Clinical impact and characteristics of erythroid dysplasia in adult aplastic anaemia: Results from a multicentre registry.

Morphological dysplasia in haematopoietic cells, defined by a 10% threshold in each lineage, is one of the diagnostic criteria for myelodysplastic neoplasms. Dysplasia limited to the erythroid lineage has also been reported in some cases of aplastic anaemia (AA); however, its significance remains unclear. We herein examined the impact of erythroid dysplasia on immunosuppressive therapy responses and survival in AA patients. The present study included 100 eligible AA patients without ring sideroblasts. Among them, 32 had dysplasia in the erythroid lineage (AA with minimal dysplasia [mini-D]). No significant sex or age differences were observed between AA groups with and without erythroid dysplasia. In severe/very severe AA and non-severe AA patients, a response to anti-thymocyte globulin + ciclosporin within 12 months was observed in 80.0% and 60.0% of AA with mini-D and 42.9% and 90.0% of those without dysplasia, with no significant difference (p = 0.29 and p = 0.24 respectively). Overall survival and leukaemia-free survival did not significantly differ between the groups. Collectively, the present results indicate that the presence of erythroid dysplasia did not significantly affect clinical characteristics or outcomes in AA patients, suggesting that its presence in AA is acceptable. Therefore, erythroid dysplasia should not exclude an AA diagnosis.

Coincidence of de novo T-lymphoblastic lymphoma and cutaneous gamma/delta peripheral T-cell lymphoma.

The coincidence of acute T-lymphoblastic leukemia/lymphoma, NOS (T-ALL/LBL), and peripheral T-cell lymphoma (PTCL) is unusual, and there have only been a few cases of their metachronous occurrence. In these cases, PTCLs emerged as recurrence after primary therapy for primary T-ALL, were the rare gamma/delta type, and uncommonly involved skin for T-ALL/LBL. We herein report the first case of de novo T-LBL that coincided with cutaneous gamma/delta PTCL before primary therapy. A 70-year-old man presented with systemic lymphadenopathy. Lymph node biopsy revealed a massive proliferation of lymphoblastoid cells; immunohistochemically, they were positive for TdT/CD1a/CD99, and cytoplasmic CD3ε, CD4, and CD8 and were negative for T-cell receptor (TCR) ßf-1. A few TCRδ-positive cells were intermingled. Atypically, TIA was focally positive, whereas granzyme/perforin was negative. Multiple papules and plaques emerged on the trunk before the initiation of treatment for T-LBL. Skin biopsy revealed a massive proliferation of medium-to-large atypical lymphoid cells that were TdT/CD1a-negative mature T-cells; they were negative for TCRßf1 and CD4, and positive for TCRδ, CD5, CD8, CD56, TIA, granzyme B, and perforin. A conventional PCR analysis of TCRG showed no identical clonal band between the two tumors. The skin lesion was diagnosed as cutaneous gamma/delta T-cell lymphoma. Whether the lesion was primary or a transformation of T-LBL was unclear. After treating with reduced hyper-CVAD/MA targeting T-LBL, molecular complete remission was achieved. When an uncommon cutaneous lesion emerges in the course of T-ALL/LBL, both need to be evaluated pathologically and genetically, whether de novo or recurrent, assuming the possibility of coincident gamma/delta PTCL.

[Thoracic SMARCA4-deficient undifferentiated tumor resembling malignant lymphoma].

We present a case of thoracic SMARCA4-deficient undifferentiated tumor that needed to be differentiated from malignant lymphoma owing to multiple lymph node swelling and marrow involvement. A 52-year-old man developed multiple lymphadenopathies along with anorexia, general fatigue, fever, and sweating 2 months prior to admission. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scan revealed a mass lesion on the right upper lung, generalized lymph node swelling, and bone metastasis, indicating the presence of suspicious lung cancer; therefore, he was referred to our hospital. Malignant lymphoma was suspected at the time of admission because of elevated levels of lactate dehydrogenase (11,977 U/l) and soluble interleukin 2 receptor (2,152 U/ml) as well as marrow infiltration of large abnormal cells. On day 11, the patient died from rapid respiratory failure. Histological and immunohistochemical features of the pleural effusion cell block led to the diagnosis of thoracic SMARCA4-deficient undifferentiated tumor. Thoracic SMARCA4-deficient undifferentiated tumor was recently introduced in the 2021 World Health Organization classification of lung tumors, with most patients being young adults with a history of heavy smoking and poor prognosis. Because of the multiple lymph node swelling and marrow involvement, this undifferentiated tumor should be distinguished from malignant lymphoma.

