Progressive disease after high-dose therapy and autologous transplantation for lymphoid malignancy: clinical course and patient follow-up.

Of 364 patients with lymphoid malignancy who underwent high-dose therapy with autologous bone marrow transplantation (ABMT) or peripheral stem cell transplantation (PSCT), 169 patients have had progressive disease after the procedure. The median survival from the time of relapse for patients with Hodgkin's disease (HD) who progressed after the transplant was 10.5 months. This compares with a median survival of 3 months for relapsed non-Hodgkin's lymphoma (NHL) patients (P = .0036). After failing transplantation, 56 patients were treated with further chemotherapy, 35 with involved field irradiation therapy, and 18 patients were treated with combination chemotherapy and irradiation. Seven patients received biologic therapy and seven patients underwent a second bone marrow transplant. The remainder of the patients were believed to be too ill for further therapy or chose not to receive further treatment for their recurrent lymphoid malignancy. Sixty of the 169 patients with progressive disease after the transplant are still alive; however, only 18 patients are alive off therapy without evidence of active disease after their relapse. Ten of the 18 patients are still less than 12 months past their posttransplant salvage therapy and are at high-risk for relapse. Five patients are progression free at 15 to 36 months after their posttransplant relapse. Only three patients (two NHL and one HD) treated with other modalities after autologous transplant failure are alive without evidence of disease and have been observed at least 4 years postrelapse. Although a few patients will have a durable response to subsequent therapy, the majority of patients who have progressive disease after an autologous transplant for lymphoid malignancy will succumb to recurrent disease within a short period of time.     

Experimental transmission and pathogenesis of immunodeficiency syndrome in cats

We describe the identification, experimental transmission, and pathogenesis of a naturally occurring powerfully immunosuppressive isolate of feline leukemia virus (designated here as FeLV-FAIDS) which induces fatal acquired immunodeficiency syndrome (AIDS) in 100% (25 of 25) of persistently viremic experimentally infected specific pathogen- free (SPF) cats after predictable survival periods ranging from less than 3 months (acute immunodeficiency syndrome) to greater than one year (chronic immunodeficiency syndrome), depending on the age of the cat at time of virus exposure. The pathogenesis of FeLV-FAIDS-induced feline immunodeficiency disease is characterized by: a prodromal period of largely asymptomatic viremia; progressive weight loss, lymphoid hyperplasia associated with viral replication in lymphoid follicles, lymphoid depletion associated with extinction of viral replication in lymphoid follicles, intractable diarrhea associated with necrosis of intestinal crypt epithelium, lymphopenia, suppressed lymphocyte blastogenesis, impaired cutaneous allograft rejection, hypogammaglobulinemia, and opportunistic infections such as bacterial respiratory disease and necrotizing stomatitis. The clinical onset of immunodeficiency syndrome correlates with the replication of a specific FeLV-FAIDS viral variant, detected principally as unintegrated viral DNA, in bone marrow, lymphoid tissues, and intestine. Two of seven cats with chronic immunodeficiency disease that survived greater than 1 year after inoculation developed lymphoma affecting the marrow, intestine, spleen, and mesenteric nodes. Experimentally induced feline immunodeficiency syndrome, therefore, is a rapid and consistent in vivo model for prospective studies of the viral genetic determinants, pathogenesis, prevention, and therapy of retrovirus-induced immunodeficiency disease.     

Successful T cell-depleted allogeneic bone marrow transplantation in a child with recurrent multiple extramedullary plasmacytomas.

Multiple plasmacytomas with IgA paraproteinemia, a low grade lymphoid neoplasm of differentiated B cells rarely seen in the young, were encountered in a 10-year-old child. T cell-depleted allogeneic bone marrow transplantation (BMT) was performed because of progressive disease despite chemotherapy. Donor T cells were infused after transplantation in gradually increasing numbers to achieve a graft-versus-tumor effect. Complete eradication of all tumor masses was achieved following BMT with normalization of serum immunoglobulin levels. The patient remains in complete remission 4 years after BMT. Allogeneic BMT should be considered early in the course of low-grade lymphoid malignancy in the younger age group.     

Low-grade B cell lymphoma of mucosa-associated lymphoid tissue (MALT) arising in the gallbladder.

Mucosa-associated lymphoid tissue (MALT) lymphomas arise in most cases in the gastrointestinal tract, and are usually of low-grade B cell origin. MALT lymphomas may rarely occur in organs where lymphoid tissue is sparse, especially following inflammatory conditions. Primary lymphomas of the gallbladder are extremely rare, and MALT lymphoma has been reported only twice. We herein describe the third case of low-grade MALT lymphoma of the gallbladder, which exhibits an unusual clinical behavior. The exceptionally advanced stage of the disease stresses the importance of early operation when cholecystectomy is indicated.     

