Disease |
T-cell prolymphocytic leukemia (T-PLL) |
Phenotype / cell stem origin |
CD4+CD8- (65-70%) CD4+CD8+ (21-25%), or CD4-CD8+ (10-13%), CD7+ bright and surface CD3 negative in 20% of cases. The coexpression of CD4 and CD8 together with weak CD3 and strong CD7 expression suggest that the T-PLL cell stage of differentiation is between a cortical thymocyte and a mature T-cell (Matutes, 1998). |
Etiology | T-PLL accounts for about 2% of all mature lymphoid neoplasms. Most patients are older than 50 years. However, some patients aged as young as 30 years have been reported. The disease affects more male than female patients (3:1 ratio) (Matutes, 1998). |
Epidemiology | The disease is widespread and does not appear to have a geographic predilection or racial clustering. |
Clinics | T-PLL is a rare and aggressive post-thymic lymphoid neoplasm characterized by a high white cell count (usually >100,000/μL) with associated anemia and thrombocytopenia (Magro et al, 1986). Often there is infiltration of the bone marrow, spleen, liver, lymph nodes, and skin. Patients often present with hepatosplenomegaly and generalized lymphadenopathy (Matutes et al, 1991). The median survival is usually < 1 year. However, occasional spontaneous remission has been reported in some cases. Morphologically, T-PLL includes 3 morphologic variants: typical, small cell, and cerebriform, all of which have a similar clinical course and genetic abnormalities (Matutes et al, 1986). Approximately 15% of patients may be asymptomatic at diagnosis (indolent phase), which might persist several years before progression occurs (Matutes et al, 1998). |
Cytology | T-PLL includes 3 morphologic variants: typical, small cell, and cerebriform, all of which have a similar clinical course and genetic abnormalities. Majority (75%) of T-PLL patients have the typical variant where the cells show a regular nuclear outline; 20% have the small cell variant; and 5% have cells with a more irregular nuclear shape similar to the cerebriform cells seen in Sezary syndrome (Costa et al, 2003). |
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| Cytology of typical T-PLL cells in peripheral blood. Cells are medium-sized with regular nuclear outline, single nucleolus, and intense basophilic cytoplasm. |
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| t(X;14) full karyotype. |
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Cytogenetics | Stimulation with a T-cell mitogen (typically PHA) is necessary to obtain metaphase cells for analysis. Most cases of T-PLL have a complex karyotype. Inversion (14)(q11.2q32.1), which leads to juxtaposition of the T-cell receptor TRA/D at 14q11.2 with the TCL1A gene at 14q32.1, is the most common abnormality present in approximately 70% of cases (Costa et al., 2003. Another 10% of patients have the variant t(14;14)(q11.2;q32.1) involving the same genes as the inv(14). Both aberrations lead to overexpression of the TCL1A gene (Mossafa et al., 1994). The t(X;14)(q28;q11.2) is present in about 20% of the cases (de Oliveira et al., 2009). This translocation juxtaposes the TRA/D with the MTCP1 gene at Xq28 and results in overexpression of the MTCP1 gene (Madani et al., 1996; Soulier et al., 1994). Only few cases have been reported with the variant t(X;7)(q28;q34) involving MTCP1 and the T-cell receptor beta (TRB), which also lead to overexpression of MTCP1 (De Schouwer et al., 2000). ADDITIONAL ABNORMALITIES Karyotypes are complex in most cases. The most common abnormalities involve chromosome 8, usually as i(8)(q10) in 45% of cases, but also t(8;8)(p12;q11) in 15% of cases, +8 in 15%, and deletion 8p in 15% of cases (Mossafa et al., 1994). Furthermore, frequent losses involving 6q, 9p, 11q, 12p, 13q, 17p/TP53, and 22q, and frequent gains of 6p and 7q have been reported in most complex karyotypes (Matutes et al., 1991; Costa et al., 2003). Mutations in the ATM (ataxia telangiectasia mutated) gene, located in the 11q22.3 region have been associated with inactivation or significantly reduced expression of the ATM protein, which is believed to function as a tumor suppressor (Stankovic et al., 2001). |
Treatment | T-PLL is a neoplasm characterized by an aggressive course, poor response to conventional chemotherapy and a short median survival. Treatment with purine analogs and the monoclonal antibody alemtuzumab has resulted in significantly higher response rates and increased survival (Szuszies et al., 2014). However, responses are transient and allogeneic hematopoietic progenitor-cell transplantation remains the only potential curative option. The proportion of patients eligible for transplant is low, owing to the older age group of patients, and nonmyeloablative transplantation is a promising alternative that needs to be explored. |
Disease |
Ataxia telangiectasia (AT) |
Epidemiology | AT onset occurs in early childhood and has an incidence of approximately 1 in 40 000-100 000 live births in the United States. AT is seen among all races and is most prominent among ethnic groups with a high frequency of consanguinity. |