Diagnostic utility of the aberrant immunohistochemical expression of CD3 molecules for peripheral T-cell lymphomas.

The histological diagnosis of peripheral T-cell lymphomas (PTCLs) is often challenging. Flow cytometry (FCM) sometimes shows the loss of pan-T-cell markers for PTCLs, suggesting the neoplastic nature of these cells. Immunohistochemically, the total loss of pan-T-cell markers has been demonstrated in PTCLs. Furthermore, except for the total loss, the aberrant immunohistochemical expressions of pan-T-cell markers have also been empirically observed in PTCLs, but the details remain unexamined. Therefore, the present study semi-quantitatively evaluated the aberrant expression of cytoplasmic CD3ε (cCD3ε), the most common immunohistochemical pan-T-cell marker, in 91 PTCL cases. The expressions of the other CD3 molecules, CD3δ, CD3γ, and CD3ζ were also examined. Frequencies of the total immunohistochemical loss of CD3 molecules and loss of surface CD3ε (sCD3ε) in FCM were analyzed for comparison. The results showed atypical, aberrant expression patterns for immunohistochemical CD3 molecules: perinuclear, cytoplasmic, membranous, and partial negative. The frequency of each molecule was as follows: cCD3ε 40.7 %, CD3δ 26.4 %, CD3γ 53.8 %, and CD3ζ 54.9 %, especially the latter two showed high frequency in peripheral T-cell lymphoma, not otherwise specified, angioimmunoblastic T-cell lymphoma, and adult T-cell lymphoma/leukemia. Immunohistochemical total loss was less than aberrant expression in all CD3 molecules, with the frequency of cCD3ε being the lowest (6.6 %). The loss of sCD3ε in FCM was observed in 43.3 % of cases, with a similar frequency to the aberrant expression of cCD3ε. In conclusion, the aberrant immunohistochemical expression of cCD3ε was a useful finding as is sCD3ε loss in FCM, but CD3γ and CD3ζ were more useful, facilitating the diagnosis of PTCLs.

Paravertebral extramedullary hematopoiesis in a case of myelodysplastic syndrome with ring sideroblasts and an SF3B1 mutation.

We present the case of a 56-year-old male patient with paravertebral extramedullary hematopoiesis (EMH) secondary to myelodysplastic syndrome with ring sideroblasts and multilineage dysplasia. In a routine health checkup over 5 years prior, he presented with asymptomatic mild anemia and a posterior mediastinal mass. Pathological and cytomorphological findings of the resected paravertebral mass were similar to those of his bone marrow specimen, and included cellularity with erythroid hyperplasia, multilineage dysplastic changes, and the presence of ring sideroblasts. A concordant SF3B1 mutation was detected in both bone marrow and paravertebral mass samples, suggesting that the EMH cells were derived from the bone marrow.

Bendamustine-induced rash is associated with a favorable prognosis in patients with indolent B-cell lymphoma.

Bendamustine is now recognized as a key drug for indolent B-cell lymphoma (iBCL), mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Skin toxicity associated with bendamustine is one of the characteristic adverse effects. We retrospectively examined the relationship between bendamustine-associated drug rashes and disease prognosis of iBCL and MCL at our institution. Between January 2011 and August 2019, 65 patients (39 men and 26 women, median age 68, range 41-84 years) were treated with bendamustine alone (n=11, 120 mg/m2 on days 1 and 2) or a combination of rituximab and bendamustine (n=54, 90 mg/m2 on days 1 and 2). Of these patients, 47 had follicular lymphoma (FL), 10 had MCL and 8 had other iBCLs. Drug rash occurred in 27 (41.5%). Eight cases (29.6%) were grade 1, 5 (18.5%) were grade 2 and 14 (51.9%) were grade 3. The onset was in the first course in 17 (63.0%), 2nd course in 5 (18.5%), 3rd course in 2 (7.4%), 4th course in 1 (3.7%) and 5th course in 2 (7.4%). No treatment was administered in 1 case (3.7%), topical steroid was applied in 10 (37.0%), antiallergic drug was administered in 2 (7.4%), topical steroid and antiallergic drug were administered in 5 (18.5%), and oral and topical steroid and antiallergic drug were administered in 9 (33.3%). The 3-year progression-free survival (PFS) and overall survival (OS) in patients with rash development were 80.0% and 85.5%, respectively, and those in patients without development were 36.4% and 54.0%, respectively (p=0.009 and 0.02, respectively). By multivariate analysis, the development of rash was associated with a better PFS and a diagnosis of iBCL was associated with a better OS. This study revealed that bendamustine-induced rash is associated with a favorable prognosis among patients with iBCL.