Castleman’s disease arising from the gallbladder neck causing difficulty in the differential diagnosis

We report a patient with Castleman’s disease arising from the gallbladder neck, which caused difficulty in making the differential diagnosis against gallbladder malignancies. A 50-year-old woman presented to our institution with epigastric pain. An abdominal computed tomography scan (CT) and magnetic resonance cholangiopancreatography (MRCP) study showed a 20-mm tumor located in the gallbladder neck for which malignancy could not be completely ruled out. For the definitive diagnosis and treatment, cholecystectomy was performed. In the operation, the main tumor and resection margins of the cystic duct were submitted for frozen section. The tumor was composed of a proliferation of lymphoid tissue with no signs of dysplasia. The ductal margin was free of tumor. The final histopathological diagnosis was unicentric Castleman’s disease, a hyaline vascular variant that developed in the gallbladder. The patient is currently in good condition without any signs of recurrence 28 months after the operation. This is the first detailed report of Castleman’s disease of the gallbladder. Making a correct diagnosis was very difficult before the operation, and only a surgical approach enabled confirmation of the diagnosis for this patient.     

胆囊癌组织中CD44v6和nm23的表达及其意义

目的研究胆囊癌组织中CD44v6、nm23蛋白表达及意义和两者之间的关系。方法用免疫组化的方法检测 36例胆囊癌和27例癌旁上皮组织中CD44v6和nm23蛋白的表达。结果胆囊癌组织中CD44v6和nm23的阳性率分别为41.7％和72.2％,均与癌旁上皮的阳性率有显著性差异:CD44v6的表达与胆囊癌的淋巴结转移呈正相关,而与组织学类型、临床分期无关;nm23的表达与胆囊癌的淋巴结转移、临床分期呈负相关,而与组织学类型无关。CD44v6和nm23蛋白的表达呈负相关。结论 CD44v6和nm23蛋白可能在胆囊癌的形成、淋巴结转移和病程进展等方面起着重要作用,且两者呈互相拮抗的关系,可作为判断胆囊癌侵袭和淋巴结转移的标记物。     

Monoclonal gammopathy after low-grade MALT lymphoma: evidence for a second neoplasm

We report the case of a patient with lymphoma of the salivary gland, at first diagnosed as lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) but later found to infiltrate the bone marrow. At diagnosis, the patient had a polyclonal increase of gamma-globulins. Five years after initial diagnosis, the patient presented with monoclonal gammopathy and infiltration of the bone marrow with neoplastic cells. Initially, the patient had received chemotherapy with different protocols (including etoposide, cyclophosphamide, fludarabin, methotrexate, and vincristine), none of which induced a lasting response. Therapy with rituximab (chimeric anti-CD20 monoclonal antibody) finally led to partial remission. Eighteen months after rituximab, progressive lymphoma in the abdomen and a monoclonal gammopathy developed. The bone marrow showed infiltration by lymphoplasmacytoid cells (monoclonal expression of the light-chain type lambda, positive for CD20, heterogeneous expression of CD45). The patient achieved another short clinical response with 4 cycles of the CHOP-protocol, but soon the lymphoma progressed again. Five years and 8 months after the initial diagnosis, the patient died from septicemia and progressive lymphoma. By polymerase chain reaction (PCR) for the IgH gene it was shown that lymphoma cells were initially oligoclonal in the salivary gland and, later, biclonal in the bone marrow. Sequencing of two bands of apparently same length showed that these manifestations of lymphoma were not identical. Taken together, our data show that the initial low-grade oligoclonal MALT lymphoma was no longer present and a more aggressive biclonal lymphoma with plasmacytoid differentiation had developed. The new lymphoma was clonally distinct and produced high amounts of monoclonal IgG lambda by immunoelectrophoresis. The relationship of the second lymphoma to the initial MALT lymphoma is discussed.     

