Lourdes Farre

Adult T-cell leukemia/lymphoma (ATL) presenting in the skin: Clinical, histological and immunohistochemical features of 52 cases

Background. Adult T-cell leukemia/lymphoma (ATL) is a severe disease caused by HTLV-I. This paper describes the clinicopathological and immunohistochemical findings of 52 cases of ATL with skin involvement and investigates whether there is any relationship between median survival time (MST) and histological patterns, primary cutaneous involvement and CD8 positivity.Material and methods. All cases were HTLV-I+ and HIV- and were clinically classified. HTLV-I proviral integration was investigated in atypical cases. Immunohistochemistry was performed using CD3, CD4, CD5, CD7, CD8, CD20, CD25, CD30 and CD45RO markers. Ki-67 was used to evaluate the proliferative index. Results. Twenty-seven cases were primary, while 25 were secondary. Monoclonal viral integration was demonstrated in all atypical cases. Patterns resembling mycosis fungoides (MF) were found in 19 cases and anaplastic large-cell lymphoma (ALCL) in two cases. Fifteen cases had an atypical immunophenotype and expressed CD8. Primary cutaneous ATL had a longer MST (48 months) than the secondary cutaneous ATL (7 months) and the difference was statistically significant, but no statistically significant difference was found between the MST of CD8-positive and negative cases.Conclusions. It is important to differentiate between primary and secondary cutaneous ATL and classify the cases histologically in order to better evaluate the prognosis. The two forms of primary cutaneous ATL, primary cutaneous smoldering and primary cutaneous tumoral (PCT), should also be identified. The smoldering type presented a longer survival (58 months) and histological aspects suggestive of better prognosis in contrast to the PCT type that had a shorter survival (20 months) and histological characteristics suggestive of worse outcome.

Adult T-cell leukemia/lymphoma in Bahia, Brazil: analysis of prognostic factors in a group of 70 patients.

The purpose of this study was to evaluate whether subdivision of adult T-cell leukemia/lymphoma (ATL) on the basis of clinical types, skin involvement, histologic features, cell size, and proliferative index (PI) was clinically relevant. Skin lesions were present in 47 cases (67%). Five cases were classified as primary cutaneous tumoral (PCT) type not included in the Shimoyama classification and characterized by skin tumors and absence of systemic involvement, lymphocytosis, and hypercalcemia. Mortality was high (61/70 [87%]). The overall median survival time (MST) was 12 months. The following variables were adversely related to survival: acute, lymphoma, and PCT types; absence of skin lesions; large cells; and PI more than 18%. The longer MST observed in cases with skin lesions was probably due to prolonged survival of the smoldering type (58 months). The MST of the PCT type (21 months) was shorter than that of the smoldering type, confirming the importance of clearly defining these 2 types of ATL.

Codon 12 and codon 13 mutations at the K-ras gene induce different soft tissue sarcoma types in nude mice

K‐ras codon 12 mutation is more oncogenic in in vitro and in vivo experimental systems than Kras codon 13 mutation. Moreover, human colorectal tumors bearing a codon 12 mutation are more aggressive, invasive, and metastatic than the same tumor types carrying a codon 13 mutation. However, despite the association between specific sarcoma types and codon 12 or codon 13 mutations, the relationship between the position of the mutated codon at ras genes and tumor aggressiveness has not been studied in this tumor type. Here, we used a nude mice model to evaluate the tumorogenic capacity of stable transfectants of NIH3T3 fibroblasts, expressing Kras mutated at codon 12 (K12) or 13 (K13), and morphologically, functionally, and molecularly compared these tumors. We found histopathological differences between them, K12‐derived tumors showing fibrosarcoma‐like features, whereas K13‐derived tumors resembled malignant fibrous histiocytomas. Moreover, K12 tumors showed shorter latency of appearance, lower apoptotic and mitotic rates, and higher expression of markers for sarcoma aggressiveness (Ki67, p53 and c‐myc) than K13 tumors. They also showed differences in the expression or activation of Ras, Ras downstream pathways [c‐Jun N‐terminal kinase (JNK), MAPK and AKT], and apoptotic [AKT, Bcl‐2, Focal adhesion kinase (FAK)] and mitotic (cyclin B1) regulators, which could explain their functional differences. Most remarkably, the significantly diminished apoptotic rate observed in K12‐derived tumors was associated with enhanced antiapoptotic signaling through the AKT pathway. These morphological, functional, and molecular differences demonstrate that codon 12 and codon 13 mutations in the K‐ras oncogene can induce two different soft tissue sarcoma types in our in vivo model.

Fas 670 promoter polymorphism is associated to susceptibility, clinical presentation, and survival in adult T cell leukemia.