Lethal macrophage-related complications of juvenile myelomonocytic leukemia with a blastic crisis: an autopsy case report.

For hematopoietic stem cell transplantation to be successful, complications must be managed. Graft-versus-host disease is particularly important, but various other complications, treatment side effects, and relapse of primary disease may also occur. We report an autopsy case of juvenile myelomonocytic leukemia with a blastic crisis, in which activated and recovered autologous macrophage-related complications after cord blood transplantation caused the patient's death. Pathological analysis of autopsy specimens revealed diffuse infiltration of mature macrophages into the skin but scarce lymphocytes. These macrophages were found in the bone marrow interspersed with a small number of blasts that had previously occupied about 60% of the bone marrow before death. The direct cause of death was an opportunistic airway infection due to bone marrow and immune failures triggered by overactivation and proliferation of macrophages. Genetic analysis showed the activated macrophages were autologous. Together these findings indicate that the patient died from macrophage-mediated complications, but not from a blastic crisis or conventional graft-versus-host disease. When macrophage activation persists after hematopoietic stem cell transplantation, macrophage-mediated complications should be considered as a differential diagnosis. To manage this complication, pathology specimens should be examined to check for the presence of effector cells at an early stage.

Chronic Enteropathy Associated with SLCO2A1 with Pachydermoperiostosis.

A 49-year-old man complained of chronic palpitation and shortness of breath, which had recently become exacerbated. A blood examination indicated severe refractory anemia and hypoproteinemia. Physical examinations revealed anemia, a systolic murmur, and spoon nails. Multiple nonspecific ileal ulcers were observed. A pathological examination indicated a small granuloma with CD68-positive histiocytes. He had a deeply wrinkled forehead, chiseled face, and clubbed fingers. Radiography revealed periostosis of the fingers and long bones in the limb. He was diagnosed with pachydermoperiostosis. SLCO2A1 demonstrated a c.1807C>T homo-mutation. He was also diagnosed with SLCO2A1-associated chronic enteropathy and thus was treated with 5-aminosalicylic acid, which temporarily improved the ileal ulcers, anemia, and hypoalbuminemia.

Pulmonary intravascular large B-cell lymphoma accompanying synchronous primary pulmonary adenocarcinoma and benign interstitial lesions.

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma, and initial or predominant presentation in the lungs is uncommon. The synchronous occurrence of IVLBCL and malignant tumors is less frequent, and no such reports have described pulmonary presentations. We report a rare case of pulmonary IVLBCL accompanying lung cancer and interstitial lesions. A 73-year-old man with a history of pneumonia underwent a follow-up examination. Computed tomography revealed diffuse, bilateral ground-glass opacities (GGO) with a partial solid mass. Histologically, the mass consisted of adenocarcinoma. However, two other types of interstitial lesions were scattered throughout the resected lung: 1) peribronchovascular thickening with the aggregation of macrophages and anthracosis, and 2) alveolar septal thickening in the centrilobular area with atypical CD20-positive large cells in the capillaries. These two types of lesions were not mixed. Computed tomography and positron emission tomography demonstrated no other organ involvement. The patient was considered to have the synchronous occurrence of pulmonary IVLBCL and lung cancer (adenocarcinoma). After R-CHOP therapy, GGO on CT disappeared. Lung cancer often accompanies benign background lesions, and the combination of these lesions with lung cancer may make it difficult to detect the presence of pulmonary IVLBCL. However, the histological distribution pattern of IVLBCL may be a clue to the correct diagnosis.

Serum ferritin levels at diagnosis predict prognosis in patients with low blast count myelodysplastic syndromes.

Serum ferritin, a marker of systemic iron status, is considered a prognostic factor for patients with myelodysplastic syndromes (MDS), despite the lack of supporting evidence. We investigated the association between serum ferritin levels at diagnosis and the prognoses of Japanese MDS patients with bone marrow blasts < 5% and peripheral blood blasts < 2%. Three hundred and ninety patients with cytopenia were registered prospectively in the multicenter database, among whom 107 patients with MDS (72 males and 35 females, with a median age of 70 years) met the eligibility criteria. The median serum ferritin level at diagnosis was 204 ng/mL; we divided the cohort into low (n = 56) and high (n = 51) ferritin groups using a cutoff of 210 ng/mL. Kaplan-Meier analyses revealed that the 3-year overall survival (OS) of the high ferritin group was significantly shorter than that of the low ferritin group (66% and 79%, respectively). The cumulative incidences of leukemic progression were similar between the groups. On multivariate analysis, age, blast percentage, cytogenetic abnormalities, and serum ferritin levels at diagnosis were independently associated with OS in our patients. Thus, modest elevations of ferritin levels at diagnosis may influence the prognoses of patients with MDS who have low blast counts.