Hematopoiesis is severely altered in mice with an induced osteoblast deficiency

We previously reported a transgenic mouse model expressing herpesvirus thymidine kinase (TK) gene under the control of a 2.3-kilobase fragment of the rat collagen alpha1 type I promoter (Col2.3 Delta TK). This construct confers lineage-specific expression in developing osteoblasts, allowing the conditional ablation of osteoblast lineage after treatment with ganciclovir (GCV). After GCV treatment these mice have profound alterations on bone formation leading to a progressive bone loss. In addition, treated animals also lose bone marrow cellularity. In this report we characterized hematopoietic parameters in GCV-treated Col2.3 Delta TK mice, and we show that after treatment transgenic animals lose lymphoid, erythroid, and myeloid progenitors in the bone marrow, followed by decreases in the number of hematopoietic stem cells (HSCs). Together with the decrease in bone marrow hematopoiesis, active extramedullary hematopoiesis was observed in the spleen and liver, as measured by an increase in peripheral HSCs and active primary in vitro hematopoiesis. After withdrawal of GCV, osteoblasts reappeared in the bone compartment together with a recovery of medullary and decrease in extramedullary hematopoiesis. These observations directly demonstrate the role of osteoblasts in hematopoiesis and provide a model to study the interactions between the mesenchymal and hematopoietic compartments in the marrow.     

Autologous bone marrow transplantation for high-grade lymphoid malignancy using melphalan/irradiation conditioning without marrow purging or cryopreservation. The Northern Regional Bone Marrow Transplant Group

We report the safety and efficacy of 34 consecutive autologous bone marrow transplant (ABMT) procedures performed in adult patients with high-grade lymphoid malignancy after remission induction therapy. Fifteen patients with acute lymphoblastic leukemia (ALL) and six with high-grade non-Hodgkin's lymphoma (NHL) received pretransplant conditioning with intravenous (IV) melphalan and fractionated total body irradiation (TBI). Thirteen other patients with NHL were conditioned with melphalan alone, having previously received local involved field radiotherapy. Unmanipulated noncryopreserved autologous marrow was reinfused within 48 hours of harvesting. Engraftment occurred in all patients with medians of 10 days of neutropenia (neutrophils less than 0.5 x 10(9)/L), 4-day platelet transfusion requirement, 3 U packed RBC transfusion, and 18 days in hospital posttransplant. There were no procedure-related deaths. Actuarial disease-free survival in the 13 patients with ALL receiving autotransplant early in first remission is 48% with a median follow-up of 3 years. Two other ALL patients who had autotransplants after a period of maintenance therapy also remain in complete remission (CR). These results compare favorably with our 34% disease-free survival (DFS) in 15 allogeneic ALL transplant patients and 21% DFS in 19 patients on standard maintenance after a common induction schedule. No relapses have occurred in the 17 NHL patients transplanted in remission (median follow-up 2 years), but the two NHL patients who developed recurrent disease before ABMT died of progressive disease after temporary responses. We conclude that this method of ABMT results in rapid reengraftment with lack of toxicity and that the conditioning treatment used shows good efficacy against disease. It is applicable in high-grade lymphoid malignancy in first remission, and our results call into question the need for marrow purging in ALL and NHL patients transplanted in first remission.     

Relapse of acute leukemia presenting as acute cholecystitis following bone marrow transplantation.

Though included in the differential diagnosis of jaundice and abdominal pain, acute acalculous cholecystitis is an uncommon hepatobiliary complication of bone marrow transplantation. Leukemic infiltration of the gallbladder presenting as acute cholecystitis is rare. We describe two cases of acute cholecystitis following marrow transplantation that represented an unexpected relapse with leukemic infiltration of the gallbladder wall.     

Disseminated histiocytosis with undetermined Langerhans' cells simulating an acute non lymphoid leukemia.

The authors report on a case of disseminated Langerhans' cell histiocytosis with a clinical presentation and a bone marrow simulating, at onset, an acute leukemia non lymphoid. A hepatic needle biopsy performed for the progressive enlargement of the liver oriented the diagnosis towards a Langerhans' cell histiocytosis. The morphological, immunohistochemical and ultrastructural study of these cells showed them to be undetermined, i.e. Langerhans' cell precursors.     

A case of gallbladder carcinoma associated with pancreatobiliary reflux in the absence of a pancreaticobiliary maljunction： A hint for early diagnosis of gallbladder carcinoma

A 62-year-old man with progressive thickening of the gallbladder wall visited our outpatient clinic. The biliary amylase level in the common bile duct was 19900 IU/L and that of the gallbladder was 127000 IU/L, although endoscopic retrograde cholangiopancreatography revealed no pancreaticobiliary maljunction. Histology demonstrated a moderately differentiated adenocarcinoma of the gallbladder. Pancreatobiliary reflux and associated gallbladder carcinoma were confirmed in the present case, in the absence of a pancreaticobiliary maljunction. Earlier detection of the pancreatobiliary reflux and progressive thickening of the gallbladder wall might have led to an earlier resection of the gallbladder and improved this patient's poor prognosis.     

