Jun Miyauchi

Anaplastic large cell lymphoma in Japanese children: retrospective analysis of 34 patients diagnosed at the National Research Institute for Child Health and Development

Summary. This report presents a retrospective study of 34 Japanese children diagnosed at a single laboratory as having anaplastic large cell lymphoma (ALCL). Most of the pathological features of the Japanese ALCL children observed, such as anaplastic lymphoma kinase protein expression, in addition to most of the clinical characteristics and the outcomes of the patients, are very similar to those reported by European groups. To our knowledge, this is the first report describing the details of the clinicopathological features of Japanese ALCL patients. A further International study, including Japanese patients, might contribute to the establishment of an optimal treatment for paediatric ALCL.

Combined fibrolamellar carcinoma and cholangiocarcinoma exhibiting biphenotypic antigen expression: a case report

Fibrolamellar carcinoma (FLC), a variant of hepatocellular carcinoma (HCC), very rarely occurs in association with cholangiocarcinoma (CC). This report describes the first case of FLC coexisting with CC (FLC-CC) from Japan. Although the major part of the tumour located in the right lobe of the liver showed the typical features of FLC, CC was admixed with the FLC, not only in the primary hepatic tumour, but also in the lymph node metastases. Immunohistochemical analysis revealed that, although carcinoembryonic antigen (CEA), which can be detected with monoclonal antibodies in the cytoplasm and the cell surface of CC cells but not HCC cells, was expressed in only the CC cells in the primary tumour, it was expressed extensively in the cytoplasm of both CC and FLC cells in the metastatic and recurrent tumours. Furthermore, Hep Par 1, a hepatocyte specific antigen, was also expressed in both the FLC and CC cells. These findings suggest that, in this case, both FLC and CC were possibly derived from the same cancer stem cell with the capacity to differentiate into both hepatocytes and bile duct epithelium, and that both the cellular components, therefore, exhibited biphenotypic antigen expression.

Expression of Cyclin-dependent Kinase Inhibitor p27/Kipl and AP-1 Coactivator p38/Jabl Correlates with Differentiation of Embryonal Rhabdomyosarcoma

Cyclin‐dependent kinase (CDK) inhibitor p27/Kip1 (p27) is a diagnostic and prognostic marker of various malignancies. Low expression of p27 reflects poor differentiation and poor prognosis, and an inverse correlation between the expression of p27 and degree of tumor malignancy has been reported. Because p27 mutation is extremely rare in human tumors, it is important to study the expression of p27 and its inactivator, p38/Jab1 (JAB1). Here we analyzed the expression of p27 and JAB1 by immunohistochemistry in embryonal rhabdomyosarcoma (E‐RMS). We first confirmed the expression of p27 and JAB1 in normal human tonsillar epithelium, and observed a coordinated expression pattern depending on cell differentiation. Subsequently, specimens of eight poorlyand three well‐differentiated E‐RMS were examined for the expression of p27 and JAB1. The analyses revealed that four out of eight poorly‐differentiated E‐RMS were negative for p27, with positivity for nuclear JAB (NJAB) (‐ /± for p27/NJAB) in three and negativity for any JAB‐1 expression (‐ / ‐) in one. The remaining four poorly‐differentiated E‐RMS expressed p27 in the nuclei, together with predominant NJAB (±/±). In three well‐differentiated E‐RMS, only one expressed nuclear p27 and all of these three expressed no NJAB (±/ ‐ for p27/NJAB), but expressed predominant cytoplasmic JAB1 (CJAB). These findings suggest that JAB1 may play an important role in determining the differentiation stage of rhabdomyosarcoma cells by modulating the activity of CDK inhibitor p27.

Anaplastic carcinoma of the pancreas: Case report and literature review of reported cases in Japan

We report a case of a 64-year-old woman with anaplastic carcinoma of the pancreas (ACP) with cyst formation and review 60 ACP cases reported in Japan. In 20% of cases, laboratory tests revealed severe anemia (hemoglobin level < 10.0 g/dL) and elevated leucocyte counts (> 12000/mm3), which were likely attributable to rapid tumor growth, intratumoral hemorrhage, and necrosis. Elevated serum CA19-9 levels were observed in 55% of cases. Cyst-like structures were observed on imaging in 47% of cases, and this finding appears to reflect subsequent cystic degeneration in the lesion. Macroscopically, hemorrhagic necrosis was observed in 77% of cases, and cyst formation was observed in 33% of cases. ACP should be considered when diagnosing pancreatic tumors with a cyst-like appearance, especially in the presence of severe anemia, elevated leucocyte counts, or elevated serum CA19-9 levels.

Expression of megakaryocytic and myeloid markers in blasts of transient abnormal myelopoiesis in a stillbirth with Down syndrome: report of histopathological findings of an autopsy case.

