Haipeng Shao

Clonally related histiocytic/dendritic cell sarcoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: a study of seven cases.

Histiocytic and interdigitating dendritic cell sarcomas are rare tumors originating from bone marrow-derived myeloid stem cells. Recent studies have shown evidence of cross-lineage transdifferentiation of B cells in follicular lymphoma to histiocytic and dendritic cell sarcomas. In this study, we report the morphologic, molecular and cytogenetic analysis of seven cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) associated with histiocytic and dendritic cell sarcomas. All seven patients were elderly males (median age 71 years). The B-cell neoplasms preceded the development of the histiocytic and dendritic cell sarcomas in six of seven patients, and one patient had both tumors diagnosed at the same time. The tumors included four interdigitating dendritic cell sarcomas: one Langerhans cell sarcoma, one histiocytic sarcoma and one immature neoplasm with evidence of histiocytic origin. Laser-capture microdissection and PCR analysis showed identical clonal immunoglobulin gene rearrangements in the two phenotypically distinct components in all cases. There was a preferential usage of IGHV4-39 by the V–D–J gene rearrangement. By fluorescence in situ hybridization (FISH) analysis, two cases showed deletion 17p in both components, whereas four cases had normal cytogenetic findings by FISH in the CLL/SLL cells, but acquired cytogenetic abnormalities in the corresponding histiocytic and dendritic tumors. Chromosome 17p abnormalities were the most common cytogenetic abnormality detected in the sarcomas, seen in five of six cases studied. Compared with the CLL/SLL cells, the histiocytic/dendritic cells were largely negative for PAX5, but showed strong expression of PU.1 and variable and weak expression of CEBPβ. Our study provides evidence for transdifferentiation of CLL/SLL B cells to tumors of dendritic and less often histiocytic lineage, and suggests that secondary genetic events may play a role in this phenomenon.

Distinguishing hairy cell leukemia variant from hairy cell leukemia: Development and validation of diagnostic criteria

Hairy cell leukemia (HCL) and hairy cell leukemia-variant (HCL-v) are rare diseases with overlapping clinico-pathological features. We performed flow cytometry analysis (FCM) of 213 cases (169 HCL, 35 HCL-v, 9 splenic marginal zone lymphoma (SMZL)), correlating results with available corresponding clinical and morphological data. FCM distinguished HCL-v from HCL and SMZL based solely upon expression of four antigens (CD11c, CD25, CD103, CD123) combined with B-cell markers (CD19, CD20, CD22). HCL-v expressed bright CD20, bright CD22, CD11c(100%), CD103(100%), dim(40%) or negative(60%) CD123, and uniformly lacked CD25(100%). HCL expressed bright CD20, bright CD22, bright CD11c, bright CD25, CD103, and bright homogeneous CD123(100%). Aberrant expression of CD5(2%/3%), CD10(12%/3%), CD23(21%/11%), CD38(14%/0%), CD2(2%/9%), CD4(0.5%/0%) and CD13(0.5%/3%), was observed in HCL/HCL-v, respectively. SMZL cases were CD103(-) and CD123(-) except for one case with dim CD123. HCL showed significantly greater marrow infiltration over HCL-v. Prominent nucleoli were observed in most HCL-v but rarely in HCL. A third of HCL and HCL-v marrows were hypocellular or aplastic-appearing. Detection of BRAFV600E mutation and annexin A1 were examined in a subset of cases to further validate FCM diagnostic criteria. HCL-v was negative for both annexin A1 (100%) and BRAFV600E mutation (100%), in contrast to HCL (74% positive for annexin A1; 76% positive for BRAFV600E mutation). HCL-v is resistant to traditional HCL therapy, making accurate diagnosis imperative. We have defined FCM criteria for differentiation of HCL-v from HCL and SMZL.

Dendritic cell and histiocytic neoplasms: biology, diagnosis, and treatment.

