Unusual relapse of adult T-cell leukemia/lymphoma after spontaneous remission

Signalling via the receptor Notch, delivered by the ligands Delta and Serrate, plays a key role in many cell fate decisions in both Drosophila and vertebrate development (for review seeArtavanis-Tsakonas, S., Matsuno, K. and Fortini, M.E., 1995. Notch signalling. Science 268, 225-232; Lewis, J., 1996. Neurogenic genes and vertebrate neurogenesis. Curr. Opin. Neurobiol. 6, 3-10; Blair, S.S., 1997. Limb development: marginal fringe benefits. Curr Biol. 7, 686-690; Irvine, K.D. and Vogt, T.F., 1997. Dorsal-ventral signaling in limb development. Curr. Opin. Cell Biol. 9, 867-876). Recently vertebrate homologues of Notch (Notch1; Myat, A., Henrique, D., Ish-Horowicz, D. and Lewis, J., 1996. A chick homologue of Serrate and its relationship with Notch and Delta homologues during central neurogeneis. Dev. Biol. 174, 233-247) and Serrate (Serrate1 and 2; Myat, A., Henrique, D., Ish-Horowicz, D. and Lewis, J., 1996. A chick homologue of Serrate and its relationship with Notch and Delta homologues during central neurogeneis. Dev. Biol. 174, 233-247; Hayashi, H., Mochii, M., Kodama, R., Hamada, Y., Mizuno, N., Eguchi, G. and Tachi, C., 1996. Isolation of a novel chick homolog of Serrate and its coexpression with Notch-1 in chick development. Int. J. Dev. Biol. 40, 1089-96; Laufer, E., Dahn, R., Orozco, O.E., Yeo, C.Y., Pisenti, J., Henrique, D., Abbott, U., Fallon, J.F. and Tabin, C., 1996. Expression of Radical fringe in limb-bud ectoderm regulates apical ectodermal ridge formation. Nature 386, 366-373; Rodriguez-Esteban, C., Schwabe, J.W., De La Pena, J., Foys, B., Eshelman, B. and Izpisua-Belmonte, J.C., 1997. Radical fringe positions the apical ectodermal ridge at the dorsoventral boundary of the vertebrate limb. Nature 386, 360-366) were shown to be expressed in early chick limb mesenchyme and apical ridge. However, later expression patterns of these genes and of Delta 1 (Henrique, D. , Adam, J., Myat, A., Chitnis, A., Lewis, J. and Ish-Horowicz, D., 1995. Expression of a Delta homologue in prospective neurons in the chick. Nature 375, 787-790) in vertebrate limbs have not been documented. We have used whole mount in-situ hybridization to document expression patterns of Notch1, Serrate1, Serrate2 and Delta1 within the mesenchyme of the developing chick limb up to stage 31 of development. We show these genes are expressed, in different combinations, in the vasculature, the musculature and the tissues of the handplate.     

A case of pregnancy with adult T-cell leukemia

The incidence of adult T-cell leukemia (ATL) arising in women of childbearing age is documented infrequently. This report is the second in the world's literature of a case of ATL that occurred during pregnancy. A 43-year-old woman developed ATL during pregnancy and died of widespread disease 4 weeks after cesarean delivery.     

Natural killing activity in patients with spontaneous regression of malignant lymphoma

Previously, we proposed a new analysis of natural killing activity, for comparison, employing an "individual effector/target cell ratio" according to the number of effector cells in blood. The activity could be measured in four patients with spontaneous regression of malignant lymphoma. Despite the absence of episodes suggesting viral infections, patients with spontaneous regression had significantly higher activities prior to their regressions than either controls or patients without regression. In one patient who had a spontaneous regression accompanied by a high level of natural killing activity, subsequent exacerbation of the disease with a reduced activity was never followed by a regression and became life-threatening. In another patient, a spontaneous regression was accelerated after greater augmentation of natural killing activity was induced by a superimposed viral infection. These facts suggest that highly elevated natural killing activity may be one of the possible mechanisms responsible for spontaneous regression of malignant lymphoma.     

