, one of the subunits in SWI/SNF chromatin remodeling complex, is frequently mutated in gastric cancers with microsatellite instability (MSI). The most frequent MSI in solid‐type poorly differentiated adenocarcinoma (PDA) has been reported, but the SWI/SNF complex status in solid‐type PDA is still largely unknown. We retrospectively analyzed 54 cases of solid‐type PDA for the expressions of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), SWI/SNF complex subunits (ARID1A, INI1, BRG1, BRM, BAF155, and BAF170) and EBER, and mutations in KRAS and BRAF. We analyzed 40 cases of another histological type of gastric cancer as a control group. The solid‐type PDAs showed coexisting glandular components (76%), MMR deficiency (39%), and complete/partial loss of ARID1A (31%/7%), INI1 (4%/4%), BRG1 (48%/30%), BRM (33%/33%), BAF155 (13%/41%), and BAF170 (6%/2%), EBER positivity (4%), KRAS mutation (2%), and BRAF mutation (2%). Compared to the control group, MMR deficiency and losses of ARID1A, BRG1, BRM, and BAF155 were significantly frequent in solid‐type PDAs. Mismatch repair deficiency was associated with the losses of ARID1A, BRG1, and BAF155 in solid‐type PDAs. In the MMR‐deficient group, solid components showed significantly more frequent losses of ARID1A, BRG1, BRM, and BAF155 compared to glandular components (P = .0268, P = .0181, P = .0224, and P = .0071, respectively). In the MMR‐proficient group, solid components showed significantly more frequent loss of BRG1 compared to glandular components (P = .012). In conclusion, solid‐type PDAs showed frequent losses of MMR proteins and the SWI/SNF complex. We suggest that loss of the SWI/SNF complex could induce a morphological shift from differentiated‐type adenocarcinoma to solid‐type PDA., Solid‐type poorly differentiated adenocarcinomas of the stomach showed frequent losses of mismatch repair proteins and SWI/SNF complex, suggesting that the loss of SWI/SNF complex could induce a solid morphology.

Solitary fibrous tumor (SFT) is a soft-tissue neoplasm of intermediate malignant potential, presenting a wide histopathological spectrum. Poorer prognosis of hemangiopericytoma of the central nervous system (CNS), hypoglycemic SFT, and dedifferentiation are well-known characters of SFT, but their clinical significance were not demonstrated enough by large-sized study. Here, the clinicopathological features of SFTs are reviewed and the relationship between genetics and clinicopathological features is examined using 145 SFT cases. All cases were STAT6 IHC-positive and/or NAB2-STAT6 fusion gene-positive. Tumor location was classified into three categories: 30 pleuropulmonary, 96 non-pleuropulmonary/non-central nervous system (CNS), and 18 CNS tumors. The tumor developed recurrence in 21 of 93 available cases (22.5%), metastasis in 11 of 93 (11.8%), and tumor death in 9 of 93 (9.6%). Hypoglycemia occurred in 2 primary tumors and 1 metastatic tumor among 63 reviewable cases, and dedifferentiation occurred in 10 cases (6.8%) including 6 primary tumors, 2 recurrent tumors, and 2 metastatic tumors. Recurrence was positively associated with CNS location (p = 0.0109) and hypoglycemia (p = 0.001); metastasis was positively associated with CNS location (p = 0.0231), hypoglycemia (p

Aim Amyloidosis is a systemic or localized disease of protein deposition characterized by amorphous eosinophilic morphology and positivity of Congo Red staining. The typing of amyloidosis is becoming increasingly important because therapeutic agents for each amyloidosis type have been developed. Herein, the authors review the autopsy cases at an institution to reveal the putative Japanese characteristics of each amyloidosis type and evaluate the clinicopathological significance of each type. Materials and methods: A total of 131 autopsy cases of systemic and localized amyloidosis were retrieved for classification by immunohistochemistry. Immunohistochemistry for transthyretin, amyloid A (AA), immunoglobulin light-chain kappa and lambda, and β2-microglobulin was performed for all cases. Results The 131 amyloidosis cases were classified as follows: 71 cases (54.2%) of transthyretin amyloidosis, 32 cases (24.4%) of AA amyloidosis, 8 cases (6.1%) of light-chain amyloidosis, and 5 cases (3.8%) of β2-microglobulin amyloidosis, along with 15 equivocal cases (11.5%). All cases showed myocardial involvement of amyloidosis. Histopathologically, the transthyretin type was significantly associated with the interstitial and nodular patterns, and with the absence of the perivascular and endocardial patterns. The AA type was significantly associated with the perivascular and endocardial patterns, and with the absence of the nodular pattern. Conclusion The authors revealed the putative characteristics of cardiac amyloidosis in Japan by using autopsy cases. About 90% of amyloidosis cases were successfully classified using only commercially available antibodies.

