Eisuke Shiozawa

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.

MmTRA1b/phospholipid scramblase 1 gene expression is a new prognostic factor for acute myelogenous leukemia

We previously found that expression of the Mm-1 cell-derived transplantability-associated gene 1b (MmTRA1b)/phospholipid scramblase 1 gene was markedly induced during the granulocytic differentiation of human myeloid leukemia cells. To evaluate the role of MmTRA1b expression in human myeloid leukemia, we investigated the relative levels of MmTRA1b transcripts in 81 patients with acute myelogenous leukemia (AML) by the reverse transcriptase polymerase chain reaction. The expression of MmTRA1b in AML-M1, -M5a and -M5b was significantly lower than that in normal bone marrow cells. The levels of MmTRA1b expression in AML-M2 and -M4 varied among patients. Higher MmTRA1b mRNA levels were associated with significantly longer overall survival in AML, especially in AML-M4 patients, independent of chromosomal aberrations such as t(8;21) and inv(16). The present results suggest that the MmTRA1b mRNA level is a new prognostic factor for AML, especially the AML-M4 subtype.

Eosinophilic Gastroenteritis due to Cow’s Milk Allergy Presenting with Acute Pancreatitis

Eosinophilic gastroenteritis (EGE) is characterized by eosinophilic infiltration of the digestive organs, most commonly of the stomach and the duodenum. Symptoms of EGE are nonspecific and include nausea, vomiting, abdominal pain, dyspepsia, malabsorption, ascites and weight loss. The various symptoms of EGE depend on its location and the depth of gastrointestinal eosinophil infiltration. We report a case presenting with acute pancreatitis caused by a milk allergy. The patient’s symptoms rapidly improved after treatment with corticosteroids, and he remained symptom-free for more than 20 months by the elimination of cow’s milk from his diet. Serum titers of pancreatic enzymes and total bilirubin simultaneously recovered and blood eosinophil counts normalized. The causative allergens of EGE are too various to detect; however, allergologic exams revealed that a cow’s milk allergy had provoked EGE in our case. Adult-onset cow’s milk allergies are rare; when seen, however, they may present severe complications such as anaphylaxis, gastroenteritis and pancreatitis. When unaccountable gastrointestinal symptoms are observed, EGE caused by food allergies should be included in the differential diagnosis.

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.

CD200 Expression on Plasma Cell Myeloma Cells is Associated with the Efficacies of Bortezomib, Lenalidomide and Thalidomide

Plasma cell myeloma (PCM) is a devastating disease with a highly heterogeneous outcome, with survival ranging from a few months to longer than 10 years. Treatment of multiple myeloma has changed markedly in the past decade due to the development of new drugs such as bortezomib, lenalidomide and thalidomide, which have greatly improved the outcome of PCM. The clinical and prognostic value of immunophenotyping in PCM remains questionable. The aim of this study was to determine the diagnostic and prognostic significance of CD200 expression in newly diagnosed PCM. We retrospectively reviewed the records of 107 patients newly diagnosed with PCM at Showa University Hospital between January 2004 and September 2013. Expression of CD200 was studied by immunohistochemistry. Clinical and pathological parameters were compared between CD200-positive and CD200-negative cases. CD200-positive PCM cases had lower serum albumin (p = 0.0001) compared to those without CD200 expression. Our results showed no significant difference in median overall survival between patients with CD200-positive and CD200-negative PCM. However, there was a strong correlation between CD200 expression and serum albumin level. In the CD200-negative group, median overall survival was significantly longer in patients who received new drug treatment. These findings suggest that CD200 expression is a useful marker for evaluation of the severity of PCM and that lack of CD200 expression may improve the sensitivity of PCM to therapy with new drugs.

Immunohistochemical CD73 expression status in gastrointestinal neuroendocrine neoplasms: A retrospective study of 136 patients

The WHO 2010 classification divides gastrointestinal neuroendocrine neoplasms (GI-NENs) into neuroendocrine tumor (NET) G1, NET G2, neuroendocrine carcinoma (NEC) and mixed adenoendocrine carcinoma (MANEC) groups. A total of 136 cases of GI-NENs diagnosed at our hospitals as gastrointestinal carcinoids, endocrine cell carcinomas and NENs over the last 11 years, using the WHO 2010 classification were assessed. Among the 136 cases, 88.2% (120/136) were classified into the NET group (NET G1/G2) and 11.8% (16/136) were classified into the NEC group (NEC/MANEC). The incidences of lymphatic and venous invasions were higher in the NEC group compared with in the NET group (P<0.0001 and P=0.0021, respectively). The immunohistochemical staining of cluster of differentiation 73 (CD73) was evaluated in GI-NENs. CD73 is a potentially useful molecule in tumor immunity. In general, CD73 on the tumor cell membrane converts adenosine monophosphate to adenosine, which restrains the production of interferon-γ and cytocidal activity. Although the association between stem cells of pancreatic NENs and CD73 has been reported, few studies have reported on CD73 expression in GI-NENs. Immunohistochemical CD73 expression on the cytomembrane of neuroendocrine cells was detected in 27.2% (37/136) of the GI-NENs. The positive ratio of CD73 was significantly higher in the NEC group compared with in the NET group (P=0.0015). CD73 is also considered as a potential biomarker of anti-programmed death-1 (PD-1) therapy. The expression of programmed death-ligand 1 (PD-L1) on the cytomembrane of GI-NENs was assessed. The positive ratio of PD-L1 was higher in the NEC group compared with in the NET group (P=0.0011). Furthermore, CD73 expression status was significantly correlated with PD-L1 expression (P<0.0001). These results indicate that CD73 may be an interesting candidate for a biomarker for certain prognostic factors and therapeutics concerning PD-1 therapy.