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Nephrotic syndrome and renal failure after allogeneic stem cell transplantation: novel molecular diagnostic tools for a challenging differential diagnosis.

BACKGROUND: Sudden onset of nephrotic syndrome after allogeneic stem cell transplantation is rare and has been associated mostly with membranous glomerulonephritis related to chronic graft-versus-host disease (cGVHD). We report a case of nephrotic syndrome and rapidly progressive renal failure occurring in a young woman 3 years after allogeneic stem cell transplantation from her HLA-identical brother. In the renal biopsy, a diffuse mononuclear cell infiltrate was observed. Furthermore, histological analysis, immunofluorescence, and electron microscopy of the kidney specimen defined the diagnosis as minimal change disease, a T-cell-mediated glomerulopathy associated with lymphoproliferative disorders, but that has never been described as an isolated manifestation of cGVHD. METHODS: The differential diagnosis was performed by using immunohistochemistry and laser capture microdissection combined with Taq-Man quantitative polymerase chain reaction. RESULTS: Infiltrating mononuclear cells in renal tissue consisted of T cells expressing DNA levels of a Y chromosome-specific gene quantitatively similar to those observed in a male subject, showing that these cells derived from the transplant donor and definitely excluding leukemia relapse. However, the large number of infiltrating T cells allowed the possibility that in this patient, minimal change disease could be related to an atypical form of GVHD. CONCLUSION: This is the first study to use molecular techniques to show the differential diagnosis of nephrotic syndrome after allogeneic stem cell transplantation. This novel method approach might represent a key tool to characterize kidney infiltrate after allogeneic stem cell transplantation.

Acute Kidney Injury↗

[Syndrome of inappropriate antidiuretic hormone secretion associated with meningeal infiltration of tumor cells and elevated interleukin-1 beta and interleukin-6 in cerebrospinal fluid of a patient with adult T-cell leukemia].

A 73-year-old man with acute adult T-cell leukemia (ATL) in remission was re-admitted to our hospital due to drowsiness, headache, and bilateral knee joint pain on May 17, 1998. On admission, examinations revealed decreased serum sodium concentration (112 mEq/l), low plasma osmotic pressure (259 mOsm/l), and elevated antidiuretic hormone(5.6 pg/ml). Cerebrospinal fluid examination showed an increased number of abnormal flower-like lymphocyte (951/microliter). Brain computed tomography and magnetic resonance imaging found no abnormality in the hypothalamus or pituitary gland. These findings yielded a diagnosis of syndrome of inappropriate antidiuretic hormone secretion (SIADH). Though ATL patients typically exhibit a variety of clinical symptoms, SIADH is rarely one of the complications. Further investigation showed that IL-1 beta and IL-6 concentrations were increased in spinal fluid but not in serum. Recently, it has been reported that exogeneous IL-6 is an inducer of ADH secretion, and that primary ATL cells and HTLV-I infected cell lines can produce IL-6. In this case, we speculated that IL-6 produced by ATL cells that infiltrated a cerebral lesion may have played an important role in the development of SIADH.

Aged↗

[Possible mechanisms of development of glomerulosclerosis in nephropathy of varying origin].

Mononuclear leucocyte infiltration of the glomerulus in glomerulonephritis, like that in the skin wound, represents a protective adaptive reaction for the reparation of the damaged structures. However, in non-inflammatory nephropathy mononuclear infiltration is not pronounced and the reparation is brought about by other mechanisms. In both cases the cell reaction primarily directed to the reestablishment of the damaged structures, may result in the development of glomerulosclerosis.

Adaptation, Physiological↗

Pictorial review: benign and malignant enlargement of the pterygo-masseteric muscle complex.

Seven cases of unilateral enlargement of the pterygoid and/or masseter muscles due to haemangioma (1), benign masseteric hypertrophy (2), rhabdomyosarcoma (2), leukaemic infiltration (1) and non-Hodgkin's lymphoma (1) are presented. The differential diagnosis of pterygo-masseteric muscle enlargement is outlined and the usefulness of computed tomography (CT) discussed.