Histopathological diagnosis of pancreatic ductal adenocarcinoma (PDAC) on endoscopic ultrasonography-guided fine-needle biopsy (EUS-FNB) specimens has become the mainstay of preoperative pathological diagnosis. However, on EUS-FNB specimens, accurate histopathological evaluation is difficult due to low specimen volume with isolated cancer cells and high contamination of blood, inflammatory and digestive tract cells. In this study, we performed annotations for training sets by expert pancreatic pathologists and trained a deep learning model to assess PDAC on EUS-FNB of the pancreas in histopathological whole-slide images. We obtained a high receiver operator curve area under the curve of 0.984, accuracy of 0.9417, sensitivity of 0.9302 and specificity of 0.9706. Our model was able to accurately detect difficult cases of isolated and low volume cancer cells. If adopted as a supportive system in routine diagnosis of pancreatic EUS-FNB specimens, our model has the potential to aid pathologists diagnose difficult cases.

A 54-year-old man with pancreatic head tumor had undergone pancreaticoduodenectomy and was diagnosed with pancreatic neuroendocrine tumor (P-NET) associated with sporadic multiple endocrine neoplasm type 1. Five years after the resection, P-NET recurred and liver metastases were observed. He was treated with a somatostatin analog. Eleven years after the resection, computed tomography revealed a new pancreatic hypodense and hypovascular mass adjacent to the P-NET that was diagnosed as pancreatic adenocarcinoma via endoscopic ultrasound-guided fine-needle aspiration. He underwent a total remnant pancreatectomy. Pathological examination showed that the lesion was constituted by a pancreatic ductal adenocarcinoma (PDAC) and a neuroendocrine tumor. Additionally, the invasive ductal carcinoma collided with the neuroendocrine tumor. Both PDAC and P-NET cells were observed in the collision area. We could observe the onset of PDAC during the treatment of P-NET. Moreover, we are the first to report the case of a collision of pancreatic endocrine and exocrine tumors diagnosed preoperatively.

"Mucoepidermoid carcinoma (MEC)" has been accepted as a synonym for pancreatic adenosquamous carcinoma (ASC). Pancreatic ASC can show salivary gland-type MEC-like morphology. CRTC1/3-MAML2 fusion gene is a characteristic molecular feature of MEC of the salivary gland. We conducted this study to clarify whether the pancreatic ASC with salivary gland-type MEC-like morphology (Pan-MEC) is a pancreatic counterpart of salivary gland-type MEC (Sal-MEC). We retrospectively analyzed 37 pancreatic ASCs including 16 Pan-MECs and 21 tumors without MEC-like features (ASC-NOS [not otherwise specified]), and we investigated (1) clinicopathologic features, (2) the presence of CRTC1/3-MAML2 fusion gene by reverse transcription polymerase chain reaction, (3) the presence of rearrangement of MAML2 gene by fluorescence in situ hybridization, and (4) mucin core proteins by immunohistochemistry. We also compared 16 Pan-MECs with 20 Sal-MECs by immunohistochemistry for mucin core protein. There were no significant differences of any clinicopathologic characteristics and survival analysis between the Pan-MECs and ASCs-NOS. Of note, the pancreatic ASCs (including Pan-MEC and ASC-NOS) were significantly more aggressive than conventional pancreatic ductal adenocarcinoma. In addition, all Pan-MECs were histologically high-grade. CRTC1/3-MAML2 fusion gene and MAML2 gene rearrangement were not detected in any ASCs including Pan-MECs. There were significant differences of MUC5AC and MUC6 between the Pan-MECs and Sal-MECs, but no significant differences of mucin core protein between the Pan-MECs and pancreatic ASCs-NOS. Pan-MEC is histologically and biologically high-grade and unrelated to CRTC1/3-MAML2 fusion gene, unlike Sal-MEC which is related to CRTC1/3-MAML2 fusion gene. Pan-MEC is not a pancreatic counterpart of CRTC1/3-MAML2 fusion gene-related Sal-MEC.

