Mikiko Kobayashi

Intrahepatic cholangiocarcinoma with predominant "ductal plate malformation" pattern: a new subtype.

Ten cases of intrahepatic cholangiocarcinoma showing a highly differentiated adenocarcinoma mimicking ductal plate malformation (DPM) are reported. The patients included 7 males and 3 females with an average age of 69.5 years. Six cases were associated with chronic liver disease and the remaining 4 cases showed mild fatty change in the parenchyma and/or minimal to mild portal inflammation. Grossly, the tumor was a single nodule 1.5 to 6.6 cm in diameter, and was whitish and solid without a fibrous capsule. Microscopically, the tumor was composed of many vague, small nodular carcinomatous areas with desmoplastic reactions, and neoplastic glands had an irregularly dilated lumen lined with a single layer of cuboidal or low columnar carcinoma cells and irregular protrusions and bulges, resembling DPM. At its border, the carcinoma seemed to replace the non-neoplastic hepatic lobules or regenerative nodules. The central parts of the tumor were variably hypocellular and fibrotic. Although these carcinomas were negative for mucin and HepParI, they were frequently positive for CK19, epithelial cell adhesion molecule, and epithelial membrane antigen. Neural cell adhesion molecule was also expressed variably. The Ki-67 labeling index was <10% and p53 was scarcely expressed. In conclusion, a new subtype of intrahepatic cholangiocarcinoma with predominant DPM pattern was identified.

Reappraisal of the Immunophenotype of Pancreatic Intraductal Papillary Mucinous Neoplasms (IPMNs)-Gastric Pyloric and Small Intestinal Immunophenotype Expression in Gastric and Intestinal Type IPMNs-.

Pancreatic intraductal papillary mucinous neoplasms (IPMNs) are mucin-producing neoplasms of the main and/or branch pancreatic ducts. To assess differences between various IPMN subtypes, immunohistochemical markers of gastric surface mucous cells (MUC5AC), gastric gland mucous cells (MUC6 and GlcNAcα1→4Galβ→R), gastric pyloric and duodenal epithelial cells (PDX1), intestinal cells (MUC2 and CDX2), small intestinal cells (CPS1) and large intestinal cells (SATB2) were evaluated in 33 surgically treated IPMNs. MUC2 expression classified IPMNs into gastric (n=17), intestinal (n=8) and mixed gastric and intestinal type (collision=7, composite=1). No differences in age or sex were observed among these types. MUC5AC and PDX1 were expressed in all IPMNs. MUC6 expression was higher in gastric and mixed types than in intestinal type. GlcNAcα1→4Galβ→R was detected in gastric and mixed type, but not in intestinal type. MUC2 and CDX2 expression were higher in intestinal type than gastric and mixed type. CPS1 expression was higher in intestinal type than gastric type. SATB2 was not observed in any IPMNs. Frequent abrupt transition between the two IPMN types in mixed-type IPMNs was observed. Gastric pyloric and small intestinal differentiation are characteristic of gastric and intestinal type IPMN, respectively, and these two IPMN types may have distinct pathogenesis.

Food allergy after cord blood transplantation in children

Delbini, P., Vaja, V., Graziadei, G., Duca, L., Nava, I., Refaldi, C. & Cappellini, M.D. (2010) Genetic variability of TMPRSS6 and its association with iron deficiency anaemia. British Journal of Haematology, 151, 281–284. Desmet, F.O., Hamroun, D., Lalande, M., CollodBeroud, G., Claustres, M. & Beroud, C. (2009) Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acid Research, 37, e67. De Falco, L., Totaro, F., Nai, A., Pagani, A., Girelli, D., Silvestri, L., Piscopo, C., Campostrini, N., Dufour, C., Al Manjomi, F., Minkov, M., Van Vuurden, D.G., Feliu, A., Kattamis, A., Camaschella, C. & Iolascon, A. (2010) Novel TMPRSS6 mutations associated with iron-refractory iron deficiency anemia (IRIDA). Human Mutation, 31, E1390–E1405. Finberg, K.E. (2009) Iron-refractory iron deficiency anemia. Seminars in Hematology, 46, 378–386. Finberg, K.E., Heeney, M.M., Campagna, D.R., Aydinok, Y., Pearson, H.A., Hartman, K.R., Mayo, M.M., Samuel, S.M., Strouse, J.J., Markianos, K., Andrews, N.C. & Fleming, M.D. (2008) Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nature Genetics, 40, 569–571. Nai, A., Pagani, A., Silvestri, L. & Camaschella, C. (2010) Increased susceptibility to iron deficiency of Tmprss6-haploinsufficient mice. Blood, 116 (5), 851–852.

Helicobacter heilmannii-like organism in parietal cells: A diagnostic pitfall.