Molecular association of functioning stroma with carcinoma cells in the ovary: A preliminary study.

The cancer stroma serves an important role in tumour behaviours, including invasion, metastasis, and response to chemotherapy. The stroma of ovarian carcinoma is sometimes specialized, with luteinisation and/or hyperthecosis, and is designated as the 'functioning stroma' because it exerts endocrine function and produces sex steroid hormones. In the present study, 14 ovarian cancers with functioning stroma, comprising 7 endometrioid carcinomas and 7 clear cell carcinomas, were analysed to evaluate the molecular association of the functioning stroma with carcinoma cells. The median age of the patients was 67 years (range, 52-85 years); 13 patients were postmenopausal, and one was in perimenopause. Serum oestrogen values ranged from 10 to 129 ng/ml, with a median of 51 ng/ml. Sequence abnormalities in AT-rich interaction domain 1A (ARID1A), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA), Kirsten rat sarcoma viral proto-oncogene (KRAS) and phosphatase and tensin homolog (PTEN) were examined in whole tumours. For cancers positive for sequence abnormalities, their localization in carcinoma cells and/or stromal cells was examined. A total of 8 mutations - ARID1A (L2155L), PIK3CA (H1047R), KRAS (Q12V, E31K, Q61L), and PTEN (C105fs*8) - were identified in the whole tumours of 5 patients. Seven of these eight mutations were detected only in carcinoma cells. However, one case of endometrioid carcinoma had a KRAS (E31K) mutation in both carcinoma and stromal cells. In conclusion, although functioning stromal cells of ovarian cancer are usually thought to be non-neoplastic, some may share an origin with carcinoma cells.

Epstein-Barr virus-associated hemophagocytic syndrome in a patient with ulcerative colitis during treatment with azathioprine: A case report and review of literature.

A 19-year-old female was diagnosed with ulcerative colitis when she presented with persistent melena, and has been treated with 5-aminosalicylic acid for 4 years, with additional azathioprine for 2 years at our hospital. The patient experienced high-grade fevers, chills, and cough five d prior to presenting to the outpatient unit. At first, the patient was suspected to have developed neutropenic fever; however, she was diagnosed with Epstein-Barr virus-associated hemophagocytic syndrome (EB-VAHS) upon fulfilling the diagnostic criteria after bone marrow aspiration. When patients with inflammatory bowel disease treated with immunomodulators, such as thiopurine preparations, develop fever, EB-VAHS should be considered in the differential diagnosis.

[Myelodysplastic/myeloproliferative neoplasm: a histopathological review].

Myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) is a type of myeloid neoplasm where at least one hematopoietic lineage exhibiting cytopenia clinically coexists with other (s) exhibiting hypercytosis. There is ineffective erythropoiesis and bone marrow coexistence of at least one hematopoietic lineage morphologically characterized by dysplasia of blood cells and other (s) characterized by pronounced proliferation. At a molecular level, various abnormalities have been identified that overlap with related diseases, and a prerequisite for MDS/MPN diagnosis includes ruling out various hematopoietic tumors and reactive conditions. Therefore, a multilateral approach involving clinical findings, morphology, and molecular biology is needed. Herein, we introduce the pathological features of MDS/MPN and the relationship between molecular abnormalities and morphological characteristics.

Interobserver concordance of assessments of dysplasia and blast counts for the diagnosis of patients with cytopenia: From the Japanese central review study.

The diagnosis of myelodysplastic syndromes (MDS) is based on morphology and cytogenetics. However, limited information is currently available on the interobserver concordance of the assessment of dysplastic lineages (<10% or ≥10% in bone marrow (BM)). The revised International Prognostic Scoring System (IPSS-R) described a new threshold (2%) for BM blasts. However, the interobserver concordance of the categories (0-≤2% and >2-<5%) has limited data. The purpose of the present study was to investigate the assessment of dysplastic lineages and IPSS-R reproducibility. Our study was divided into two Steps. In each Step, the microscopic examinations were performed separately by two morphologists. Regarding the category of BM blasts ≤2% and >2-<5%, interobserver agreement was more than 'moderate' in all pairs (kappa test: 0.43-0.90). Regarding dysgranulopoiesis (dysG) and dyserythropoiesis (dysE) in BM, interobserver agreement was more than 'moderate' in all pairs (kappa test, dysG: 0.45-0.96, dysE: 0.45-0.81). Regarding the category of dysmegakaryopoiesis (dysMgk) in BM, interobserver agreement was more than moderate in 4 out of 5 pairs (kappa test: 0.58-1.00), and was fair for one pair (kappa test: 0.37). We consider that high interobserver concordance may be possible for the BM blast cell count (≤2% or >2-<5%) and dysplasia (<10% or ≥10%) of each lineage.