Fas (TNFRSF6/Apo‐1/CD95) is a type I transmembrane receptor, which mediates apoptosis. Fas gene mutations, aberrant transcripts, and abundant expression of Fas have been reported in adult T cell leukemia (ATL). To further elucidate the role of Fas in ATL pathogenesis, we investigated whether the –670 FAS promoter A/G polymorphism (STAT1‐binding site) might contribute to susceptibility and clinical outcome in ATL. Thirty‐one patients with ATL, 33 healthy, human T lymphotropic virus type 1‐infected individuals, and 70 healthy, uninfected controls were genotyped for the FAS –670 polymorphism by PCR‐restriction fragment‐length polymorphism. The AA genotype was significantly over‐represented in ATL patients in comparison with healthy controls (P=0.006), as well as asymptomatics (P=0.037), corresponding to an odds ratio (OR) of 3.79 [95% confidence intervals (CI; 1.28–11.41)] and 4.58 [95% CI (1.13–20.03)], respectively. The AA group also comprised significantly more aggressive (acute and lymphoma) clinical subtypes [P=0.012; OR=8.40; 95% CI (1.60–44.12)]. In addition, we observed a statistically significant association between GG genotype and survival (log rank test, P=0.032). Finally, IFN‐γ‐induced but not basal FAS mRNA levels were increased significantly (P=0.049) in PBMCs from AA versus GG individuals, demonstrating the IFN‐dependent functionality of the –670 polymorphism. In conclusion, our results demonstrate that a functional Fas promoter polymorphism is significantly associated to susceptibility, clinical manifestation, and survival in ATL.

Early sequential development of infective dermatitis, human T Cell lymphotropic virus type 1–associated myelopathy, and adult T Cell leukemia/lymphoma

We describe a patient with human T cell lymphotropic virus type 1 (HTLV-1)-associated infective dermatitis who developed HTLV-1-associated myelopathy/tropical spastic paraparesis and adult T cell leukemia/lymphoma at 16 years of age. Long inverse polymerase chain reaction was used to demonstrate monoclonal integration of proviral DNA in the lymphomatous skin lesion.

High HTLV-1 proviral load, a marker for HTLV-1 associated myelopathy/tropical spastic paraparesis, is also detected in patients with infective dermatitis associated with HTLV-1

Salvador (BA, Brazil) is an endemic area for human T-cell lymphotrophic virus type 1 (HTLV-1). The overall prevalence of HTLV-1 infection in the general population has been estimated to be 1.76%. HTLV-1 carriers may develop a variety of diseases such as adult T-cell leukemia/lymphoma, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and infective dermatitis associated with HTLV-1 (IDH). IDH is a chronic and severe form of childhood exudative and infective dermatitis involving mainly the scalp, neck and ears. It has recently been observed that 30% of patients with IDH develop juvenile HAM/TSP. The replication of HTLV-1 has been reported to be greater in adult HAM/TSP patients than in asymptomatic HTLV-1 carriers. In the current study, the proviral load of 28 children and adolescents with IDH not associated with HAM/TSP was determined and the results were compared to those obtained in 28 HTLV-1 adult carriers and 28 adult patients with HAM/TSP. The proviral load in IDH patients was similar to that of patients with HAM/TSP and much higher than that found in HTLV-1 carriers. The high levels of proviral load in IDH patients were not associated with age, duration of illness, duration of breast-feeding, or activity status of the skin disease. Since proviral load is associated with neurological disability, these data support the view that IDH patients are at high risk of developing HAM/TSP.

Strongyloidiasis and infective dermatitis alter human T lymphotropic virus-1 clonality in vivo.

Human T-lymphotropic Virus-1 (HTLV-1) is a retrovirus that persists lifelong by driving clonal proliferation of infected T-cells. HTLV-1 causes a neuroinflammatory disease and adult T-cell leukemia/lymphoma. Strongyloidiasis, a gastrointestinal infection by the helminth Strongyloides stercoralis, and Infective Dermatitis associated with HTLV-1 (IDH), appear to be risk factors for the development of HTLV-1 related diseases. We used high-throughput sequencing to map and quantify the insertion sites of the provirus in order to monitor the clonality of the HTLV-1-infected T-cell population (i.e. the number of distinct clones and abundance of each clone). A newly developed biodiversity estimator called “DivE” was used to estimate the total number of clones in the blood. We found that the major determinant of proviral load in all subjects without leukemia/lymphoma was the total number of HTLV-1-infected clones. Nevertheless, the significantly higher proviral load in patients with strongyloidiasis or IDH was due to an increase in the mean clone abundance, not to an increase in the number of infected clones. These patients appear to be less capable of restricting clone abundance than those with HTLV-1 alone. In patients co-infected with Strongyloides there was an increased degree of oligoclonal expansion and a higher rate of turnover (i.e. appearance and disappearance) of HTLV-1-infected clones. In Strongyloides co-infected patients and those with IDH, proliferation of the most abundant HTLV-1+ T-cell clones is independent of the genomic environment of the provirus, in sharp contrast to patients with HTLV-1 infection alone. This implies that new selection forces are driving oligoclonal proliferation in Strongyloides co-infection and IDH. We conclude that strongyloidiasis and IDH increase the risk of development of HTLV-1-associated diseases by increasing the rate of infection of new clones and the abundance of existing HTLV-1+ clones.