To the Editor: Helicobacter heilmannii-like organism (HHLO) is the general term for Helicobacter species other than H. pylori found in human gastric mucosa. The prevalence of HHLO ranges from 0.1% to 0.6%. HHLO has been subclassified as H. heilmannii types 1 and 2. Type 1 is identical to H. suis, which colonizes the stomachs of pigs. Type 2 represents a group of species including H. felis, H. bizzozeronii, H. salomonis, and the previously named Candidatus H. heilmannii or H. heilmannii. As with H. pylori, HHLO infection induces chronic gastritis, peptic ulcer disease, and gastric mucosa-associated lymphoid tissue lymphoma. Thus, the detection and eradication of HHLO is important. Compared with H. pylori, HHLO is longer (3.5–7.5 μm), contains 6 to 8 coils per cell, has up to 12 sheathed flagella at each pole, and is present in small groups within mucous gel covering the gastric mucosa and in gastric pits without adhesion to surface mucous cells. Additionally, HHLO is found in the intracellular canaliculi of parietal cells. HHLO in the intracellular canaliculi of parietal cells cannot be detected with nonspecific histologic staining for Helicobacter. We herein present a case of gastritis associated with HHLO (H. suis, formerly designated H. heilmannii type 1) that was preferentially localized in parietal cells. A 40-year-old woman underwent upper gastrointestinal endoscopy for a medical checkup. Nodular gastritis was observed in the antrum. Regular arrangement of collecting venules (RAC) and fundic gland polyps were seen in the corpus. Histologic examination of the gastric antrum showed moderate mononuclear cell infiltration with large lymphoid follicles and slight neutrophil infiltration, without epithelial reactive changes common in H. pylori-related gastritis (Fig. 1a). Helicobacter pylori could not be identified on hematoxylin and eosin-stained sections (Fig. 1b). Immunostaining for H. pylori using an anti-H. pylori antibody (Dako, Carpinteria, CA, USA) was performed using the Histofine detection system (Nichirei Biosciences, Tokyo, Japan) with 3,3′-diaminobenzidine (DAB) as a chromogen. Before immunostaining, antigen retrieval was achieved by microwaving in 10 mmol/L citrate buffer (pH 6.0). This antibody is generated using the whole H. pylori bacterial extract as the antigen, and it exhibits cross-reactivity with HHLOs including H. suis. The cross-reactivity of anti-H. pylori antibody from a source different from that of H. suis is reportedly similar. The immunostaining showed dot-like or rod-like positive-staining structures only in parietal cells (Fig. 1c). However, the urea breath test (UBT) and H. pylori culture were negative. Four years later, without eradication therapy for H. pylori, the patient’s gastric mucosa showed an endoscopic appearance similar to the previous one. However, histopathologic examination of gastric antral biopsy specimens showed mild mononuclear infiltration in the lamina propria and long, tightly coiled bacteria in the mucous gel covering the gastric mucosa, in the gastric pits without adhesion to gastric epithelial cells (Fig. 2a), and within parietal cells. These bacteria were positive to anti-H. pylori antibody (Dako) (Fig. 2b). The size and shape of the bacteria were more consistent with HHLO than H. pylori. Transmission electron microscopic observation of paraffin-embedded biopsy tissues highlighted features of helical bacteria consistent with HHLO in the mucous layer (Fig. 2c). Immunoreactivity of parietal cells to anti-H+/K+-ATPase (proton pump) antibody (clone: 1H9, MBL, Nagoya, Japan) showed no differences between parietal cells with and without HHLO. A serum antibody test for H. pylori (Eiken Kagaku, Tokyo, Japan) was negative. Diagnosis of HHLO infection was made, and the patient was treated with 1 week of triple therapy comprising lansoprazole (60 mg/d), amoxicillin (1500 mg/d), and metronidazole (500 mg/d) according to the standard second-line protocol for eradication of H. pylori infection. Fifteen weeks after cessation of the first treatment, the patient’s gastric mucosa showed an endoscopic appearance similar to the pre-eradication one, and bacteria positive for anti-H. pylori antibody (Dako) were found in the gastric mucous gel, within the gastric pits, and within parietal cells. The patient was treated with 1 week of triple therapy comprising rabeprazole (40 mg/d), amoxicillin (1500 mg/d), and sitafloxacin (200 mg/d) according to the third-line protocol for eradication of H. pylori infection. Sixteen weeks after cessation of the second treatment, endoscopic examination showed a slight improvement in the nodular gastritis, and gastric mucosal biopsies showed no HHLOs as evaluated by histological examination and immunostaining with anti-H. pylori antibody (Dako). However, polymerase chain reaction (PCR) of the urease gene in the gastric lavage fluid revealed H. suis (formerly designated H. heilmannii type 1). Endoscopic evidence of nodular gastritis was still present 8 months later. Gastric mucosal biopsies showed mild mononuclear cell infiltration in the antrum and no HHLOs as evaluated by histology and immunostaining with anti-H. pylori antibody (Dako). Seven months later, endoscopic examination showed regression of the nodular gastritis, and gastric mucosal biopPathology International 2016; 66: 120–122 doi:10.1111/pin.12349 bs_bs_banner

Principal cells in gastric neoplasia of fundic gland (chief cell predominant) type show characteristics of immature chief cells.