BACKGROUND Dendritic and histiocytic cell neoplasms are rare malignancies that make up less than 1% of all neoplasms arising in lymph nodes or soft tissues. These disorders have distinctive disease biology, clinical presentations, pathology, and unique treatment options. Morphology and immunohistochemistry evaluation by a hematopathologist remains key for differentiating between these neoplasms. In this review, we describe tumor biology, clinical features, pathology, and treatment of follicular dendritic cell sarcoma, interdigitating dendritic cell sarcoma, indeterminate dendritic cell sarcoma, histiocytic sarcoma, fibroblastic reticular cell tumors, and disseminated juvenile xanthogranuloma. METHODS A literature search for articles published between 1990 and 2013 was undertaken. Articles are reviewed and salient findings are systematically described. RESULTS Patients with dendritic cell and histiocytic neoplasms have distinct but variable clinical presentations; however, because many tumors have recently been recognized, their true incidence is uncertain. Although the clinical features can present in many organs, most occur in the lymph nodes or skin. Most cases are unifocal and solitary presentations have good prognoses with surgical resection. The role of adjuvant therapy in these disorders remains unclear. In cases with disseminated disease, prognosis is poor and data on treatment options are limited, although chemotherapy and referral to a tertiary care center should be considered. Excisional biopsy is the preferred method of specimen collection for tissue diagnosis, and immunohistochemistry is the most important diagnostic method for differentiating these disorders from other entities. CONCLUSIONS Dendritic cell and histiocytic cell neoplasms are rare hematological disorders with variable clinical presentations and prognoses. Immunohistochemistry remains important for diagnosis. Larger pooled analyses or clinical trials are needed to better understand optimal treatment options in these rare disorders. Whenever possible, patients should be referred to a tertiary care center for disease management.

Nodal and Extranodal Plasmacytomas Expressing Immunoglobulin A: An Indolent Lymphoproliferative Disorder With a Low Risk of Clinical Progression

Plasmacytomas expressing immunoglobulin A are rare and not well characterized. In this study, 9 cases of IgA-positive plasmacytoma presenting in lymph node and 3 in extranodal sites were analyzed by morphology, immunohistochemistry, and polymerase chain reaction examination of immunoglobulin heavy and κ light chain genes. Laboratory features were correlated with clinical findings. There were 7 males and 5 females; age range was 10 to 66 years (median, 32 y). Six of the patients were younger than 30 years of age, 5 of whom had nodal disease. About 67% (6 of 9) of the patients with nodal disease had evidence of immune system dysfunction, including human immunodeficiency virus infection, T-cell deficiency, autoantibodies, arthritis, Sjögren syndrome, and decreased B cells. An IgA M-spike was detected in 6 of 11 cases, and the M-protein was nearly always less than 30 g/L. All patients had an indolent clinical course without progression to plasma cell myeloma. Histologically, nodal IgA plasmacytomas showed an interfollicular or diffuse pattern of plasma cell infiltration. The plasma cells were generally of mature Marschalko type with little or mild pleomorphism and exclusive expression of monotypic IgA. There was an equal expression of κ and λ light chains (ratio 6:6). Clonality was showed in 9 of 12 cases: by polymerase chain reaction in 7 cases, by cytogenetic analysis in 1 case, and by immunofixation in 1 case. Clonality did not correlate with pattern of lymph node infiltration. Our results suggest that IgA plasmacytomas may represent a distinct form of extramedullary plasmacytoma characterized by younger age at presentation, frequent lymph node involvement, and low risk of progression to plasma cell myeloma.

Minimal Residual Disease Detection by Flow Cytometry in Adult T-Cell Leukemia/Lymphoma

Little information exists regarding the detection of minimal residual disease (MRD) in adult T-cell leukemia/lymphoma (ATLL). We evaluated 75 peripheral blood samples from 17 ATLL cases using flow cytometry (FC); 50 of the samples were concurrently evaluated by polymerase chain reaction (PCR) for clonal T-cell receptor gamma chain (TRG) gene rearrangement and the presence of human T-cell lymphotropic virus-1 proviral sequences. Residual ATLL cells were identified using a multiparametric approach to identify aberrant T-cell immunophenotypes. Malignant T cells were CD4+, CD3 dim+, CD26-, CD25 bright, CD7+, and CD27+, with occasional dim expression of CD2 or CD5. FC exhibited a high sensitivity, detecting as few as 0.29% ATLL cells/WBC (4.9 cells/microL) in the peripheral blood. PCR for TRG gene rearrangement was slightly more sensitive, and FC and PCR complemented each other in detecting MRD. In 2 patients, there was complete remission; 4 patients had disease refractory to therapy, and 3 died; 11 others had persistent disease with variable numbers of ATLL cells in the peripheral blood. Higher levels of ATLL cells appeared to correlate with disease severity. FC detection of aberrant T cells permits sensitive and quantitative monitoring of MRD in ATLL.