Successful donor lymphocyte infusion for Epstein-Barr virus-associated lymphoproliferative disorder after allogeneic bone marrow transplantation from an HLA 1-locus-mismatched sibling donor in a patient with acute lymphocytic leukemia]

We report a case of Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD) after allogeneic bone marrow transplantation (allo-BMT) from a partially mismatched related donor for acute lymphocytic leukemia, which was treated successfully by donor lymphocyte infusion (DLI). A 54-year-old woman in first complete remission from acute lymphocytic leukemia received an unmanipulated bone marrow transplant from an HLA-A 1-locus-mismatched sibling donor after preconditioning with cyclophosphamide and total body irradiation. Prophylaxis against graft-versus-host disease (GVHD) was done with tacrolimus and short-term methotrexate. Skin GVHD (grade I) occurred on day 36, but this subsided spontaneously without treatment. On day 61, rapidly progressive cervical lymphadenopathy with fever developed. Lymph node biopsy revealed lymphoid cell proliferation, which was positive for LCA, L26 and LMP-1. A diagnosis of EBV-LPD was made. After withdrawal of the tacrolimus, DLI (1 x 10(6) CD3 cells/kg) resulted in remission. This case suggests that even in the absence of risk factors such as severe GVHD, intensive immunosuppressive therapy and ATG administration, allo-BMT from an HLA 1-locus-mismatched related donor can be complicated by EBV-LPD, and that reduction of immunosuppressive therapy and DLI can be an effective treatment for it.     

Intravascular lymphomatosis diagnosed by bone marrow biopsy

Intravascular lymphomatosis (IVL) is a rare malignancy characterized by neoplastic proliferation of lymphoid cells within the lumina of small vessels. We report a case of IVL in a 69-year-old woman, who presented with pancytopenia and elevation of the serum LDH level. There was no skin eruption or neurological abnormalities. Clusters of abnormal lymphoid cells were barely evident in a peripheral blood smear. Laboratory examinations revealed high levels of LDH (2,602 IU/l) and sIL-2R (5,640 U/ml). Bone marrow aspiration revealed a normal cellular marrow with mild hemophagocytosis, but no tumor cells were detected. After admission, respiratory failure due to multiple pulmonary embolisms progressed, and continuous infusion of heparin had no apparent effect. Bone marrow vessels filled with lymphoma cells were observed in a biopsy specimen, thus establishing a diagnosis of IVL. Chemotherapy with the CHOP regimen was immediately instituted. The respiratory failure was dramatically improved, resulting in disappearance of the abnormal lymphoid cells from the bone marrow. After eight courses of CHOP, low-dose etoposide therapy was administered, and no symptoms of relapse were noticed. The diagnosis of IVL is difficult because it does not form masses of tumor cells. Bone marrow biopsy may be helpful for early diagnosis of IVL if the disease is suspected and searched for.     

Defects in T-cell-mediated immunity to influenza virus in murine Wiskott-Aldrich syndrome are corrected by oncoretroviral vector-mediated gene transfer into repopulating hematopoietic cells

The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by immune dysfunction, thrombocytopenia, and eczema. We used a murine model created by knockout of the WAS protein gene (WASP) to evaluate the potential of gene therapy for WAS. Lethally irradiated, male WASP- animals that received transplants of mixtures of wild type (WT) and WASP- bone marrow cells demonstrated enrichment of WT cells in the lymphoid and myeloid lineages with a progressive increase in the proportion of WT T-lymphoid and B-lymphoid cells. WASP- mice had a defective secondary T-cell response to influenza virus which was normalized in animals that received transplants of 35% or more WT cells. The WASP gene was inserted into WASP- bone marrow cells with a bicistronic oncoretroviral vector also encoding green fluorescent protein (GFP), followed by transplantation into irradiated male WASP- recipients. There was a selective advantage for gene-corrected cells in multiple lineages. Animals with higher proportions of GFP+ T cells showed normalization of their lymphocyte counts. Gene-corrected, blood T cells exhibited full and partial correction, respectively, of their defective proliferative and cytokine secretory responses to in vitro T-cell-receptor stimulation. The defective secondary T-cell response to influenza virus was also improved in gene-corrected animals.     