Adolescent↗

Loss of CD20 expression following treatment with rituximab (chimaeric monoclonal anti-CD20): a retrospective cohort analysis.

A retrospective analysis of CD20 expression following rituximab for B-cell non-Hodgkin's lymphoma demonstrated a significant change in immunophenotype in 6/25 (24%) patients with persistent bone marrow (BM) infiltration. In three out of six patients, the B cells were uniformly CD20-/CD79alpha+, consistent with frank loss of CD20 expression. In the remaining three cases, the BM infiltrate was predominantly (> 80%) CD20-/CD79alpha+. Two of the former but none of the latter three cases achieved a clinical response. In three further cases, the post-treatment BM infiltrate was composed entirely of benign or reactive CD3+ T cells. Frank loss of CD20 was not seen in 25 post-treatment lymph node biopsies. Immunophenotyping is therefore an important adjunct in the diagnosis of BM infiltration following rituximab.

Antibodies, Monoclonal↗

The application of a PCR technique for the detection of immunoglobulin heavy chain gene rearrangements in fresh or paraffin-embedded skin tissue.

Although detection of a clonal sequence of the heavy chain gene of immunoglobulin by the polymerase chain reaction (PCR) is frequently used to assess lymphoid infiltrates in skin biopsy specimens, there are no data on the sensitivity and specificity of this test in detecting clonal B cell populations. Having refined a PCR technique for the detection of immunoglobulin heavy chain (IgH) gene rearrangement in both fresh and formalin-fixed, paraffin-embedded skin samples, we undertook to define the role of this assay in the diagnostic setting. Thirty-one cases of cutaneous B cell lymphoma (CBCL), 19 cases of B cell pseudolymphoma (lymphocytoma cutis), 34 cases of benign lymphocytic infiltrates of the skin and one case of cutaneous T cell lymphoma (CTCL) were studied using the polymerase chain reaction assay. All biopsies were formalin-fixed, paraffin-embedded skin sections apart from 13 of the 31 CBCL specimens which were fresh skin specimens. DNA from the framework region 3 (FR3) sequence of the IgH genes was amplified to ascertain the presence of a clonal IgH gene rearrangement. The findings were correlated with histological and immunophenotyping results on all samples. The assay performed with 73% sensitivity and 100% specificity, comparable to results obtained examining fresh lymphoid tissue specimens from patients with B cell tumours. The results indicate that this technique is a useful tool in the work up of suspected CBCL and in differentiating between CBCL and mixed lymphocytic infiltrates, a clearly important distinction with regards to prognosis and treatment.

Clone Cells↗

Lymphomatous infiltrates within leptomeninges and spinal roots in adult patients with non-Hodgkin's lymphomas after intrathecal methotrexate administration.

Based on post-mortem neuropathological evaluation the authors analyzed the incidence and distribution of the lymphomatous infiltrates within the leptomeninges and spinal roots in 21 patients with high grade non-Hodgkin's lymphomas (HGNHL) treated with intrathecal methotrexate (ITMTX) prophylaxis. The investigations revealed that lymphomatous infiltrates were most frequent within cerebellar leptomeninges and around spinal roots. In spinal leptomeninges and roots the infiltrates occurred significantly rare after more than 3 ITMTX injections, but further ITMTX applications did not diminish infiltrates incidence in the mentioned regions. In the remaining regions infiltrates incidence was similar, irrespective of the number of ITMTX injections. From the neuropathological point of view ITMTX prophylaxis isn't able to prevent the development of the infiltrates in the mentioned regions. In an attempt to determine the clinical usefulness of the ITMTX prophylaxis in adult patients with HGNHL and to elaborate optimal prophylactic management, the more detailed clinical and pathological evaluations are required.

Adolescent↗

Infiltrative capacity of T leukemia cell lines: a distinct functional property coupled to expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1).