The Role of c-MYC in B-Cell Lymphomas: Diagnostic and Molecular Aspects

c-MYC is one of the most essential transcriptional factors, regulating a diverse array of cellular functions, including proliferation, growth, and apoptosis. Dysregulation of c-MYC is essential in the pathogenesis of a number of B-cell lymphomas, but is rarely reported in T-cell lymphomas. c-MYC dysregulation induces lymphomagenesis by loss of the tight control of c-MYC expression, leading to overexpression of intact c-MYC protein, in contrast to the somatic mutations or fusion proteins seen in many other oncogenes. Dysregulation of c-MYC in B-cell lymphomas occurs either as a primary event in Burkitt lymphoma, or secondarily in aggressive lymphomas such as diffuse large B-cell lymphoma, plasmablastic lymphoma, mantle cell lymphoma, or double-hit lymphoma. Secondary c-MYC changes include gene translocation and gene amplification, occurring against a background of complex karyotype, and most often confer aggressive clinical behavior, as evidenced in the double-hit lymphomas. In low-grade B-cell lymphomas, acquisition of c-MYC rearrangement usually results in transformation into highly aggressive lymphomas, with some exceptions. In this review, we discuss the role that c-MYC plays in the pathogenesis of B-cell lymphomas, the molecular alterations that lead to c-MYC dysregulation, and their effect on prognosis and diagnosis in specific types of B-cell lymphoma.

Prognostic significance of soft tissue extension, International Prognostic Index, and multifocality in primary bone lymphoma: a single institutional experience

Primary bone lymphoma (PBL) is a rare disease. The literature is inconsistent in regard to definition, stage and prognostic factors. We examined the PBL cases seen at the Moffitt Cancer Center between 1998 and 2013 using the 2013 World Health Organization criteria for bone/soft tissue tumours. Seventy PBL patients were included, of whom 53 (75·7%) patients were histologically classified as primary bone diffuse large B‐cell lymphoma (PB‐DLBCL). Femur was the most commonly involved site in PBLs with unifocal bone lesions, whereas PBLs with multifocal bone lesions most frequently presented with spine disease. Further analysis of the PB‐DLBCL subgroup showed that these patients had 3‐ and 5‐year progression‐free survival (PFS) of 61·2% and 46·9%, respectively and 5‐ and 10‐year overall survival (OS) of 81·1% and 74·7%, respectively. Multivariate analysis identified soft tissue extension and International Prognostic Index (IPI) score as the most important unfavourable prognostic factors for both PFS and OS. Multifocality was also highly significantly associated with a worse PFS (P = 0·002) and OS (P < 0·001), although it was not identified in multivariate analysis due to its incorporation into the IPI. The results warrant further investigation regarding whether PBL with multifocal bone lesions could be considered as a systemic and more aggressive disease rather than a conventional PBL.

Clinical characteristics and prognostic factors of bone lymphomas: focus on the clinical significance of multifocal bone involvement by primary bone large B-cell lymphomas