Clinics | AT is an autosomal recessive disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene. Classic ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between ages one and four years, oculomotor apraxia, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, and frequent infections. The disease is included in the group of chromosome instability syndromes associated with an increased risk for malignancy, particularly leukemia and lymphoma. AT children tend to develop B-cell acute lymphoblastic leukemia whereas T-cell acute lymphoblastic leukemia and T-PLL tend to occur in teenager patients. Various carcinomas are reported to occur in adults. Diagnosis of AT relies on clinical findings, including slurred speech, truncal ataxia, and oculomotor apraxia; neuroimaging; and family history. Laboratory findings that support the diagnosis include: severely depleted levels of intracellular ATM protein, elevated serum alpha-fetoprotein concentration (Swift, 1990). |
Cytogenetics | Spontaneous chromatid/chromosome breaks, triradials, quadriradials (less prominent phenomenon than in Fanconi anemia), telomeric associations. The best diagnosis test is on the (pathognomonic) highly elevated level (10% of mitoses) of inv(7)(p14q35), t(14;14)(q11;q32), and other nonclonal stable chromosome rearrangements involving 2p12, 7p14, 7q 35, 14q11, 14q32, and 22q11 (illegitimate recombinations between immunoglobulin superfamily genes Ig and TCR); normal level of those rearrangements are: 1/500 [inv(14)), 1/200 (t(7;14)], 1/10 000 (inv(7)) clonal rearrangements further occur in 10% of patients, but without manifestation of malignancy: t(14;14), inv(14), or t(X;14) (Bartram et al., 1976; Taylor et al., 1992; Thick et al., 1994). |
Chromatid exchanges in ataxia telangiectasia, Bloom syndrome, Werner syndrome, and xeroderma pigmentosum. |
Bartram CR, Koske-Westphal T, Passarge E |
Ann Hum Genet. 1976;40(1):79-86. |
PMID 962324 |
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T-cell prolymphocytic leukaemia: antigen receptor gene rearrangement and a novel mode of MTCP1 B1 activation. |
De Schouwer PJ, Dyer MJ, Brito-Babapulle VB, Matutes E, Catovsky D, Yuille MR |
Br J Haematol. 2000;110(4):831-8. |
PMID 11054065 |
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Expression of p13MTCP1 is restricted to mature T-cell proliferations with t(X;14) translocations. |
Madani A, Choukroun V, Soulier J, Cacheux V, Claisse JF, Valensi F, Daliphard S, Cazin B, Levy V, Leblond V, Daniel MT, Sigaux F, Stern MH |
Blood. 1996;87(5):1923-1927. |
PMID 8634440 |
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Trisomy 8q due to i(8q) or der(8) t(8;8) is a frequent lesion in T-prolymphocytic leukaemia: four new cases and a review of the literature. |
Mossafa H, Brizard A, Huret JL, Brizard F, Lessard M, Guilhot F, Tanzer J |
Br J Haematol. 1994;86(4): 780-785. |
PMID 7918072 |
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The MTCP-1/c6.1B gene encodes for a cytoplasmic 8 kD protein overexpressed in T cell leukemia bearing a t(X;14) translocation. |
Soulier J, Madani A, Cacheux V, Rosenzwajg M, Sigaux F, Stern MH |
Oncogene. 1994;9(12):3565-3570. |
PMID 7970717 |
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Genetic aspects of ataxia-telangiectasia. |
Swift M |
Immunodefic Rev. 1990;2(1):67-81. |
PMID 2196911 |
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Loss of donor chimerism in remission after allogeneic stem cell transplantation of T-prolymphocytic leukemia patients following alemtuzumab induction therapy. |
Szuszies CJ, Hasenkamp J, Jung W, Koch R, Trümper L, Wulf GG. |
Int J Hematol. 2014;100(5):425-8. |
PMID 25258193 |
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Translocations t(X;14)(q28;q11) and t(Y;14)(q12;q11) in T-cell prolymphocytic leukemia. |
de Oliveira FM, Tone LG, Simões BP, Rego EM, Marinato AF, Jácomo RH, Falco RP |
Int J Lab Hematol. 2009;31(4):453-6. |
PMID 18294235 |
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High levels of chromosomal imbalances in typical and small-cell variants of T-cell prolymphocytic leukemia. |
Costa D, Queralt R, Aymerich M, Carrió A, Rozman M, Vallespè T, Colomer D, Nomdedeu B, Montserrat E, Campo E. |
Cancer Genet Cytogenet. 2003;147(1):36-43. |
PMID 14580769 |
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T-cell prolymphocytic leukemia: an aggressive T cell malignancy with frequent cutaneous tropism. |
Magro CM, Morrison CD, Heerema N, Porcu P, Sroa N, Deng AC. |
J Am Acad Dermatol. 2006;55(3):467-77. |
PMID 16908353 |
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Clinical and laboratory features of 78 cases of T-prolymphocytic leukemia. |
Matutes E, Brito-Babapulle V, Swansbury J, Ellis J, Morilla R, Dearden C, Sempere A, Catovsky D. |
Blood. 1991;78(12):3269-74. |
PMID 1742486 |
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T-cell prolymphocytic leukaemia. |
Matutes E. |
Cancer Control. 1998;5(1):19-24. |
PMID 10761013 |
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Recurrent ATM mutations in T-PLL on diverse haplotypes: no support for their germline origin. |
Stankovic T, Taylor AM, Yuille MR, Vorechovsky I. |
Blood. 2001;97(5):1517-8. |
PMID 11243240 |
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Development of T-cell leukaemia in an ataxia telangiectasia patient following clonal selection in t(X;14)-containing lymphocytes. |
Taylor AM, Lowe PA, Stacey M, Thick J, Campbell L, Beatty D, Biggs P, Formstone CJ |
Leukemia. 1992;6(9):961-6. |
PMID 1518308 |
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A gene on chromosome Xq28 associated with T-cell prolymphocytic leukemia in two patients with ataxia telangiectasia. |
Thick J, Mak YF, Metcalfe J, Beatty D, Taylor AM |
Leukemia. 1994;8(4):564-73. |
PMID 8152252 |
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