To the Editor: In the normal gastric fundic mucosa, the digestive-enzymes secreting chief cells differentiate from mucous neck cells via the transdifferentiation route. Mucous neck cells possess MUC6 bearing GlcNAcα1→4Galβ→R structures specifically recognize by paradoxical Concanavalin A staining and monoclonal antibody HIK1083 (HIK1083 mAb), TFF2, which is a lectin binding with high specificity to O-linked α1,4-GlcNAc-capped hexasaccharides on gastric mucin, and pepsinogen I. Chief cells tend to lose MUC6 and TFF2

Large intestinal type-urachal adenocarcinoma with focal expression of prostatic specific antigen

We present a case of colonic‐type adenocarcinoma, which might arise from an urachal remnant through a villous adenoma. The cancer tissue in the present case showed focal immunoreaction to prostate‐specific antigen (PSA). This is the first report of urachal adenocarcinoma expressing PSA.

In vasculitis of small muscular arteries, activation of vessel-infiltrating CD8 T cells seems to be antigen-independent

The etiology of polyarteritis nodosa (PAN) and localized PAN is still unknown, although a T cell-mediated immune mechanism has been considered. CD8 T cells participate not only in the antigen-dependent adaptive immune system, but also in the antigen-independent innate immune system. Non-antigen-activated CD8 T cells express a unique phenotype: granzyme B (GrB) positive /CD25 negative /programmed death-1 (PD-1) negative. The aims of this study were to assess the participation of T cells, especially innate CD8 T cells, in the development of vasculitis. Twenty-eight consecutive cases of skin biopsy specimens with cutaneous vasculitis of small muscular arteries (CVSMA) were retrieved. The series comprises of 21 cases of cutaneous arteritis, three cases of PAN, and four cases of rheumatoid vasculitis. Cases of antineutrophil cytoplasmic antibody-associated vasculitis were excluded. The phenotypes of infiltrating lymphocytes in vasculitis lesions were evaluated by immunohistochemistry. In most cases of CVSMA, the number of CD8 T cells infiltrating the intima was higher than that of CD4 T cells, and significant numbers of GrB-positive cells, which represent activated CD8 T cells, were observed. However, GrB/CD25-double-positive cells, which correspond to antigen-activated T cells, were very few in a small number of cases. Cells positive for PD-1, which is also expressed on antigen-activated CD8 T cells, were not detected. We conclude that a T cell-mediated immune mechanism, involving cytotoxic CD8 T cells, may play a role in the development of CVSMA. Low expression of CD25 in activated CD8 T cells suggests that activation was antigen-independent.

Early-stage idiopathic mesenteric phlebosclerosis incidentally combined with adenocarcinoma of the ascending colon: A report of two cases