Infiltrative capacity was found to distinguish separate T leukemia cell lines. Of seven T-cell lines four exhibited capacity to infiltrate Matrigel. Analysis of infiltration was performed at the single-cell level throughout the Matrigel using a depth meter. Further, we examined differences in migration capacity and metalloproteinase production between infiltrating and non-infiltrating T-cell lines. The capacity to infiltrate was not directly correlated to the capacity to adhere to the Matrigel or to migrate on/to extracellular matrix components. It is concluded that infiltration capacity does not simply reflect capacity to migrate but represents a distinct functional property. The production of metalloproteinases and their inhibitors by the separate T-cell lines was analyzed using rt PCR, biosynthetic labelling, zymography, immunoprecipitation and ELISA. All T-cell lines with capacity to infiltrate produced matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) while non-infiltrating cell lines did not express MMP-9. Expression of MMP-1, 2, 3, 10, 14 and 17 showed no correlation to capacity to infiltrate. Analysis of infiltration in the presence of a metalloprotease inhibitor showed an increased number of cells within the gel. This enhancement of infiltration suggests that the function of MMPs and/or their inhibitors in lymphocyte infiltration is more complex than previously thought.

Cell Adhesion↗

Cholecystitis caused by infiltration of immature myeloid cells: a case report.

A 59-year-old man with myelodysplastic syndrome who was hospitalized for evaluation of fever and generalized fatigue had elevated levels of C-reactive protein and pancytopenia. A search for a site of infection and empiric treatment with antibiotics were unsuccessful. Over 5 to 6 weeks right upper quadrant pain and rebound tenderness developed. Sonographic Murphys sign was present. Computed tomography showed thickening of the gallbladder wall, and repeated ultrasonography demonstrated changes consistent with cholecystitis. Open cholecystectomy was performed as an emergency procedure. Macroscopically the resected gallbladder showed an edematous and thickened wall. Histopathologic examination revealed transmural infiltration by atypical mononuclear cells with distinct nuclei. The cells showed immunohistochemical staining for CD15, indicating myeloid lineage. By 10 days after surgery, counts of leukocytes and leukoblasts had markedly increased, reaching 36,700/microL and 76.0%, respectively. The blast crisis was thought to indicate progression from myelodysplastic syndrome to leukemia. The patient died of progressive disease 12 days after surgery. We have described a rare case of acute cholecystitis caused by infiltration of immature myeloid cells to the gallbladder. An acute abdomen complicating hematologic disorders is life-threatening and requires prompt and appropriate treatment.

Acute Disease↗

Adult T-cell leukemia (ATL) cells which express neural cell adhesion molecule (NCAM) and infiltrate into the central nervous system.

We encountered a patient with adult T-cell leukemia/lymphoma (ATL) which expressed neural cell adhesion molecule (NCAM). The tumor cells markedly infiltrated the central nervous system (CNS) during the course of the ATL. The patient died 20 months after disease onset, which was considered to be early in the course. During the invasion of the CNS, the surface phenotype of the peripheral blood ATL cells by flow cytometric analysis was CD2+, CD3+, CD4+, CD7-, CD8-, CD16-, NCAM (CD56)+, HLA-DR-. We speculate that the infiltration of ATL cells into the CNS was closely related to the expression of the NCAM in this patient.

Blotting, Southern↗

Chronic lymphocytic leukemia with prostate infiltration mediated by specific clonal membrane-bound IgM.

Chronic lymphocytic leukemia (CLL) is characterized by an accumulation of monoclonal B lymphocytes in the hematopoietic organs. Rarely, CLL cells accumulate in a single atypical site. The mechanism underlying this unusual distribution of CLL cells has not been studied previously. We obtained peripheral blood from five patients having early stage CLL with heavy prostate infiltration. These patients' circulating CLL cells bound strongly in vitro to cultured prostate cell lines PC3, LNCaP, and DU145 and to short-term cultures of fresh prostate cells but not to colon, breast, or bladder cells. CLL cells from patients without prostate infiltration did not bind in vitro to any cell line. Peripheral blood CLL cells from one patient with CLL with heavy prostate infiltration were fused with a mouse-human heteromyeloma line to make hybridomas expressing the same monoclonal IgM as the patient's CLL cells. The hybridoma cells bound specifically to prostate cells. IgM secreted by the hybridoma blocked binding of the patient's CLL cells to prostate cells. Flow cytometry and immunohistochemistry demonstrated that the secreted IgM bound specifically to prostate cells. These results indicate that CLL with atypical prostate infiltration can be mediated by specific surface-bound IgM against an antigen expressed specifically by prostate cells and suggest that a similar mechanism might also apply to cases of CLL with atypical infiltration into other organs.