Clonal change of HTLV-1 infected lymphocytes before onset of adult T-cell leukemia/lymphoma

A 73-year-old HTLV-1 infected male developed overt ATL following 3-years observation, and the clonality of HTLV-1 infected cells changed before overt ATL onset. 10 micrograms of DNA, extracted from mononuclear cells was digested with PstI, and the clonal proliferation of HTLV-1 infected cells was examined by Southern blotting with LTR probe. 4 bands were observed 3 years prior to ATL onset, and 2 different bands were detected 2 years and 6 months later. This suggests that in some ATL cases, the clonality of monoclonally proliferated HTLV-1 infected cells may be changeable before overt ATL onset.     

Detection of HTLV-1 by polymerase chain reaction in situ hybridization in adult T-cell leukemia/lymphoma

A method for nonradioactive polymerase chain reaction in situ hybridization was developed and used to determine the distribution of human T-lymphotropic virus type I (HTLV-I) proviral DNA in paraffin-embedded surgical specimens of adult T-cell leukemia/lymphoma (ATLL). As controls, we used biopsy samples of five cases of mycosis fungoides, cells of an HTLV-I-infected cell line (MT2), as well as HTLV-1-negative cells (YAS). We successfully detected the amplicon of the HTLV-1 tax sequence in the nuclei of the cutaneous infiltrating lymphoid cells in 90% (9/10) of ATLL cases. Studies also revealed the existence of HTLV-1 provirus DNA in nuclei of sweat gland epithelial cells and vascular endothelial cells as well as lymphoid cells in ATLL patients. Mycosis fungoides and YAS cells were negative for the HTLV-I tax sequence, but MT2 cells were strongly positive. The results indicated that this technique was more sensitive in detecting intracellular amplicons than was the previous in situ hybridization method. Through its use, we were able to easily determine the distribution of HTLV-I-positive cells among the various cells and tissues of paraffin-embedded archival materials.     

The radiological features of adult T-cell leukaemia/lymphoma

Adult T-cell leukaemia/lymphoma (ATLL) results from a monoclonal expansion of T-cells infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Six cases of ATLL, three males and three females all from the Caribbean and with a mean age of 55 years, have been reviewed retrospectively, illustrating the wide spectrum of radiological changes. One patient had extensive mediastinal adenopathy, hitherto an unrecorded finding in ATLL.     

Adult T-cell leukemia/lymphoma on a background of clonally expanding human T-cell leukemia virus type-1-positive cells

Tumorous and nontumorous samples from patients with various forms of adult T-cell leukemia/lymphoma (ATLL) were analyzed using the sensitive inverse polymerase chain reaction (PCR) technique. In all samples, oligoclonal expansion of human T-cell leukemia virus (HTLV)-1 bearing T cells were detected, even for the tumorous samples that were mainly monoclonal by Southern blotting. For one case of smouldering ATLL, chemotherapy apparently reduced the number of detectable clones. Taken together with similar data on asymptomatic and symptomatic HTLV-1 carriers without malignancy, it would appear that ATLL appears on a prior background of HTLV-1-initiated oligoclonal expansion.     

Satisfactory remission achieved by PUVA therapy in a case of crisis-type adult T-cell leukaemia/lymphoma with generalized cutaneous leukaemic cell infiltration

We used PUVA therapy in a patient with crisis-type adult T-cell leukaemia/lymphoma and generalized cutaneous leukaemic cell infiltration. PUVA proved very effective in reducing leukaemic cells and in clearing the eruption. To understand the way in which PUVA produced a reduction in the number of leukaemic cells, we examined peripheral blood cells by light and electron microscopy. Light microscopy was of little help, but electron microscopy revealed that PUVA induced apoptosis-like changes in circulating leukaemic cells. This suggests that apoptosis-like changes in leukaemic cells might be the reason for the success of this treatment.     