The prognostic significance of tumor lymphangiogenesis and lymphatic vessel density in endometrioid carcinoma of the uterine corpus.

The present study aimed to assess the prognostic significance of tumor lymphangiogenesis and lymphatic vessel density (LVD) in endometrioid carcinoma of the uterine corpus. The association between LVD and various factors, including lymphatic vessel invasion (LVI), and nodal metastases, were investigated. Among 202 surgically treated cases, 19 cases with nodal metastases with the infiltration reaching the outer-half myometrium (N+ group) were selected. The LVDs of hotspots in each case were examined at 100× magnification on D2-40 stained slides of the inner- and outer-half myometrium of the peritumoral, and control compartments. Furthermore, for the peritumoral compartment, the LVDs in two types of areas, LVI-present and LVI-absent, were examined for each location of myometrium, which amounted to 6 spots/case. They were statistically compared. Second, to determine whether the existing myometrium influenced LVD, LVDs in the intratumoral compartment were investigated, which were defined as a region where residual muscular tissue was unrecognizable with desmin-immnostaining. As a negative control group, LVDs of the inner- and outer-half myometrium of the peritumoral, and control compartments of 29 cases without nodal metastases in stage IB (N- group) were examined. No significant association was identified between the LVD and frequency of LVI. However, the LVDs in the peritumoral compartment and inner-half myometrium were higher compared those in the control compartment, and outer-half myometrium in N+ and N- groups, respectively. No significant differences were identified in LVD of the peritumoral compartment between groups. The lymphatic vessels were absent where the existing muscular tissue was absent in 16/19 cases. Although higher LVDs in the peritumoral compartment suggested tumor lymphangiogenesis, it was not associated with LVI and nodal metastases. Other factors that influenced LVD were the location in the myometrium and the existing myometrium.

Validation of the revised International Prognostic Scoring System in patients with myelodysplastic syndrome in Japan: results from a prospective multicenter registry.

The Japanese National Research Group on Idiopathic Bone Marrow Failure Syndromes has been conducting prospective registration, central review, and follow-up study for patients with aplastic anemia and myelodysplastic syndrome (MDS) since 2006. Using this database, we retrospectively analyzed the prognosis of patients with MDS. As of May 2016, 351 cases were registered in this database, 186 of which were eligible for the present study. Kaplan-Meier analysis showed that overall survival (OS) curves of the five risk categories stipulated by the revised international prognostic scoring system (IPSS-R) were reasonably separated. 2-year OS rates for the very low-, low-, intermediate-, high-, and very high-risk categories were 95, 89, 79, 35, and 12%, respectively. In the same categories, incidence of leukemic transformation at 2 years was 0, 10, 8, 56, and 40%, respectively. Multivariate analysis revealed that male sex, low platelet counts, increased blast percentage (>2%), and high-risk karyotype abnormalities were independent risk factors for poor OS. Based on these data, we classified Japanese MDS patients who were classified as intermediate-risk in IPSS-R, into the lower risk MDS category, highlighting the need for careful assessment of treatments within low- and high-risk treatment protocols.

A Case of Abdominal Aortic Retroperitoneal and Mesenteric Amyloid Light Chain Amyloidoma.

We report the case of a Japanese woman with amyloid light chain (AL) amyloidoma in the abdominal aortic retroperitoneum and mesentery. Irregular soft tissue mass lesions with calcification in the abdominal aortic retroperitoneum and mesentery were initially detected by computed tomography at another hospital. The lesions gradually compressed the duodenum, causing symptoms of bowel obstruction. The patient was clinically diagnosed with retroperitoneal fibrosis, and prednisolone was administered at a dose of 40 mg/day. However, the lesions did not change in size and her symptoms continued. She was transferred to our hospital and underwent mesenteric biopsy for histopathology using abdominal laparotomy. The histopathological and immunohistological findings of the mesenteric specimen demonstrated lambda light chain deposition. Accordingly, the patient was finally diagnosed with AL amyloidoma with no evidence of systemic amyloidosis. After laparotomy, her general condition worsened because of complications of pneumonia and deep vein thrombosis. She died suddenly from acute myocardial infarction. We have concluded that abdominal aortic retroperitoneal and mesenteric AL amyloidoma may have very poor prognoses in accordance with previous reports. In addition, the size and location of AL amyloidoma directly influence the prognosis. We suggest that early histopathology is important for improving prognosis.