Spontaneous tumor lysis syndrome with resolution of pancytopenia and disappearance of lymphadenopathy in a patient with peripheral T cell lymphoma unspecified

Tumor lysis syndrome is a well-described, serious complication of chemotherapy administered to treat malignancies. However, a very rare event resulting in the spontaneous necrosis of a tumor prior to therapy can also occur, which is termed spontaneous tumor lysis syndrome (STLS). We present a case of a 27-year-old male who presented to the hospital with epistaxis, dyspnea, and cervical lymphadenopathy. Laboratory findings included progressive pancytopenia, hyperuricemia, and acute renal failure. Bone marrow biopsy showed a T cell lymphoid neoplasm that had entirely infiltrated the marrow stroma. The patient was diagnosed with STLS in the setting of a T cell lymphoma with bone marrow infiltration. The patient was immediately treated with a blood transfusion and hemodialysis. After this urgent treatment, the patient’s pancytopenia resolved and the lymphadenopathy disappeared spontaneously. One month post-treatment, the patient’s cervical lymphadenopathy recurred and peripheral T cell lymphoma, not otherwise specified, was confirmed. STLS has previously been reported, however, most known cases of STLS did not show a decreased tumor burden resulting from massive tumor cell death. We present a rare case of STLS with resolution of pancytopenia and disappearance of lymphadenopathy in a patient with peripheral T cell lymphoma not otherwise specified.     

Bone marrow lymphoid nodules in myeloproliferative disorders: association with the nonmyelosclerotic phases of idiopathic myelofibrosis and immunological significance

The presence of lymphoid nodules in bone marrow biopsy was investigated at diagnosis in 200 patients with chronic myeloproliferative disorders (MPD). Twelve out of 51 patients with idiopathic myelofibrosis (IM) showed such a feature (23.5%), versus two out of 100 with Ph1-positive chronic myeloid leukaemia, two of 32 with polycythaemia vera, and one of 17 with essential thrombocythaemia, the difference between IM and the remaining MPD being statistically significant (P less than 0.0001). When IM patients were compared for their initial characteristics according to the presence or not of bone marrow lymphoid nodules, patients with such a histological finding showed significantly lower values for either WBC counts, number of primitive cells in the blood, and serum lactic dehydrogenase levels. Moreover, it was observed that virtually all patients with lymphoid nodules were in the nonmyelosclerotic phases of IM. Finally, among the 14 of 32 IM patients (44%) investigated for circulating immune complexes who gave a positive test, a significant association between this immunological abnormality and bone marrow lymphoid nodules was found. The above results reinforce the immunological significance of the finding of bone marrow lymphoid nodules in IM and give support to the hypothesis of an immune component in the pathogenesis of the disorder.     

Multiple lymphoid nodules in bone marrow have the same clonality as underlying myelodysplastic syndrome recognized with fluorescent in situ hybridization technique

Benign nodular lymphoid lesions are not rare in the bone marrow of patients with myelodysplastic syndrome (MDS). Herein, we report a case of MDS with clonal lymphoid aggregates in the bone marrow but without evidence of systemic lymphoma. The case of a 71-year-old man was evaluated for cytopenia. His bone marrow was initially hypocellular, with 10% blasts and a few small lymphoid aggregates. The diagnosis of refractory anemia with excess blasts was made. The disease progressed gradually, and he received erythropoietin and granulocyte colony-stimulating factor for a short time. Forty-two months later, acute leukemia (M1) developed, with 60% to 70% blasts in the bone marrow. The bone marrow also showed large aggregates of lymphocytes. Immunohistochemical study of these cells in the nodular lesions showed 50% CD3+ and 50% CD20+. Cytogenetic and molecular genetic studies revealed monosomy 7 and T- and B-cell clonal gene rearrangement. Fluorescent in situ hybridization study with centromere-specific probes of a bone marrow specimen showed monosomy 7 in both nodular lymphoid lesions and surrounding bone marrow cells, indicating that both processes originated from the same abnormal pluripotential progenitor. Am. J. Hematol. 59:252–257, 1998. © 1998 Wiley-Liss, Inc.     

Prednisone-responsive aplastic anemia associated with T-lymphocyte proliferation

In some cases, bone marrow aplasia has been thought to result from immunologic abnormalities. Our patient had severe transfusion-dependent aplastic anemia, which responded to treatment with prednisone on two occasions. The exacerbations of aplastic anemia were associated with lymphocytic proliferation which on one occasion had the characteristics of T-cell chronic lymphocytic leukemia. Though he had had mild lymphoproliferation for a number of years, he ultimately died with progressive diffuse lymphoid infiltration of the bone marrow and other organs. The simultaneous occurrence of the T-cell lymphoproliferation and aplastic anemia and their simultaneous response to therapy suggests that this may be a clinical example of T-lymphocyte mediated suppression of erythropoiesis.