Toshiko Yamochi-Onizuka

Disappearance of CD21-positive Follicular Dendritic Cells Preceding the Transformation of Follicular Lymphoma: Immunohistological Study of the Transformation Using CD21, p53, Ki-67, and P-glycoprotein

Some follicular lymphomas histologically transform into diffuse aggressive lymphomas, the prognosis of which is poor. There are, however, no reliable histological criteria for predicting which cases will later undergo such transformation. In low-grade B-cell lymphomas, follicular dendritic cells form dense mesh-like networks that contain accumulating neoplastic B-cells. These are rare in high-grade lymphomas. We immunohistochemically analyzed CD21-positive follicular dendritic cells in 32 follicular lymphomas, including 3 transformed lymphomas, in addition to immunohistological study using P-glycoprotein, p53, and Ki-67. We found that the mesh-like networks in follicles are more clearly defined in low-grade lymphomas than in high-grade lymphomas (p = 0.015). Neoplastic follicles in 2 transformed lymphomas lost the networks of follicular dendritic cells before transformation despite the existence of morphologically clear follicles. This differed from the non-transformed cases of the same cytological grades. Prognosis was statistically better for patients with low-grade tumor than for those with high-grade tumor (p = 0.026), and there was a trend toward poorer survival among CD21-negative cases (p = 0.186). P-glycoprotein, p53, and Ki-67 expressions did not provide sufficient information to predict the transformation of follicular lymphoma. The presence of CD21-positive follicular dendritic cells in neoplastic follicles might help predict the potential of follicular lymphoma to transform to diffuse large B-cell lymphoma.

Senile EBV-associated B-cell lymphoproliferative disorder of indolent clinical phenotype with recurrence as aggressive lymphoma

Senile EBV‐associated B‐cell lymphoproliferative disorder (LPD) was proposed as a new disease entity in 2003. This condition has a high incidence in elderly people without underlying immunodeficiencies, and is characterized by EBV‐positive B‐cell proliferation with a polymorphic composition. Histologically, the disease has two subtypes. The polymorphic LPD (PLPD) subtype has a preferable prognosis, whereas the large cell lymphoma (LCL) subtype involves aggressive disease progression. Reported herein is a case of senile EBV‐BLPD with indolent clinical features and PLPD subtype in the initial phase that recurred as an aggressive lymphoma 3 years after the initial diagnosis. In the recurrent phase, Southern blotting confirmed monoclonal proliferation of large lymphoid B‐cells. In both the initial and recurrent phases, polymerase chain reaction (PCR) yielded a single discrete band of a similar size due to an immunoglobulin heavy‐chain gene rearrangement, indicating that the large lymphoid B‐cells retained identical monoclonality throughout the histological progression and over the whole clinical course. These results suggest that the PLPD subtype is a histological finding in early phase senile EBV‐BLPD and that the LCL subtype reflects the progressive phase of the disease.

Autopsy case of CD4/CD8 cutaneous T-cell lymphoma presenting disseminated pagetoid reticulosis with aggressive granulomatous invasion to the lungs and pancreas.

Pagetoid reticulosis is a rare cutaneous T‐cell lymphoma with striking epidermotropism similar to that present in Pagets disease. There are two forms of pagetoid reticulosis: localized and disseminated. Reported herein is an autopsy case of disseminated pagetoid reticulosis with CD4–/CD8– phenotype T cells and massive invasion of the lungs and pancreas. The abnormal cells in the epidermis expressed a protein derived from a rearranged T‐cell receptor β gene, and this feature was used to confirm the monoclonality of these cells by polymerase chain reaction. At present, the World Health Organization (WHO) classification system considers pagetoid reticulosis to be an indolent form of primary cutaneous T‐cell lymphoma and a variant of mycosis fungoides/Sézary syndrome with prominent epidermotropism. Some differences have been observed between pagetoid reticulosis and mycosis fungoides in terms of clinical course, tumor cell phenotype, and genetic findings; and these differences are highlighted in the present case. The relation between disseminated pagetoid reticulosis,  CD4–/CD8–  cutaneous  T‐cell  lymphoma,  and γδ  T‐cell lymphoma, including whether pagetoid reticulosis is a variant of mycosis fungoides, remains unclear.