To the Editor: Idiopathic mesenteric phlebosclerosis (IMP) is a rare chronic disease that usually develops in the proximal colon. Since Koyama et al. reported the first patient with IMP in 1991, there have been less than 100 cases reported. Most cases have occurred in Asian countries. IMP is characterized by venous calcifications extending from the colon wall to the mesentery, thus causing chronic colonic ischemia due to venous return impairment. However, it has been reported that no definite calcification has been observed during the very early stage of IMP. The pathogenesis of IMP remains unclear; however, the long-term oral intake of herbal medicine, especially sanshishi, has been suggested to contribute to IMP onset. We report two cases of earlystage IMP incidentally combined with adenocarcinoma of the ascending colon. Both patients had a history of herbal medicine intake for several years. Case 1 was a 63-year-old woman who presented to Saku Central Hospital Advanced Care Center for investigation of fecal occult blood (FOB). She had a medical history of climacteric disorder. She did not report any abdominal symptoms. Computed tomography (CT) revealed a mass in the ascending colon. No lymph node or distal metastasis was observed. No definite calcification was found. Colon endoscopy revealed an ulcerative tumor in the ascending colon. No erosive or ulcerative lesion, discoloration, or edematous changes in the background colonic mucosa were observed. Therefore, colonic cancer was diagnosed and laparoscopic right hemicolectomy was performed. Case 2 was a 77-year-old woman who presented to Nagano Red Cross Hospital for investigation of melena, abdominal pain, and anemia (hemoglobin, 7.8 g/dL). CT revealed a mass in the ascending colon, and swelling of the regional lymph nodes was observed. No distal metastasis was detected. Scattered calcifications were found in the middle colic artery; however, characteristic calcification patterns such as serpentine calcification next to the colonic and mesenteric veins on CT scan and thread-like calcifications on abdominal radiography were not identified. Colon endoscopy revealed an ulcerative tumor in the ascending colon. No erosive or ulcerative lesion, discoloration, or edematous changes in the background colonic mucosa were observed. Therefore, she was diagnosed with colonic cancer and right hemicolectomy was performed. Histopathologically, in both cases, adenocarcinoma invading the subserosa was observed. In addition, marked fibrous thickening of the vascular wall and mild fibrosis were observed in the submucosa (Fig. 1a). Also, eosinophilic deposition was observed in the subepithelium and perivascular region (Fig. 1c). These findings were observed from the near part of the Bauhin valve to the anal side margin of the ascending colon in Case 1, and from the near part of the Bauhin valve to the anal side margin of the ascending colon but not in the appendix (Case 2). These lesions were negative for Congo red staining and stained green by Elastica-Goldner staining (Fig. 1b, d); therefore, we judged these lesions as collagen deposits. Furthermore, some small calcifications (approximately 1mm in diameter) of the vessel wall were observed in the mesenteric vein, therefore, adenocarcinoma (pT3N0M0) and IMP were diagnosed. After the histopathological diagnosis, we confirmed their medical history and found that the Case 1 patient was prescribed kamisyoyosan and kamikihito, which are herbal medicines containing sanshishi, for climacteric disorder for more than 10 years (detailed term was unknown), and the Case 2 patient was prescribed kamisyoyosan for approximately 32 years. Both patients stopped using these herbal medicines and have been followed-up without treatment for 1 year. Radiological diagnosis of early-stage IMP is quite difficult because it lacks definite calcification. IMP causes abdominal symptoms; however, IMP is often asymptomatic. Furthermore, the severity of mesenteric venous calcification is associated with the number of active symptoms (i.e., fever, abdominal pain, severe constipation, bowel obstruction, vomiting, or diarrhea). Therefore, patients may experience only mild clinical symptoms or may be asymptomatic, especially during the early stage, and they may not have visited the hospital. Thus, it is difficult to detect early-stage IMP using clinical findings, as was the case for our patients. Eleven combined cases of IMP and colonic cancer have been reported in the English and Japanese literature with an English summary. Summaries of these 11 cases and our two cases are shown in the Supporting Information (Supporting Table S1). Patients were predominantly female (10; 77%) and had a mean age of 72.7 years (range, 57–82). Of these, 12 had abdominal imaging findings. Six cases (50%) lacked the characteristic calcifications found during preoperative examination. All these patients

First pathological report of a de novo CD5-positive diffuse large B-cell lymphoma patient presenting with Guillain-Barré syndrome-like neuropathy due to neurolymphomatosis: Neurolymphomatosis and “CD5+” DLBCL

Peripheral neuropathy occurs in approximately 5% of the patients with lymphoma. Two major causes of peripheral neuropathy associated with lymphoma are neurolymphomatosis and paraneoplastic neuropathy such as demyelinating neuropathy. The differential diagnosis between neurolymphomatosis and demyelinating neuropathy is difficult, because electrophysiological findings suggestive of demyelination are frequently observed even in patients with neurolymphomatosis. Here, we report a patient with de novo CD5‐positive diffuse large B‐cell lymphoma (DLBCL) who presented with Guillain–Barré syndrome (GBS)‐like neuropathy. Demyelination due to paraneoplastic neuropathy was clinically suspected. However, autopsy demonstrated that the cause of the neuropathy was neurolymphomatosis. Clinical courses of neurolymphomatosis vary and neurolymphomatosis cases presenting with GBS‐like neuropathy are reported. In addition, DLBCL is the most frequent histological type of malignant lymphoma that develops neurolymphomatosis. Furthermore, “CD5‐positive” DLBCL may tend to develop neurolymphomatosis. If a patient with “CD5‐positive” DLBCL develops peripheral neuropathy, neurolymphomatosis should be considered and imaging studies performed and, if possible, nerve tissue biopsy, regardless of clinical symptoms of the neuropathy. To our knowledge, this is the first report of a patient with de novo CD5‐positive DLBCL with neurolymphomatosis who presented with GBS‐like neuropathy.

Myelodysplastic syndrome in an infant with constitutional pure duplication 1q41-qter

We report on a Japanese female infant as the fourth patient with the constitutional pure duplication 1q41-qter confirmed by chromosomal microarray and as the first who developed myelodysplastic syndrome (MDS) among those with the constitutional 1q duplication. Common clinical features of the constitutional pure duplication 1q41-qter include developmental delay, craniofacial characteristics, foot malformation, hypertrichosis, and respiratory insufficiency. The association between MDS and the duplication of the genes in the 1q41-qter region remains unknown.