Cases of “pancreatic ductal adenocarcinoma (PDAC) concomitant with intraductal papillary mucinous neoplasm” (IPMN) have multiple PDAC lesions more frequently than cases of “PDAC without IPMN”. However, the mechanism of carcinogenesis in this former disease category remains unknown. The main objective of this work was thus to investigate the effects of chronic inflammation on carcinogenesis in PDAC cases. We selected 31 “PDAC concomitant with IPMN” patients and 58 “PDAC without IPMN” patients and pathologically evaluated their background pancreatic parenchyma. Fibrosis and inflammation scores of background pancreas were higher in “PDAC concomitant with IPMN” than in “PDAC without IPMN” (P

Background/Objectives This single-center study aimed to evaluate treatment outcomes and long-term prognosis of patients with pancreatic neuroendocrine neoplasms (PanNENs) based on the World Health Organization (WHO) 2017 classification. Methods We enrolled 245 patients with PanNENs treated at Kyushu University Hospital between January 1987 and March 2018. PanNENs were categorized according to the WHO 2017 classification or further subdivisions of Ki-67 index. Clinicopathological features, median survival time (MST), and prognostic factors were retrospectively analyzed. Results The number of PanNENs, especially non-functioning PanNENs, has increased over the last decade. The mean MST of all patients was 202 months; which was longest in patients with NET G1 (n = 145, MST = 261 months) relative to NET G2 (n = 72, 132 months), NET G3 (n = 3, 34 months) and NEC G3 (n = 17, 9 months). Prognosis in patients with surgery as the first-line treatment was significantly better than in those with drug therapy. However, 26% of patients who underwent curative resection developed recurrence after a median time of 28.7 months. In unresectable PanNENs (n = 97), the MST and 5-year survival rate were 78 months and 55.8%, respectively. Poor differentiation, Ki-67 index of >10% and presence of liver metastasis were significant unfavorable predictors. Response to first-line therapy (stable disease/partial response) and three or more treatment regimens were significant favorable predictors for unresectable PanNENs according to multivariate analyses (p Conclusions We demonstrated the utility of the WHO 2017 classification for PanNENs in the real clinical setting. For better prognosis in PanNENs, the use of three or more regimens should be considered.

The RNA-binding protein HuC/D displays a neuron-specific expression and is involved in neuronal differentiation and the maintenance of the nervous system. Here we investigated the diagnostic value of HuC/D in neuroblastomas. We evaluated 85 neuroblastic tumors: 81 neuroblastomas; 3 ganglioneuroblastomas, intermixed; 1 ganglioneuroma, maturing; and 101 other tumors consisting of 34 Ewing sarcomas, 14 nephroblastomas, 11 rhabdomyosarcomas, 15 pulmonary small cell carcinomas, 18 pancreatic neuroendocrine tumors, and 9 pheochromocytomas. Immunohistochemistry for HuC/D, PHOX2B, and tyrosine hydroxylase was performed. The immunoreactivity for HuC/D was semiquantified using the total score (TS; range, 0-8). HuC/D positivity was defined as a TS ≥6. The TS of the neuroblastic tumors (mean TS, 7.94) was significantly higher than those of the other small round cell tumors and neuroendocrine tumors (P < .001) except for the pheochromocytomas (mean TS, 6.89; P = .074). HuC/D was positive in all 85 neuroblastic tumors, 1 (2.9%) Ewing sarcoma, 1 (6.7%) pulmonary small cell carcinoma, and 8 (89%) pheochromocytomas. PHOX2B was positive in all of the neuroblastic tumors and pheochromocytomas. Tyrosine hydroxylase was positive in 80 (94%) neuroblastic tumors, 1 (9.1%) rhabdomyosarcoma, and all of the pheochromocytomas. Therefore, HuC/D serves as a highly sensitive diagnostic marker to distinguish neuroblastomas from other small round cell tumors. The combination of HuC/D and PHOX2B staining may be valuable for the diagnosis of neuroblastic tumors, especially in the assessment of small sections. HuC/D expression in tumors may be related to catecholamine production or a neural crest-derived cell origin.

Since adenoma components disappear with tumor progression, it is not known whether colorectal carcinomas (CRCs) are derived from an adenoma-carcinoma sequence or are de novo. We compared 38 cases of ≤10-mm flat CRCs without an adenoma component (de novo type) with 39 cases of ≤10-mm flat CRCs with an adenoma component (carcinoma in adenoma (CIA) type). Compared to the CIA type, the de novo-type CRCs were more frequently located in the proximal colon; more frequently invaded submucosa, and more frequently had venous permeation. Regarding the phenotypic classification based on the immunohistochemical expressions of CD10, MUC2 and MUC5AC, the incidence of unclassified type (CD10-, MUC2- and MUC5AC-) was significantly more frequent in the de novo (32%) than CIA (5%) type. In one de novo-type case, mismatch repair (MMR) protein loss was judged, because MLH1 and PMS2 protein expressions were immunohistochemically negative. BRAF mutation (V600E) was seen in one de novo-type case and two CIA-type cases, but none of these cases had MMR protein loss. In conclusion, small-intestinal type (CD10+ and MUC5AC-) is the most common in flat CRC and unclassified type is mainly characteristic of de novo type. In this study, small flat CRCs with BRAF mutation do not have MMR protein loss.