Clinicopathological comparison of the World Health Organization/Wotherspoon score to the Groupe d’Etude des Lymphomes de l’Adult grade for the post‐treatment evaluation of gastric mucosa‐associated lymphoid tissue lymphoma

Background and Aim:  The World Health Organization (WHO) has adopted criteria for the histological differential diagnosis of gastric extranodal marginal zone B‐cell lymphoma of mucosa‐associated lymphoid tissue (GML) based on the criteria proposed by Wotherspoon in 1993 (WHO/Wotherspoon score). These histological criteria are commonly used by pathologists for initial diagnoses, but have not been adopted uniformly for the post‐treatment evaluation of GML. In 2003, the Groupe d’Etude des Lymphomes de l’Adult (GELA) proposed a new histological grading system (GELA grade) in preference to use of the WHO/Wotherspoon score for post‐treatment evaluation. In the present study, we compared the WHO/Wotherspoon and GELA systems to examine which histological criterion is better for post‐treatment evaluation.

CD20 gene deletion causes a CD20-negative relapse in diffuse large B-cell lymphoma.

In diffuse large B‐cell lymphoma (DLBCL), a CD20‐negative relapse is clinically significant because it is associated with chemo‐refractory phenotypes and loss of a therapeutic target. The alteration of the CD20 gene is reported as infrequent in CD20‐negative relapse in B‐cell lymphoma. We established a DLBCL cell line with loss of CD20 expression (SD07) from a patient at CD20‐negative relapse. She was initially diagnosed with CD20‐positive DLBCL and received repeated immuno‐chemotherapy that included rituximab. SD07, which has an immunoglobulin κ rearrangement identical to that of lymphoma cells at CD20‐negative relapse, showed homozygous deletion of the CD20 gene with loss of the copy number of 11q12. SD07 is the first case in which it is proven that the loss of CD20 expression in relapsed DLBCL is the result of deletion of the CD20 gene. Deletion of the CD20 gene is a molecular mechanism of CD20‐negative relapse in a subset of DLBCL.

Discordant lymphoma: MALT lymphoma of the stomach and follicular lymphoma of the parotid gland

More than one histological type of malignant lymphoma can occur simultaneously in an individual. The entity is classified as either composite or discordant lymphoma. Both types of lymphoma, particularly discordant lymphoma comprised of extranodal marginal zone B‐cell lymphoma of mucosa‐associated lymphoid tissue lymphoma (MALT‐L) and follicular lymphoma (FL), are rare. We report a case of discordant lymphoma comprising MALT‐L in the stomach and FL in the parotid gland. The patient was a 50‐year‐old Japanese woman who visited the University Hospital of Showa (Tokyo, Japan) because a barium study showed erosive gastric lesions. A gastro‐intestinal endoscopy was performed 2 months after the barium study, which showed irregular erosions throughout the stomach body. A gastric biopsy showed MALT‐L, and Helicobacter pylori (H. pylori) infection was confirmed. The patient had noticed a painless and elastic hard tumor mass of about 2 cm in diameter in the area of the left parotid gland 6 months before the barium study. We removed the parotid gland tumor and diagnosed it as FL 6 months after the barium study. We were able to diagnose the MALT‐L and FL by morphological, immunohistochemical and molecular analyses of paraffin‐embedded sections. This appears to be the first reported case of MALT‐L and FL occurring together as a discordant lymphoma.

