Low-grade tracheal adenocarcinoma with ETV6::NTRK3 fusion: unique morphology akin to subsets of sinonasal low-grade non-intestinal-type adenocarcinoma.

The prevalence of NTRK fusions in non-small cell carcinoma (NSCLC) is only approximately 0.2%, most of which harbor NTRK1 fusions. NSCLCs with NTRK3 fusions are extremely rare. Herein, we report a case of low-grade tracheal adenocarcinoma in a 64-year-old woman. Histologically, areas of complicated tubule-papillary or cribriform patterns constituted a major component of the tumor and comprised cuboidal to columnar epithelial tumor cells with pale eosinophilic cytoplasm and cytoplasmic mucin, similar to subsets of sinonasal low-grade non-intestinal-type adenocarcinomas. Immunohistochemically, the tumor was positive for MUC5AC and MUC4 and showed nuclear expression of the pan-Trk antibody. ETV6::NTRK3 was identified by reverse transcription-polymerase chain reaction using formalin-fixed paraffin-embedded tissues. To the best of our knowledge, this is the first case of low-grade tracheal adenocarcinoma with ETV6::NTRK3 fusion. Our case illustrates that low-grade adenocarcinomas with ETV6::NTRK3 fusion may exist throughout the respiratory tract.

Keratin 19 as a key molecule in progression of human hepatocellular carcinomas through invasion and angiogenesis.

BACKGROUND: Keratin (K) 19-positive hepatocellular carcinoma (HCC) is well known to have a higher malignant potential than K19-negative HCC: However, the molecular mechanisms involved in K19-mediated progression of HCC remain unclear. We attempted to clarify whether K19 directly affects cell survival and invasiveness in association with cellular senescence or epithelial-mesenchymal transition (EMT) in K19-positive HCC. METHODS: K19 expression was analysed in 136 HCC surgical specimens. The relationship of K19 with clinicopathological factors and survival was analysed. Further, the effect of K19 on cell proliferation, invasion, and angiogenesis was examined by silencing K19 in the human HCC cell lines, HepG2, HuH-7, and PLC/PRF/5. Finally, we investigated HCC invasion, proliferation, and angiogenesis using K19-positive HCC specimens. RESULTS: Analysis of HCC surgical specimens revealed that K19-positive HCC exhibited higher invasiveness, metastatic potential, and poorer prognosis. In vitro experiments using the human HCC cell lines revealed that K19 silencing suppressed cell growth by inducting apoptosis or upregulating p16 and p27, resulting in cellular senescence. In addition, transfection with K19 siRNA upregulated E-cadherin gene expression, significantly inhibited the invasive capacity of the cells, downregulated angiogenesis-related molecules such as vasohibin-1 (VASH1) and fibroblast growth factor 1 (FGFR1), and upregulated vasohibin-2 (VASH2). K19-positive HCC specimens exhibited a high MIB-1 labelling index, decreased E-cadherin expression, and high microvessel density around cancer foci. CONCLUSION: K19 directly promotes cancer cell survival, invasion, and angiogenesis, resulting in HCC progression and poor clinical outcome. K19 may therefore be a novel drug target for the treatment of K19-positive HCC.

[Left Lower Lobectomy for an Elderly Patient with Anomalous Systemic Arterial Supply to the Basal Segment of the Left Lung;Report of a Case].

A 76-year-old man was referred to our department for an abnormal shadow on a chest X-ray. Computed tomography showed an aberrant artery arising from the descending thoracic aorta to the basal segment of the left lung. The aberrant artery was dilated and tortuous, and its wall had remarkable calcifications. Bronchial branching to the basal segment of the left lung were normal. The diagnosis of anomalous systemic arterial supply to normal basal segment was established, and division of the aberrant artery and left lower lobectomy were performed successfully. His postoperative course was uneventful, and he was discharged on the 14th postoperative day. We describe herein a rare case of the elderly patient surgically treated for this disease along with a brief review of the literatures.

[Highly Advanced Gastric Cancer Leading to Immediate Perforation on Day Three of Chemotherapy with S-1 plus Oxaliplatin].