Genetic heterogeneity in human T-cell leukemia/lymphoma virus type II

DNA from the peripheral blood mononuclear cells of 17 different individuals infected with human T-cell lymphoma/leukemia virus type II (HTLV-II) was successfully amplified by the polymerase chain reaction (PCR) with the primer pair SK110/SK111. This primer pair is conserved among the pol genes of all primate T-cell lymphoma viruses (PTLV) and flanks a 140-bp fragment of DNA which, when used in comparative analyses, reflects the relative degree of diversity among PTLV genomes. Cloning, sequencing, and phylogenetic comparisons of these amplified 140-bp pol fragments indicated that there are at least two distinct genetic substrains of HTLV-II in the Western Hemisphere. These data were confirmed for selected isolates by performing PCR, cloning, and sequencing with to 10 additional primer pair-probe sets specific for different regions throughout the PTLV genome. HTLV-II isolates from Seminole, Guaymi, and Tobas Indians belong in the new substrain of HTLV-II, while the prototype MoT isolate defines the original substrain. There was greater diversity among HTLV-II New World strains than among HTLV-I New World strains. In fact, the heterogeneity among HTLV-II strains from the Western Hemisphere was similar to that observed in HTLV-I and simian T-cell lymphoma/leukemia virus type I isolates from around the world, including Japan, Africa, and Papua New Guinea. Given these geographic and anthropological considerations and assuming similar mutation rates and selective forces among the PTLV, these data suggest either that HTLV-II has existed for a long time in the indigenous Amerindian population or that HTLV-II isolates introduced into the New World were more heterogeneous than the HTLV-I strains introduced into the New World.     

Allelotype analysis of adult T-cell leukemia

Allelotype analysis of adult T-cell leukemia (ATL) was undertaken for the first time to identify chromosomal loci relevant to the development of acute/lymphomatous ATL. Loss of heterozygosity (LOH) was screened using 94 highly polymorphic microsatellite markers, distributed among all nonacrocentric, autosomal chromosomes. In each of the 22 cases, DNA obtained from their leukemic cells in acute/lymphomatous phase was compared with their constitutional DNA from mononuclear cells in chronic or remission phase. Allelic losses of at least on one chromosome arm occurred in 91% of the cases (20 individuals). Among 39 chromosome arms, allelic losses were observed on 31 arms at least for one sample. A high frequency of allelic loss (>30%) was seen on chromosome arms 6q (41%) and 17p (48%). The mean fractional allelic loss (FAL) was 0.109. These findings suggest that a novel tumor suppressor gene on chromosome arm 6q, as well as the p53 gene on chromosome arm 17p, probably have an important role in the development of acute/lymphomatous ATL.     

Unique eosinophil granules in a case of T-cell lymphoma

A 41-year-old man developed intense itching without visible cutaneous changes, epigastric pressure pain, and a slight intolerance to alcohol. He was found to have persistent blood eosinophilia. The eosinophil granulocytes were of abnormal appearance in the light microscope: larger than normal, the nuclei were multilobulated (4-6 lobes), the cytoplasm contained atypical, large granules, ample glycogen, and up to 12 vacuoles. In the electron microscope too the eosinophil granules were entirely atypical, having an electron-dense matrix, often with a light central inclusion body which was inhomogeneous, having longitudinally oriented structures with a periodicity of about 10 nm. These findings are quite contrary to normal eosinophil granules. Enzymic studies of cytoplasmic enzymes from the granulocytes revealed a greatly reduced content of eosinophil cationic proteins, whereas 5 (7) other enzymes were present in a normal or slightly reduced quantity. The phagocytic capacity of the eosinophils against latex particles was normal. The patient developed generalized lymphomas, histologically very malignant, of the convoluted, acid phosphatase positive cell type (T-cell lymphoma). Sub-population studies of lymphocytes from a lymph node revealed 58% TE cells, while the remainder were B cells. At death, 3-1/2 years after the onset of symptoms, severe endomyocardial fibrosis was found. The thymus could not be identified. It is concluded that lymphomas should be described on the bais of clinical, histological, and histochemical criteria as well as studies of lymphocyte sub-populations and that the highly unusual eosinophil granulocytes still deserve particular attention. The endocardial fibrosis is assumed to have been due to substances liberated from the eosinophil cells.     