Transient abnormal myelopoiesis in neonates with Down syndrome is an unusual leukemia that spontaneously regresses within several months of life and is thought to arise in the fetal liver. It is largely unknown how the leukemic blasts proliferate and differentiate in fetal tissues. We report the histopathological findings of an autopsy case of a stillbirth with transient abnormal myelopoiesis. Blood vessels in almost all organs were filled with immature leukemic cells, most of which expressed megakaryocyte antigen CD42b. In contrast, leukemic cells infiltrating the tissues, including the pericardium, expressed myeloperoxidase. These findings indicate that leukemic progenitors in transient abnormal myelopoiesis can differentiate along both megakaryocytic and myeloid lineages, which may be influenced by microenvironmental factors. Numerous dysplastic mature/immature megakaryocytes and blasts were present in the liver, whereas the bone marrow contained predominantly myeloid cells at various stages of differentiation, suggesting that the fetal liver is the major organ for proliferation of blasts in transient abnormal myelopoiesis.

Blasts in transient leukaemia in neonates with Down syndrome differentiate into basophil/mast‐cell and megakaryocyte lineages in vitro in association with down‐regulation of truncated form of GATA1

Mutations of GATA1, leading to aberrant expression of a truncated form of GATA1 (called GATA1s), are present in transient leukaemia (TL) in neonates with Down syndrome. Using these molecular markers of TL, we investigated the growth and differentiation potential of TL blasts in the presence of hematopoietic growth factors (HGFs). Interleukin‐3, stem cell factor and granulocyte‐macrophage colony‐stimulating factor potently stimulated the growth of TL blast progenitors and induced differentiation towards basophil/mast cell lineages, whereas thrombopoietin induced differentiation towards megakaryocytes. GATA1s was expressed in TL blasts in all five patients examined but was down‐regulated during differentiation induced by these HGFs, while full‐length GATA1 was not expressed throughout the culture. GATA1 mutations were detected in TL blasts in four patients, including one patient with two distinct mutations. The cells of this patient exhibited identical and only mutated sequences both before and after culture with HGFs, confirming the leukemic cell origin of these differentiated cells. Erythroid differentiation of TL blasts was not evident with any HGFs. These data indicate that TL blasts have the potential to grow and differentiate towards particular hematopoietic lineages in the presence of specific HGFs and that the down‐regulation of GATA1s might be involved in blast cell differentiation.

Histologic survey of neuroblastomas after intensive induction chemotherapy

Histology after intensive induction chemotherapy is expected to become a beacon indicating when and how extensively radical surgery and lymph node dissection should be performed in advanced neuroblastoma. A thorough histologic review of surgical specimens was undertaken.

Abnormalities of the p53 gene in juvenile myelomonocytic leukaemia

Juvenile chronic myelomonocytic leukaemia (JMML) is a rare myeloproliferative disorder of childhood. Fewer than 30% of cases of JMML terminate in a blast crisis; however, its molecular mechanism is unknown. Since mutation and/or deletion of the p53 gene has been reported to be associated with disease progression in a wide variety of human cancers, including adult‐type chronic myelogenous leukaemia, we studied the p53 gene in 20 patients with JMML (16 samples in chronic phase and seven at blast crisis). Exons 4–8 of the p53 gene, which cover all the hot spots of point mutations, were amplified by the polymerase chain reaction (PCR) method and subjected to mutation screening by single‐strand conformation polymorphism analysis. No mobility shift of single‐strand DNA of PCR products in polyacrylamide gel electrophoresis, indicating point mutations, was found in 19/20 patients. DNA of the remaining patient in the chronic phase failed to be amplified by PCR and Southern blot analysis with XbaI‐digested genomic DNA revealed a gross rearrangement (presumed deletion) of the p53 gene. These data indicate that abnormalities of the p53 gene are rare in JMML and not responsible for acute transformation, but could be involved in the pathogenesis of some cases of JMML.

Clinico-Pathologic Conference: Case 4

A 13-month-old Japanese boy presented with painless swelling in a left mandible and cheek. Intraoral examination revealed swelling in the left mandible and hemorrhage of oral mucosa due to biting. CT images revealed a wide osteolytic lesion of the left mandible with floating teeth. Biopsy was carried out and histopathological diagnosis was discussed.

Unusual chromaffin cell differentiation of a neuroblastoma after chemotherapy and radiotherapy: report of an autopsy case with immunohistochemical evaluations.

Neuroblastomas are derived from neural crest cells that are capable of multilineage differentiation. Ganglionic neuronal differentiation of childhood neuroblastoma is seen with increasing age, leading to more differentiated tumors called ganglioneuroblastomas or ganglioneuromas. Despite the fact that neuroblastomas most often arise from the adrenal medulla, chromaffin-cell differentiation in neuroblastomas is not widely recognized. Tumor cells with a chromaffin-cell nature have only been detected using histochemical techniques in neuroblastoma cell lines or focal areas of certain in vivo tumors. We describe a neuroblastoma that exhibited an unusual differentiation toward chromaffin cells in a patient that had been treated with surgery, intensive chemotherapy, and radiotherapy. Although a biopsy specimen of the retroperitoneal primary tumor was extensively necrotic, possibly because of a previous chemotherapy regimen, surgically resected metastatic tumors of bilateral ovaries were viable and diagnosed as poorly differentiated neuroblastomas according to the International Neuroblastoma Pathology Classification system. However, metastatic tumors of bilateral lungs examined at the time of autopsy exhibited histologic features similar to those of a pheochromocytoma/paraganglioma, and immunohistochemical examinations demonstrated that these tumors were composed of extra-adrenal chromaffin cells. This case confirms that neuroblastomas in childhood can transform into pheochromocytoma/paraganglioma-like tumors under special conditions.