A 68-year-old woman was diagnosed with advanced gastric cancer with a type 3 deep ulcer of the middle stomach by endoscopy. An abdominal computed tomography scan revealed multiple lymph node metastases and peritoneal disseminations. The clinical stage was determined to be T4a(SE), N2P1M1(PER), H0 and stage IV . A gastrectomy was scheduled after 2 courses of S-1 plus oxaliplatin(SOX)with curative intent. On day 3 after initiatingSOX therapy, the patient complained of severe abdominal pain. Because the abdominal CT scan showed intra-abdominal free air and a defect in the gastric wall, we performed an emergency total gastrectomy. The defect in the gastric wall was about 1 cm in diameter and was located in the anterior wall of the lower body, consistent with the center of the tumor. The operative findings suggested that the perforation was caused by chemotherapy-induced necrosis of gastric cancer cells. The patient was discharged 16 days after surgery and received post-operative chemotherapy. Our findings suggest that the risk of gastric perforation should be considered when administeringchemotherapy to patients with advanced gastric cancer and a deep ulcer.

Angiomyolipoma of the liver: a reappraisal of morphological features and delineation of new characteristic histological features from the clinicopathological findings of 55 tumours in 47 patients.

AIMS: The aim of this study was to characterize and delineate the broad histological spectrum of hepatic angiomyolipoma (AML) and to obtain a better understanding of its clinicopathological diagnosis by reviewing a large series of AMLs. METHODS AND RESULTS: According to the proportions of three histological components, AML could be classified into 10 types; 36 of 55 tumours (65%) were classified as myomatous, eight as myoangiomatous, six as mixed (conventional), two as lipomatous, two as myolipomatous, and one as lipomyomatous. The morphology of smooth muscle cells (SMCs) in AML was quite variable, giving a wide variety of growth patterns. Fourteen (25%) of 55 tumours showed severe cellular atypia, and invasive growth of tumour cells was found in 69% of the tumours. However, except for two autopsy cases, all of the patients were in good health at follow-up, without metastases. Immunostaining for HMB-45 was positive in all cases. We found frequent lymphocyte infiltration, and the occasional presence of abnormally large blood vessels around the tumour at the tumour-background liver interface, features which have not been reported previously. CONCLUSIONS: The majority of hepatic AMLs were myomatous in type, showing variable cellular morphology and growth patterns. Cellular atypia and invasive growth were frequent, indicating that hepatic AMLs often show malignancy-like histological features. Although the majority of cases behave as benign tumours, AML should be considered to have uncertain malignant potential, and careful follow-up of patients is recommended. Immunostaining for HMB-45 is specific for AML, and establishes the diagnosis. The occasional presence of abnormally large blood vessels around the tumour may give new insights into the evaluation of findings from imaging.

Lymph node infarction in classical Hodgkin's lymphoma.

Among lymphoproliferative disorders, lymph node infarction appears to be most frequently seen in diffuse large B-cell lymphoma, followed by follicular lymphoma, with other types being rare. We experienced one such case, classical Hodgkin's lymphoma (cHL) associated with lymph node infarction, in which Reed-Sternberg (RS) cells were positive for CD15, CD30, fascin, PAX-5, p53, latent membrane protein-1 (LMP-1), Bcl-2, and EBV-encoded small non-polyadenylated RNAs. Furthermore, RS cells in the infarcted area were still positive for CD30, fascin, p53, and Bcl-2. For definitive diagnosis of nodal lymphomas including Hodgkin's lymphoma, identification of the effacement of normal nodal architecture is essential. Although this could not be evaluated in our case because of predominant reactive follicular hyperplasia with interfollicular distribution of RS cells, the presence of large cells with RS cell-related molecules together with the distorted distribution of cCD3-positive cells and CD20-positive cells led us to make a definitive diagnosis of cHL. It is, therefore, considered that immunohistochemical evaluation of the infarcted lymph node is, at least on some occasions, still informative for more accurate diagnosis of lymphoid neoplasia. Hodgkin's lymphoma should also be considered when one encounters lymph node infarction.

Hepatic cyst infection in a healthy older male.

Simple hepatic cysts are usually asymptomatic and are not associated with impaired hepatic function. However, complications, such as obstructive jaundice, rupture, intracystic haemorrhage and infection, can occur. The authors describe the case of a 82-year-old man with fever and elevated C-reactive protein. A repeat contrast-enhanced abdominal CT scan revealed enlargement with peripheral enhancement in the left lateral segment of the liver. A diagnosis of infected hepatic cyst was made, and percutaneous transhepatic drainage of the cyst was performed. When a patient has liver cysts and high-grade fever, liver cysts should be considered as a focus of infection. Repetition of ultrasonography and/or CT studies should be considered, even if no typical findings are obtained initially. It is of note that conventional Ga-scintigraphy may be useful for the detection of infected site.