Adult T-cell leukemia/lymphoma in London: clinical experience of 21 cases

An aminopeptidase N (APN) with a molecular weight of 110kDa was released from the midgut membrane of Bombyx mori by phosphatidylinositol-specific phospholipase C (PI-PLC), and purified to a homogeneous state. This 110-kDa APN was different from the 100-kDa APN that we previously reported, in chromatographic behaviors, substrate specificity, and N-terminal and internal amino acid sequences. However, the N-terminal sequence of 110-kDa APN, DPAFRLPTTTRPRHYQVTLT, was highly homologous with those of Manduca sexta and Heliothis virescens APNs, which were identified as a receptor for an insecticidal toxin of Bacillus thuringiensis. From a B. mori midgut cDNA library, we cloned the 110-kDa APN cDNA that possessed a 2958-bp open reading frame encoding a 111573-Da polypeptide of 986 residues. The sequence of the eicosa-peptide Asp42Thr61 deduced from the cDNA was completely matched with the N-terminal sequence of the mature 110-kDa APN. One potential N-glycosylation site, HEXXHXW zinc-binding motif and characteristic proline-rich repeats were observed in the ORF. Moreover, the primary sequence contained two hydrophobic peptides on N- and C-termini. The N-terminal peptide sequence showed characteristics of leader peptide for secretion and the C-terminal peptide contained a possible glycosylphosphatidylinositol (GPI) anchoring site. Taken together, the deduced amino acid sequence suggests that the 110-kDa APN is a GPI-anchored protein and a specific receptor protein for B. thuringiensis CryIA delta-endotoxin.     

Diagnostic case. Angiotrophic lymphoma with T-cell immunophenotype

In patients with infectious mononucleosis, abdominal pain is usually attributed to visceral enlargement. A teenage girl with symptoms of appendicitis was found at laparotomy to have mesenteric adenitis. Postoperatively, she developed classic features of Epstein-Barr virus (EBV)-induced mononucleosis. The lymphoproliferation characteristic of EBV infection can cause severe localized abdominal pain that predates the onset of mononucleosis.     

A case of infantile digital fibromatosis with spontaneous regression

We reported a fourteen-month-old boy with infantile digital fibromatosis. At the age of seven months, a nodule appeared on the back of the left third toe, and developed into a slight red tumor divided into five hemispherical nodules. Histopathologically, spindle-shaped tumor cells with an eosinophilic inclusion body in the cytoplasm were seen in the dermis. Electron microscopy showed a dense body in the cytoplasm of the tumor cells. One year and two months after the first visit, the tumor regressed without any aggressive treatment. Japanese cases of infantile digital fibromatosis were reviewed. The literature review and our case suggest that the tumor should be observed without any aggressive treatment unless it causes mobile dysfunction of the affected finger or toe.     

Varioliform mucosal polypoid lesions in intestinal tract in a patient with adult T-cell leukemia

We have investigated the significance of local recurrence on survival in 173 patients with localised soft-tissue sarcomas of the limbs and of the trunk. The overall survival rates at five and ten years were 75.2% and 68.0%, respectively. After definitive surgery at our hospitals, there was local recurrence in 25 patients (14.5%). After inadequate operations elsewhere, there was a higher incidence of late local recurrence (28.3%), in comparison with those with primary tumours treated by us (9.0%), or patients referred to us immediately after inadequate surgery elsewhere (10.2%). Because of small numbers these differences in the survival rates were not statistically significantly different. Univariate survival analysis showed that local recurrence after definitive surgery (p = 0.006) together with the histological grade (p = 0.0002), the size of the tumour (p = 0.002), its depth in relation to deep fascia (p = 0.003), and the surgical margin (p = 0.0001) were the significant prognostic factors. Local recurrence at the initial presentation did not affect survival. Multivariate analysis showed that local recurrence after definitive surgery also lost its apparent prognostic significance.