BackgroundMalignant bone lymphoma can be classified as primary (PBL) or secondary (SBL) bone lymphoma. However, the clinico-pathological characteristics and prognostic factors of PBL versus SBL have not yet been well defined. Whether lymphoma with multifocal bone involvement should be considered as stage IV PBL or SBL still remain controversial throughout the literature.MethodsIn this study, we retrospectively reviewed 127 patients with bone lymphoma diagnosed from1998 to 2013 at the Moffitt Cancer Center. Patients were classified as PBL (81 cases) and SBL (46 cases) using the 2013 WHO Classification of Bone/Soft Tissue Tumors and PBL patients were further subdivided into: 1) PBL with unifocal bone disease (uPBL, 46 cases), 2) PBL with multifocal bone involvement (mPBL, 35 cases). Patient characteristics, survival, and prognostic factors were analyzed.ResultsDiffuse large B-cell lymphoma (DLBCL) was the most common histological subtype in all three groups (37/46 of uPBL, 23/35 of mPBL, 23/46 of SBL). B symptoms, lymph node involvement, and bone marrow involvement were found to be more common in mPB-DLBCL and SB-DLBCL groups than in the uPB-DLBCL group. Femur was found to be the most common affected site in uPB-DLBCL patients, while spine was most commonly involved in the other two groups. Survival analysis indicated that uPBL-DLBCL patients had a significantly better progression-free survival (PFS) and overall survival (OS) than those in the other two groups (P < 0.05). We also found by univariate analysis that multifocality, and stage IV were significantly poor prognostic factors for both PFS and OS in PBL patients. Using multivariate analysis, multifocality remained an independent prognostic factor for both PFS and OS (P = 0.0117, RR: 3.789, 95% CI: 1.275-11.256).ConclusionOverall, our results suggest that mPBL is more similar to SBL in characteristics and survival rather than uPBL, and thus should be better classified and treated as SBL.

Cutaneous gamma-delta T-cell lymphoma with central nervous system involvement: report of a rarity with review of literature.

Primary cutaneous gamma‐delta (γδ) T‐cell lymphoma is an extremely rare and aggressive variant of cutaneous lymphoma. Central nervous system (CNS) involvement, a rare finding, and hemophagocytic syndrome are two complications that are commonly fatal. We describe a 58‐year‐old patient presenting with skin plaque who subsequently developed subcutaneous nodules diagnosed as cutaneous T‐cell lymphoma (CTCL), clinically resembling ‘mycosis fungoides’. The patient was treated with repeat topical radiation therapies but had frequent relapsed disease. Approximately 4.5 years after, the patient presented with third and sixth cranial nerve palsies and was found to have CNS involvement by lymphoma per positron emission tomography—computed tomography (PET/CT) and a biopsy of foramen magnum. Phenotypically, the tumor cells were CD3(+)/CD4(−)/CD8(−)/CD7(+)/CD5(−)/CD30(−)/TCRαβ(−)/TCRγδ(+). Despite aggressive strategies taken, the patient expired 3 months after the diagnosis of the CNS lesion. A retrospective investigation proved the original CTCL to be γδ T‐cell in origin, confirming an indolent cutaneous γδ T‐cell lymphoma with eventual CNS manifestation. We present this case to draw attention to the entity, which can occasionally present with misleading histopathologic and clinical features. In addition, we provide a review of the literature to summarize clinical and pathologic features of the reported similar cases.

Concurrent splenic diffuse red pulp small B-cell lymphoma and benign clonal proliferation of T-cell large granular lymphocytes.

Splenic diffuse red pulp small B-cell lymphoma (SDRPSBCL) is newly recognized primary B-cell lymphoma of the spleen [1]. t shows overlapping clinical features with splenic marginal zone ymphoma (SMZL), including massive splenomegaly, leukemic nfiltrate in the spleen, bone marrow and peripheral blood, and nfrequent B-symptoms. The diagnosis of SDRPSBCL is mainly based n histological examination of the spleen. In contrast to SMZL, DRPSBCL is characterized by diffuse infiltrate of the red pulp with onomorphic small to medium-sized B-cells [2]. The neoplastic B-cells show a nonspecific phenotype. Patients with SDRPSBCL typically have a relatively favorable clinical course. T-cell large granulocytic lymphocytic leukemia (T-LGL) is a chronic T-cell lymphoproliferative disorder usually with an indolent clinical course [1,3]. Patients with T-LGL typically present with neutropenia with or without anemia, moderate lymphocytosis and moderate splenomegaly. T-LGL is often diagnosed in patients with autoimmune disorders, especially rheumatoid arthritis. It is characterized by clonal proliferation of CD8+CD57+ cytotoxic T-cells. The diagnosis of T-LGL is based on the clinical features and demonstration of clonal expansion of abnormal CD8+ LGL cells by flow cytometry and molecular studies. The spleen and bone marrow are commonly infiltrated by T-LGL cells to a variable extent. T-LGL has occasionally been associated with B-cell lymphoproliferative