Autopsy case of primary myelofibrosis in which myeloid sarcoma was the initial manifestation of tumor progression.

Myeloid sarcoma (MyS) is defined as an extramedullary tumor-forming neoplasm consisting of immature myeloid cells with/without maturation. We experienced a case involving a 68-year-old Japanese male patient who had been followed-up for four years with a diagnosis of chronic idiopathic myelofibrosis/primary myelofibrosis (PMF) and noticed a painful mass in his left axilla. A wedge biopsy characterized the lesion as MyS that displayed megakaryoblastic/megakaryocytic differentiation. As his complete blood count included a few myeloid blasts (1% of WBC) and a bone marrow biopsy detected fibrosis without evidence of acute myelogenous leukemia (AML), a diagnosis of extramedullary blastic transformation of PMF was made, which was confirmed later by V617F mutation in Janus kinase-2 in both initial bone marrow biopsy and axillary tumor biopsy specimens. The patient died of pneumonia eight months after developing the axillary tumor. At autopsy, multiple MyS masses were detected in his soft tissue, but his bone marrow only contained fibrosis. Although MyS rarely develops before the leukemic transformation of PMF, no evidence of AML could be found in the patient's bone marrow at any point during the course of his disease. Thus, it is possible that the blasts in his peripheral blood were derived from the remaining MyS. Furthermore, the present case indicates that extramedullary blastic transformation, which is occasionally seen in CML, can also occur in PMF. Therefore, it is important to recognize that there is a wide variation in the pathogeneses of MyS and PMF.

A comparison of epidermal growth factor receptor expression in malignant peritoneal and pleural mesothelioma.

An evaluation of epidermal growth factor receptor (EGFR) phenotypic expression in malignant pleural and peritoneal mesothelioma was undertaken, using immunohistochemical (IHC) and fluorescence in situ hybridization (FISH) analysis. Thirty-eight malignant mesothelioma (MM) specimens were subjected to IHC staining and FISH to evaluate the expression of EGFR protein and gene status. Overall positive IHC reaction was detected in 20/38 (53%) cases, in 11/22 (50%) pleural MM, and in 9/16 (56%) peritoneal MM. Our study confirmed that EGFR membranous expression is a common feature in MM, but not in benign mesothelial lesion. Thirty-seven cases did not show a gene copy number gain. Only one case showed a copy number gain. The protein overexpression of EGFR was not related to a gene copy number gain.

Epidermal growth factor receptor mutations in malignant pleural and peritoneal mesothelioma.

BACKGROUND: Epidermal growth factor receptor (EGFR) gene mutation at the kinase domain and EGFR gene amplification are reported to be predictors of the response to EGFR tyrosine kinase inhibitors in lung cancer cases. In malignant mesothelioma (MM), the role of EGFR is less clear. METHODS: Thirty-eight MM specimens were submitted to EGFR mutation evaluation, and compared with the results of immunohistochemical staining and fluorescence in situ hybridization (FISH) analysis. DNA was extracted from paraffin blocks and PCR was performed to amplify exon regions 18-21 of the EGFR gene. Direct sequencing of the purified PCR products was performed. RESULTS: Five EGFR missense mutations were detected in six of the 38 patients (16%); two of these mutations were novel, two were originally detected in non-small cell lung carcinoma, and one resembled a location previously noted for malignant peritoneal mesothelioma. CONCLUSION: As far as the authors are aware there has been no report of the EGFR mutation of MM in Japanese cases, but in this study EGFR missense mutations were detected in some cases. EGFR mutation results were not related to immunohistochemical and FISH analysis.

Genomic gains and losses in malignant mesothelioma demonstrated by FISH analysis of paraffin-embedded tissues.

