Kohei Morita

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.

Nonomura A, Enomoto Y, Takeda M, Takano M, Morita K & Kasai T 
(2012) Histopathology 61, 863–880

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.

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 patients 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 retrospective study of patients with follicular lymphoma (FL): identification of in situ FL or FL-like B cells of uncertain significance in lymph nodes resected at the time of previous surgery for carcinomas

Background and aims In situ follicular lymphoma (iFL)/intrafollicular neoplasia and follicular lymphoma (FL)-like B cells of uncertain significance represent proliferation of Bcl-2/t(14;18)-positive B cells solely in the germinal centres. The condition is interpreted as an early event in the multi-step lymphomagenesis of FL. The aim of this study is to examine the issue more specifically. Methods We reviewed medical history of FL patients in whom thoracoabdominal surgery with lymphadenectomy had been performed for management of carcinomas. These previously resected lymph nodes as well as the current FL nodes were analysed by immunohistochemistry, fluorescent in situ hybridisation, and PCR amplification with direct sequencing. Results We studied four such FL patients from a total of 150 patients with FL; all had iFL in the previously resected lymph nodes. Clonal relation was verified and suggested in one case each. The time from lymphadenectomy to the diagnosis of FL was 23–120 months. There appeared to be a reverse correlation between the rate of Bcl-2-positive follicle proliferation and the time from surgery to diagnosis of FL. Conclusions Although the rate for development of FL in individuals having iFL has been reported to be low from prospective studies, the present data indicate that follow-up studies for a longer period is necessary; the rate of Bcl-2-positive follicle proliferation could be a factor to predict development of FL in prospective studies. Such a retrospective study may contribute to elucidate mechanism(s) involved in lymphomagenesis of FL.

Comparison of genomic abnormality in malignant mesothelioma by the site of origin

Aims Malignant mesothelioma (MM) results from the accumulation of a number of acquired genetic events at the onset. In MM, the most frequent changes are losses in 9p21, 1p36, 22q12 and 14q32, and gains in 5p, 7p and 8q24 by comparative genomic hybridisation analysis. We have examined various genomic losses and gains in MM and benign mesothelial proliferation by fluorescence in situ hybridisation (FISH) analysis. 9p21 deletion was reported to be less frequent in peritoneal than in pleural MMs. This study analysed various genomic losses and gains in MM by the site of origin using FISH analysis. Materials and methods We performed FISH analysis using paraffin-embedded tissues from 54 cases (40 pleural and 14 peritoneal) of MMs and compared the frequency of genomic abnormality by the site of origin. Results 9p21 deletion was shown in 34 of 40 cases (85%) of pleural MMs, and was less frequent in five of 14 cases (36%) of peritoneal MMs (p<0.001) by FISH analysis. By contrast, 5p15 and 7p12 amplification was more significantly frequent in peritoneal than in pleural MMs. No difference between the two sites of MM in other genes was found. Conclusions 9p21 homozygous deletion assessed by FISH has been reported to be useful for differentiating MM from reactive mesothelial proliferation, but it should be noted that 9p21 deletion was less frequent in peritoneal MM. Our study suggests that the pathway of the genetic abnormality might vary between pleural and peritoneal MM.

SALL4 positive fetal gut‐like adenocarcinoma of the duodenum

Fetal gut‐like adenocarcinoma is a rare carcinoma, previously reported in the stomach, which features clear cytoplasm cell papillotubular carcinoma and morphology similar to the fetal gut epithelium. SALL4, a novel marker for progenitor‐type tumors, has shown high expression in fetal gut‐like adenocarcinoma, which may represent oncofetal protein expression and fetal differentiation. Herein, we report the first case of fetal gut‐like adenocarcinoma of the duodenum. An 81‐year‐old man was admitted on account of jaundice. A deeply ulcerating duodenal tumor formed a 4 cm periampullar mass. Pancreatoduodenectomy with lymphadenectomy was performed. Funicular and solid growth of clear cytoplasmic cells that resembled the fetal gut epithelium formed a poorly differentiated adenocarcinoma. Lymph node metastasis was present. Immunohistochemistry analysis showed diffuse nuclear positivity for SALL4. For postoperative therapy, S‐1 was administered. The patient is alive with no recurrence, 83 months postoperatively. This case may contribute to further elucidate the disease entity of SALL4 positive, fetal‐type carcinomas.

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

BackgroundKeratin (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.MethodsK19 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.ResultsAnalysis 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.ConclusionK19 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.

Primary intrathoracic malignant neurogenic tumor: report of three cases and comparison with benign neurogenic tumors resected at our institution

We present three patients with intrathoracic malignant neurogenic tumor. Two lesions showed no sign of invasion into adjacent structures, while the third lesion extended to the intraspinal canal with vertebral involvement. Although all three lesions were completely excised, each patient relapsed within 1 year of the initial treatment. One patient with local recurrence underwent radiation therapy, but the recurrent tumor continued to progress. Chemotherapy was subsequently performed. Two patients with distant metastases also received chemotherapy. Because there is no effective chemotherapeutic regimen for intrathoracic malignant neurogenic tumor, all three patients received high-dose chemotherapy followed by hematopoietic stem cell transplantation. Although the relapsed lesions temporarily regressed after treatment, all three patients showed disease recrudescence and ultimately died of their disease. A comparison of the intrathoracic malignant neurogenic tumors and the benign neurogenic tumors resected at our institution revealed no meaningful differences distinguishing malignant from benign neurogenic tumors prior to surgery.

A case of severe neonatal asphyxia due to umbilical artery thrombosis

Taito Kitano, Ayako Ohgitani, Kumiko Takagi, Ikuyo Arai, Hajime Yasuhara, Reiko Ebisu, Yoshinori Takeda, Satoko Ishibashi, Kohei Morita and Hideki Minowa Department of Neonatal Intensive Care Unit, Nara Prefecture General Medical Center, Nara, Japan; Department of Obstetrics and Gynecology, Nara Prefecture General Medical Center, Nara, Japan; Department of Pathology, Nara Medical University, Nara, Japan

Immunohistochemical Reappraisal Regarding the Frequency of Primary Salivary Gland Follicular Lymphoma

Although it has been described that extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas) are the most common type among primary salivary gland lymphomas (SGLs), some studies revealed that the frequency of follicular lymphomas (FLs) was as high as that of MALT lymphomas. However, it has been reported that many of these FLs may have developed in lymph nodes attached to the capsule of the glands or intraglandular lymph nodes. Clinical, histological, immunohistochemical, and cytogenetic features of 11 SGL cases, which were extracted from our surgical pathology file consisting of consecutive pathology cases, were reevaluated to further characterize whether they were actually primary SGLs. There were 3 (27%) cases of FLs, 5 (46%) cases of MALT lymphomas, and 3 (27%) cases of diffuse large B-cell lymphomas. Although all of our FL cases fulfilled the criteria of primary SGL, tumors of several FL cases were surrounded by podoplanin (by D2-40)–positive elongated vessels or linear structures indicative of nodal subcapsular sinuses (open or remnant). This finding would support the aforementioned possibility, and podoplanin staining is necessary before concluding that a FL is a primary SGL.