Synchronous colorectal carcinoma (CRC) is a unique disease associated with a high prevalence (∼35%) of microsatellite instability and occasionally with Lynch syndrome. The clinicopathologic and molecular features of synchronous CRC are poorly understood, particularly in Japanese patients. We examined 118 Japanese patients (236 tumors) with synchronous CRC and 117 Japanese patients (117 tumors) with solitary CRC with immunohistochemical staining for TP53 and mismatch repair (MMR) protein (MLH1, MSH2, PMS2, and MSH6) and mutation analyses of KRAS and BRAF genes. The results revealed no significant differences in clinicopathologic, histologic, and molecular findings between the synchronous and solitary CRC groups. Among the 118 synchronous CRC patients, 15 (12.7%) showed loss of MMR protein(s) expression in at least 1 tumor, whereas 103 (87.3%) showed intact expression of all 4 MMR proteins in both tumors. Of note, all patients with MMR deficiency had excellent prognoses. The 15 patients were further subdivided into 2 groups: the Concordant group, with concordant MMR loss (n=9, 7.6%) and the Discordant group, with discordant MMR loss (n=6, 5.1%). The Concordant patients showed concurrent MLH1/PMS2 loss (n=3), concurrent MSH2/MSH6 loss (n=4) and isolated MSH6 loss (n=2) in both tumors, whereas the Discordant patients showed concurrent MLH1/PMS2 loss (n=2), isolated PMS2 loss (n=2) and isolated MSH6 loss (n=2) in a single tumor. On the basis of the MMR expression pattern and BRAF mutation, the Concordant and Discordant groups were suspected to include Lynch syndrome, Lynch-like syndrome and sporadic MLH1 promoter hypermethylated CRC. In addition, KRAS mutation was present in only 1 tumor in a single patient in each group. In conclusion, the frequency of MMR protein deficiency in synchronous CRC in the Japanese population may be lower compared with the reported data from Western populations. MMR protein loss and KRAS and BRAF mutations in synchronous CRCs were heterogenous even in an individual patient.

Rationale Esophageal carcinosarcoma generally comprises 2 histological components: squamous cell carcinoma (SqCC) and sarcoma. Esophageal carcinosarcoma comprising 3 components is extremely rare and no reports have described therapeutic effects for this disease with metastasis. Patient concerns A 76-year-old man with dysphagia presented to a local clinic. Gastrointestinal endoscopy revealed a polypoid tumor in the middle esophagus and he was referred to our hospital. Diagnosis and interventions Thoracoscopic esophagectomy with super-extended (D3) nodal dissection and gastric tube reconstitution was performed, which resulted in carcinosarcoma comprising neuroendocrine carcinoma (NEC), SqCC, and sarcoma. Pathological stage was T1bN1M0 stage IIB according to the TNM Classification of Malignant Tumors-7th edition. The NEC component was observed in lymph node. At 47 days after surgery, lymph nodes, liver, and bone metastasis appeared, and tumor markers such as ProGRP and NSE were elevated. Combination chemotherapy with cisplatin and etoposide (EP) adapted to NEC was performed. Outcomes The patient showed complete response within 4 cycles of chemotherapy. However, the disease recurred 5.5 months after the final course of EP chemotherapy. Lessons A therapeutic strategy based on assessment of which component caused metastasis might be important for metastatic carcinosarcoma comprising 3 components, although more accumulation of data about the efficacy of chemotherapy is necessary. Moreover, elucidation of the mechanisms underlying generation of carcinosarcoma is expected in the future.

A 58-year-old woman visited a local physician for evaluation of collagen disease and screening computed tomography (CT) showed a posterior mediastinal tumor. After referral to our hospital, CT and magnetic resonance imaging (MRI) showed a mass, approximately 2 cm in diameter, located on the right of the 1st thoracic vertebra. Since a neurogenic tumor was suspected, thoracoscopic excision was performed. Surgical findings revealed a tumor between the 1st and 2nd ribs in the close vicinity of the right brachiocephalic vein. We severed blood vessels flowing into the tumor and removed it. The tumor, 25 mm in maximal diameter, was diagnosed as hemangioma by histological examinations. The prevalence of a hemangioma is less than 0.5% of all mediastinal tumors. Since it lacks specific imaging findings, its preoperative diagnosis is quite difficult to establish. Although a hemangioma in the mediastinum is quite rare, it should be included in the differential diagnoses of mediastinal tumors.