Animals↗

Systemic B-cell chronic lymphocytic leukemia first presenting as a cutaneous infiltrate arising at the site of a herpes simplex scar.

Cutaneous infection by Herpes virus (simplex or zoster) is a common non-specific skin manifestation in patients affected by B-cell chronic lymphocytic leukemia (B-CLL) or other malignant lymphomas and is attributed to the patients' immunodeficiency. Persistent or shortly recurrent lesions, however, may represent specific cutaneous infiltrates of systemic B-CLL of several months' duration. The occurrence of these lesions as first manifestation of B-CLL is rare and previously reported only on herpes zoster scars. A case of a 63-year-old male patient with cutaneous B-CLL infiltrate of the right oral commissure at the site of herpes simplex scar as first sign of the disease is herein reported.

Antigens, CD20↗

Purpuric adult T-cell leukaemia/lymphoma: expansion of unusual CD4/CD8 double-negative malignant T cells expressing CCR4 but bearing the cytotoxic molecule granzyme B.

A 78-year-old Japanese woman with adult T-cell leukaemia/lymphoma (ATL) presented with an unusual purpuric and erythematous eruption on the face and trunk. Immunohistochemical and flow cytometric analyses showed that the tumour cells were CD4/CD8 double-negative, and expressed CCR4 T-helper (Th) 2 chemokine receptors. Despite these features, the cells aberrantly produced granzyme B, which is a cytotoxic molecule usually produced by CD8(+) cytotoxic T cells, natural killer cells, or occasionally by Th1 cells. In a purpuric lesion, extravasation of erythrocytes was associated with an infiltrate of these cytotoxic tumour cells. Our case suggests phenotypical and functional heterogeneity of tumour cells in ATL, which may be closely related to the clinical appearance of the skin eruption.

Aged↗

ATL and HTLV-I: in vivo cell growth of ATL cells.

The mechanism of leukemogenesis or neoplastic cell growth in adult T cell leukemia (ATL) still remains unclear, although Tax of human T cell leukemia/lymphoma virus type I (HTLV-I), the etiologic virus, has been reported to affect the expression of various cellular genes which encode molecules involved in cell growth or cell death. We have studied the cell growth of HTLV-I-infected human T cells in severe combined immunodeficiency (SCID) mice and found that fresh leukemic cells or cell lines derived from leukemic cell clones but not HTLV-I-infected cell lines of nonleukemic cell origin showed tumorigenicity, and neither HTLV-I nor IL-2 expression was needed for cell growth in vivo, indicating that accumulating changes in addition to the initial events induced by HTLV-I infection were required for the development of ATL. The interaction between ATL cells and vascular endothelial cells appears to be one of the important factors which determine the pattern of organ infiltration by leukemic cells. E-selectin and its ligand are one of the major cell adhesion pathways between ATL cells and human umbilical vein endothelial cells (HUVEC). Another pathway that had not been identified was studied using newly developed monoclonal antibodies capable of blocking cell adhesion. The molecules which directly mediate adhesion between ATL cells and HUVEC were determined to be OX40 and gp34, a member of the tumor necrosis factor receptor (TNF-R) family and TNF family, respectively. The OX40/gp34 system may play a key role in the trafficking and homing of not only ATL cells but also activated normal T cells.

Animals↗

Lymphoma- and leukemia-associated cutaneous atypical CD30+ T-cell reactions.