AIMS: Malignant mesothelioma (MM) results from the accumulation of a number of acquired genetic events at the onset. In MM, the most frequent changes were losses in 9p21, 1p36, 14q32 and 22q12, and gains in 5p, 7p and 8q24 by comparative genomic hybridisation analysis. Although the diagnostic utility of 9p21 homozygous deletion by fluorescence in situ hybridisation (FISH) analysis in MM has been reported recently, alterations of other genes have not been examined to any great extent. This study analysed the frequency of various genomic gains and losses in MM using FISH analysis. MATERIALS AND METHODS: The authors performed a FISH analysis using paraffin-embedded tissues from 42 cases of MM. RESULTS: Chromosomal losses in MM were found at 9p21 (83%), 1p36 (43%), 14q32 (43%) and 22q12 (38%), whereas gains were found at 5p15 (48%), 7p12 (38%) and 8q24 (45%). There were no cases of adenomatoid tumour, benign mesothelial multicystic tumour, reactive mesothelial hyperplasia or pleuritis showing any gains or losses. At least one genomic abnormality was identified in all cases of MM. Among various histological subtypes, the chromosomal abnormality tended to be more common in cases showing sarcomatous elements (biphasic or pure sarcomatoid) than in cases showing an epithelioid histology. CONCLUSIONS: The authors found various genomic gains and losses in MM by FISH analysis. The frequency of each genomic gain or loss examined in MM by FISH analysis almost agreed with the comparative genomic hybridisation technique in previous studies. This study suggests that genomic evaluation by FISH analysis might be helpful in distinguishing MM from benign mesothelial proliferation.

[A case of multiple gastrointestinal stromal tumors of the small intestine associated with von Recklinghausen disease].

A 63-year-old woman was admitted to our hospital because of tarry stool several years previously. At the time, café-au-lait spots and dermal nodules were found on her entire body, and a diagnosis of von Recklinghausen disease was established. Small bowel endoscopy revealed a submucosal tumor in the jejunum. Laparotomy was therefore performed on the suspicion of intestinal GIST. Numerous extramural tumors with a diameter of 3-5mm were observed along the jejunum and ileum, in addition to the primary tumor. Partial resection of the jejunum, including the primary tumor and only one small nodule was performed to prevent short bowel syndrome. Immunopathological studies of the tumors were positive for KIT and CD34 and we diagnosed multiple intestinal GISTs. Imatinib mesylate was not administered, but no growth of the residual tumors have been recognized for 10 months after surgery.

Hibernoma of the axillary region: a rare benign adipocytic tumor.

Hibernoma is a rare benign tumor considered to arise from remnants of fetal brown adipose tissue. It tends to occur in sites where brown fat persists beyond fetal life, such as the interscapular region, but can occur in sites where brown fat is usually absent in adults. Clinicallywell, hibernomas are slow-growing, asymptomatic tumors. However, unlike lipomas, MRI findings sometimes mislead clinicians to diagnose a malignant neoplasm. We describe a 63-year-old male with an axillary hibernoma involving the brachial neurovascular bundles and mimicking a well-differentiated liposarcoma, from which it should be distinguished.

Negative association of Epstein-Barr virus or herpes simplex virus-1 with tumefactive central nervous system inflammatory demyelinating disease.

Central nervous system (CNS) demyelination has been suggested to be associated with infections caused by the Epstein-Barr virus (EBV) or herpes simplex virus (HSV)-1. CNS inflammatory demyelinating disease (IDD) rarely presents as a large lesion. We evaluated samples of serum and cerebrospinal fluid (CSF) by enzyme-linked immunosorbent assay to detect recent infection with these viruses and analyzed CSF and brain specimens by polymerase chain reaction (PCR) or immunohistochemical studies for evidence of these viruses in three patients with biopsy-proven CNS IDD. The results of PCR tests for EBV and HSV in CSF or brain specimens were negative. Elevated anti-EBV or -HSV antibody levels were not found in serum or CSF in any patient. Immunohistochemical studies showed that IDD lesions were negative for latent membrane protein (LMP)-1, Epstein-Barr nuclear antigen (EBNA)-2, and EBNA noncoding RNA (EBER)-1. These results suggest a negative association between CNS IDD and EBV or HSV.

[A case of resected endocrine cell carcinoma in the remnant stomach].