Over-expression of CCL3 MIP-1α in a blastoid mantle cell lymphoma with hypercalcemia

We analyzed a case with the blastoid variant of mantle cell lymphoma (MCL‐BV), a rare subtype of B‐cell lymphoma, presenting with marked hypercalcemia at diagnosis. Enzyme‐linked immunosorbent assay (ELISA) showed elevated serum levels of interleukin‐6 (IL‐6), tumor necrosis factor‐α (TNF‐α), macrophage inflammatory protein‐1α (MIP‐1α), and type I collagen telopeptide, but not parathyroid hormone, calcitriol or parathyroid hormone‐related peptide at diagnosis, suggesting local osteoclastic hypercalcemia in this case. By reverse transcription polymerase chain reaction (RT‐PCR) analysis, we found predominant expression of mRNA for MIP‐1α in addition to those for receptor‐activator of nuclear‐factor kappa B ligand (RANKL), TNF‐α, and IL‐6 in lymphoma cells obtained from the patient. Furthermore, recombinant MIP‐1α significantly stimulated 3H‐thymidine uptake by isolated MCL cells in vitro. Treatment with intravenous fluids, bisphosphonate, and methylprednisolone followed by combination chemotherapy promptly corrects the hypercalcemia and successfully induced complete remission, which was accompanied by a decrease of these cytokines in the serum, including MIP‐1α. In the present case, MIP‐1α, an osteoclast‐activating factor produced by mantle lymphoma cells, may contribute to the development of hypercalcemia. It likely acts through RANKL expression in tumor cells and/or stroma cells, as indicated in multiple myeloma (MM) and adult T‐cell leukemia/lymphoma (ATLL). Furthermore, MIP‐1α is also involved in the development of an aggressive phenotype on MCL by stimulating proliferation of these lymphoma cells. In summary, the present study demonstrated that MIP‐1α is an important factor in the development of both hypercalcemia and an aggressive phenotype in some types of B‐cell lymphoma.

A case of Degos disease: demonstration of C5b-9-mediated vascular injury

Abstract A 68-year-old Japanese male presented with atrophic erythematous white lesions with peripheral dark reddish rims on his back. Multiple ulcers were detected from his stomach to his large intestine using endoscopy. Although the patient was given high doses of a steroid, aspirin, dipyridamole, and intravenous immunoglobulin therapy, he died of gastrointestinal hemorrhage, perforation and septic shock. An autopsy examination revealed pauci-inflammatory thrombotic microangiopathy with endothelial cell injury, fibrous occlusive arteriopathy, and vascular C5b-9 deposition in the wall of the gastrointestinal tract from the esophagus to the large intestine as well as in the dermis of the skin.

p53 Protein Expression in Chronic Myelomonocytic Leukemia-1 Correlates with Progression to Leukemia and a Poor Prognosis

CMML-1 is controversial. Herein, we performed a retrospective study of the clinical features of patients with CMML-1 in a single institution. In our institution, 20 patients with CMML-1 reclassified retrospectively based on the WHO (2008) criteria and diagnosed as having CMML based on the FAB or WHO (2001) classification were included in this study. Rearrangement of PDGFRA or PDGFRB was excluded in case of eosinophilia. Our series excluded cases of secondary CMML associated with therapy-related MDS/AML. Patients were followed up from 1996 to 2008. Mutational analysis was performed on DNA from BM cells from the study participants. All samples were obtained with informed consent, and the protocols were approved by our institution’s ethics committee. The clinical characteristics and laboratory data were determined by a review of medical records. Laboratory and physical examination data of all patients were obtained at diagnosis. BM aspiration and biopsy samples were taken and analyzed at diagnosis and at the time of transformation to AML. Chromosomal analyses of BM cells were performed by G-banding techniques. Hydroxyurea was used as a cytoreductive drug in some of the CMML patients. After the Chronic myelomonocytic leukemia (CMML) is characterized by persistent monocytosis and by features of a myeloproliferative neoplasm and a myelodysplastic syndrome (MDS). CMML is subdivided into CMML-1, with

Elevation of carcinoembryonic antigen coinciding with disease activity of ulcerative colitis.

We report on three cases of ulcerative colitis who presented with increased levels of serum carcinoembryonic antigen (CEA) during the active stage. All cases were pancolitis with a moderate to severe disease course. After remission induction with medical therapies, serum CEA levels decreased to the normal reference range. Immunohistochemical analyses demonstrated the existence of CEA not only along with the apical surface of the colonic epithelia but also at the cytosol of the inflamed epithelia where goblet cells were depleted during the active stage. We speculate that CEA was up-regulated by inflammatory response particularly in the process of epithelial regeneration.