Cutaneous CD30+ lymphoid infiltrates appear cytologically atypical and occasionally may be misinterpreted as recurrent disease when they occur in patients treated for other primary hematologic malignancies. We recently encountered two such cases and present our findings. One patient with B-cell lymphoma and another with myeloid leukemia developed cutaneous eruptions after chemotherapy displaying highly atypical perivascular lymphoid cells on histology that mimicked recurrent disease. In both cases, the lymphocytes were CD30+ T cells by immunohistochemistry. The skin lesions spontaneously resolved and have not recurred. Because one case was initially misinterpreted as recurrent leukemia, we conclude that close clinical correlation and immunophenotypic confirmation should be done for atypical cutaneous lymphoid infiltrates in patients with primary hematologic malignancies. We discuss the differential diagnosis of atypical CD30+ infiltrates in this setting, which include recurrent lymphoma or myeloid leukemia, primary cutaneous anaplastic large cell lymphoma (ALCL), lymphomatoid papulosis (LyP), carbamazepine-induced CD30+ pseudolymphoma, viral infection and an atypical eruption of lymphocyte recovery.

Carbamazepine↗

Intrasinusoidal bone marrow infiltration: a common growth pattern for different lymphoma subtypes.

We report a retrospective immunohistochemical study on bone marrow biopsies of 43 patients with different types of lymphomas showing unusual intrasinusoidal infiltration. Most of these patients presented with splenomegaly (74.4%) and peripheral lymphocytosis (83%). In 20/43 patients, lymphoid infiltrates were not detectable on haematoxylin-eosin sections. After immunohistochemistry on bone marrow biopsies and blood and bone marrow smear examinations, the following diagnoses were made: splenic marginal zone lymphoma with villous lymphocytes (SLVL) in 24 patients, large granular lymphocyte (LGL) leukaemia in 14 patients, hepatosplenic T-cell lymphoma in two patients, anaplastic large cell lymphoma in two patients and intravascular large B-cell lymphoma in one patient. In the presence of intrasinusoidal infiltrates of small lymphocytes, a B-cell phenotype (CD20+, CD76/DBA44+/-) was associated with splenic marginal zone lymphoma whereas intrasinusoidal CD3/CD45RA-positive T-cell infiltrates were strongly suggestive of LGL leukaemia. Intrasinusoidal bone marrow infiltration appears to be a common feature of distinct lymphoma subtypes. Immunohistochemical analysis is essential to detect intrasinusoidal medullary infiltrates (which may be minimal) and should be systematically performed in patients with splenomegaly and peripheral lymphocytosis.

Adolescent↗

Cutaneous infiltration in T-cell prolymphocytic leukaemia.

T-cell prolymphocytic leukaemia (T-PLL) is an aggressive leukaemia accounting for over 30% of all mature T-cell malignancies. We describe the clinical manifestations and histology of cutaneous involvement in a series of 92 patients with T-PLL. Of the 92 patients, 26 (28%) had cutaneous involvement, and in 23 this was present at the time of the diagnosis of the leukaemia. Skin manifestations included a diffuse infiltrated erythema, infiltration localized to the face and ears, nodules and erythroderma. Histology showed a perivascular and periappendageal dermal infiltrate of lymphoid cells with the morphology of prolymphocytes. An early skin biopsy in these patients should help to reveal the underlying diagnosis.

Adult↗

Transient leukaemia cutis in chronic lymphocytic leukaemia.

Leukaemia cutis arises due to cutaneous infiltration of neoplastic leukocytes or their precursors. Recent evidence suggests that this sign does not necessarily herald a poor prognosis. We describe a 72-year-old woman with B-cell chronic lymphatic leukaemia (CLL) who developed a papular eruption on her breast at the site of a recent herpetic eruption. Histology and immunostaining showed a dense dermal B-cell infiltrate in keeping with leukaemia cutis. The papules cleared in 6 months without treatment, leaving atrophic scars. The histological features and possible aetiological mechanisms of post-herpetic papular eruptions in CLL are reviewed.

Aged↗