We report a rare case of resected endocrine cell carcinoma in the remnant stomach. A 68-year-old man had undergone laparoscopy-assisted distal gastrectomy for gastric cancer. Eleven months later, postoperative endoscopy survey showed a flat, depressed lesion in the posterior wall of the remnant gastric cardia. After 3 months, endoscopic re-examination indicated that the tumor had grown rapidly and had changed in shape. Endocrine cell carcinoma was diagnosed by biopsy. He then underwent total resection of the remnant stomach with lymph node dissection. Although adjuvant chemotherapy was given, multiple liver metastases and lymph node recurrence were found 13 months after the second surgery. A new regimen of chemotherapy was not effective and he died 18 months after surgery.

9p21 deletion in the diagnosis of malignant mesothelioma, using fluorescence in situ hybridization analysis.

Homozygous deletion of 9p21, the locus harboring the p16 gene, has been reported as one of the most common genetic alterations in malignant mesotheliomas (MMs). Previous studies showed that this alteration might be useful for differentiating benign from malignant mesothelial tumors in cytology and surgical specimens. Although the diagnostic utility of 9p21 homozygous deletion by fluorescence in situ hybridization (FISH) analysis has been reported only recently, it has not been well demonstrated. The purpose of this study is to evaluate the diagnostic utility of 9p21 homozygous deletion assessed by FISH in mesothelial neoplasm and hyperplasia of Japanese patients using paraffin-embedded tissue. Simultaneously, p16 protein immunoexpression was explored as a potential diagnostic aid. FISH analysis demonstrated 9p21 deletion in 35 of 40 cases with MM (88%) (P < 0.001). In contrast, no cases of adenomatoid tumor, benign mesothelial multicystic tumor, reactive mesothelial hyperplasia or pleuritis showed 9p21 deletion (P < 0.005). 9p21 homozygous deletion correlated well with p16 protein expression in the tumor cells. Our study suggests that 9p21 homozygous deletion assessed by FISH on paraffin-embedded tissue may be very useful for differentiating MM from reactive mesothelial proliferation.

Application of a new histological staging and grading system for primary biliary cirrhosis to liver biopsy specimens: Interobserver agreement.

Recently the authors proposed a new staging and grading system for primary biliary cirrhosis (PBC) that takes into account necroinflammatory activity and histological heterogeneity. Herein is proposed a convenient version of this system. Scores for fibrosis, bile duct loss, and chronic cholestasis were combined for staging: stage 1, total score of 0; stage 2, score 1-3; stage 3, score 4-6; and stage 4, score 7-9. Cholangitis activity (CA) and hepatitis activity (HA) were graded as CA0-3, and HA0-3, respectively. Analysis of interobserver agreement was then conducted. Digital images of 62 needle liver biopsy specimens of PBC were recorded as virtual slides on DVDs that were sent to 28 pathologists, including five located overseas. All participants were able to apply this version in all 62 cases. For staging, kappa was 0.385 (fair agreement) and the concordance rate was 63.9%. For necroinflammatory activity, the kappa and concordance rate were 0.110 (slight agreement) and 36.9% for CA, and 0.197 (slight agreement) and 47% for HA, respectively. In conclusion, this new staging and grading system for PBC seems to be more convenient and practical than those used at present, but more instruction and guidance are recommended for the grading of necroinflammatory activity in practice.

Hepatocellular carcinoma of the iliac bone with unknown primary.

We report a case of hepatocellular carcinoma of the iliac bone in which the primary tumor was not detected. No malignant primary lesions such as hepatocellular carcinoma or hepatoid carcinoma were detected at the time or during 10 years' follow-up. In this case, transcatheter arterial chemo-embolization and radiation therapy resulted in complete regression of the iliac bone tumor and in long-term survival. We focus in particular on the clinical, histological, and therapeutic aspects of the presented case, as well as the imaging and diagnostic aspects.

[A surgical (right lobectomy) case of liver metastasis of colon cancer after chemotherapy using mFOLFIRI and cetuximab].

A man in his early seventies underwent low anterior resection and partial resection of the liver for the rectal cancer and liver metastasis. However, 4 months after the surgery, he was found to have a liver tumor at S5 and S7 by abdominal CT scan. Then, he underwent chemotherapy (mFOLFOX6), but the metastatic tumor was progressive. We selected FOLFIRI + cetuximab regimen for second-line therapy to resect the metastatic tumor. As the metastatic lesion was become smaller after 4-course of the regimen including cetuximab, we decided to perform a radical resection. We conducted a right lobectomy of the liver, and the tumor was completely resected.