Celecoxib induces anoikis in human colon carcinoma cells associated with the deregulation of focal adhesions and nuclear translocation of p130Cas

Celecoxib, a selective cyclooxygenase‐2 (COX‐2) inhibitor, is effective as chemopreventive against colon cancer and it is the only nonsteoroidal antiinflammatory drug approved by the FDA for adjuvant therapy in patients with familial adenomatous polyposis. It is also being evaluated, within Phase II and III clinical trials, in combination with standard chemotherapy to treat sporadic colorectal cancer. Nevertheless, its antitumor mechanism of action is still not fully understood. In this study, we have evaluated the in vitro growth inhibitory effect of celecoxib in colon carcinoma cells and analyzed its mechanism of action. We report that the deregulation of the focal adhesion assembly protein Crk‐associated substrate 130 kDa (p130Cas) by celecoxib plays a relevant role in the cytotoxic effect of this drug. Thus, celecoxib induces the proteolysis of p130Cas and the nuclear translocation of the 31 kDa generated fragment leading to apoptosis. Furthermore, overexpression of wild‐type p130Cas reverts, in part, the growth inhibitory effect of celecoxib. In contrast, FAK and AKT do not appear to be involved in this activity. Our data suggest, for the first time, that the antitumor mechanism of action of celecoxib includes the induction of anoikis, an effect that is not related to COX‐2 inhibition. Besides providing new insights into the antitumor effect of celecoxib, this novel mechanism of action holds potential relevance in drug development. Indeed, our results open the possibility to develop new celecoxib derivatives that induce anoikis without COX‐2 inhibition so as to avoid the cardiovascular toxicity recently described for the COX‐2 inhibitors.

Adult T-cell leukemia/lymphoma triggered by adalimumab

Here, we describe a 48-year-old woman infected by the human T-cell lymphotropic virus type 1 (HTLV-1) with spondyloarthritis, uveitis, bilateral episcleritis and neurogenic bladder. She had a history of a probable infective dermatitis associated with HTLV-1 (IDH) in childhood. After the use of adalimumab, she developed lymphocytosis and a cutaneous lymphoma associated with IDH. She had the diagnoses of IDH and of chronic adult T-cell leukemia/lymphoma, supported by the demonstration of proviral integration in the cutaneous lesion.

Infective Dermatitis Associated With Human T-Cell Lymphotropic Virus Type 1: Evaluation of 42 Cases Observed in Bahia, Brazil

BACKGROUND Infective dermatitis associated with human T-cell lymphotropic virus type 1 (HTLV-1; IDH) is a chronic recurrent eczema affecting HTLV-1-infected children. The epidemiological and dermatological characteristics of IDH are described, and their principal diagnostic criteria are reevaluated. METHODS Forty-two patients were included: 40 patients serologically positive for HTLV-1 and 2 seronegative patients who tested positive in polymerase chain reaction (PCR) assays. RESULTS The mean age at onset of the disease was 2.6 ± 2.4 years (range, 2 months-11 years). The mean duration of breast-feeding was 24.2 months. The lesions were erythematous, scaly, and crusted, always affecting the scalp and retroauricular regions. Crusting of the nostrils was observed in 64.3% of the patients. Of the 36 patients followed up, 23 had the active disease. The age at which IDH disappeared in the others was 10-20 years. CONCLUSIONS The onset of IDH may occur earlier than reported in the literature. The scalp and retroauricular regions are always affected, and lesions are invariably present in ≥3 areas. Crusting of the nostrils cannot be considered an obligatory factor for the diagnosis of IDH. The recurring nature of IDH was a characteristic found in all cases. Patients with classic IDH lesions who are serologically negative should be investigated by PCR. Therefore, the indispensable criteria for diagnosis are (1) presence of erythematous-scaly, exudative, and crusted lesions involving ≥3 areas, including the scalp and retroauricular regions; (2) recurring nature of the lesions; and (3) a finding of HTLV-1 infection by serology or molecular biology.