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Angioimmunoblastic T-cell lymphoma

1. GENERAL INFORMATION

1.1 Definition

Angioimmunoblastic T cell Lymphoma (AITL) is a rare neoplasia accounting for about 2% of all non Hodgkin’s lymphoma (NHL), but represents the most common subtype (15-20%) of peripheral T-cell lymphomas (PTCL). AITL is recognized as a distinct clinical and hystological entity by the WHO classification (Jaffe 2001). A CD4+ve T-cell subset homing in the lymph nodes germinal centers, the germinal centre T-helper cell (GC-th cell), has recently been suggested being the putative normal cell counter-part for AITL (Grogg 2005).

1.2 Risk factors and etiology

The aetiology and pathogenesis of AITL are unknown. In a high percentage of cases the diagnosis is preceded by allergic reactions, infections and/or exposure to drugs, particularly antibiotics (Freter 1993). All these features are more likely to be consequences of the severe immune derangement than putative risk factors. Biomolecular footprints of a wide array of viruses have been detected in affected lymph nodes, but not in the neoplastic cells. B-cell EBV genomes are detected by PCR and/or FISH analysis in up to 100% of AITL lymph nodes (Weiss 1992). However, EBV can be detected only in B-cells and making it unlikely to be somehow involved in the development of AITL (Brauningher 2001). Most of the large B-cells in the lymph node interfollicular area are EBV positive. Other Herpes viruses, HHV6 and HHV8, have been reported in AITL, but the expression is absent in the neoplastic T-cells (Luppi 1996).

2. PATHOLOGY and BIOLOGY

2.1 Morphology

The nodal architecture is completely or partially effacted by an interfollicular infiltrate and regressed follicles can be evident. The neoplastic infiltrate, mostly confined to the paracortex often leaks beyond the nodal capsule. Peripheral sinuses are frequently preserved and dilated. The infiltrate is composed of small to medium-sized lymphocytes with clear cytoplasm and minimal cytological atypia, along with an inflammatory background composed of plasma cells, macrophages, eosinophyls, large lymphoid blasts, and rare Sternberg-Reed cells (Suchi 1987; Patsouris 1989). Other two prominent features, along with the polymorphous infiltrate, are a proliferation of small arborizing high endothelial venules (HEV), many of which show thickened or hyalinized PAS+ walls, and a coarse irregular extrafollicular meshwork of follicular dendritic cell (FDC). The latter surrounds the vessels and may have the appearance of “burn out” germinal centers (Feller 1988). This highly characteristic feature has been proposed as a crucial clue of help in the differential diagnosis. In near one half of cases, small clusters or even sheets of atypical immunoblasts are found, particularly in the perivascular areas. According to the presence of residual reactive hyperplastic B-cell follicles, degree of nodal architecture effacement and presence of cytological features of malignancies three different overlapping pattern have been described (Dogan 2003).

Figure 1:

1_angioimmunoblastic-1
Angioimmunoblastic T-cell lymphoma. A) Prominent blood vessels are evident among the lymphoid cells (arrows). B) CD4 immunostaining highlights neoplastic cells around the arborizing blood vessels. C) A conspicuous number of interfollicular CD10+ cells is detected in the context of the neoplastic infiltrate. D) A CD21+ meshwork of dendritic cells extends from the vessels resembling “burn-out” germinal centres.

2.2 Immunophenotype

Neoplastic cells account for a small fraction of the infiltrate, varying from 5% to 30%.The tumor clone in AITL derives from CD4+ T cells. Single-cell microdissection and molecular analysis have confirmed immunophenotypic studies suggesting that neoplastic cell have a T-helper cell phenotype expressing CD3,CD4 and frequently CD10 (Attygalle 2002). The neoplastic CD10+ cells show a striking cytoplasmic expression of CXCL13 (Grogg 2005), a chemokine that is over expressed by GC-Th cells (Kim 2004) and express Th1-cell cytokines (Tsuchiya 2004). The aberrant CD10 expression is a useful phenotypic marker for diagnosis of AITL also in most involved extranodal sites, except bone marrow (Attygalle 2004). In a recently reported large retrospective series, CD10 immunoreactivity was detected in 39% of AITL cases, suggesting that this marker is a useful but not absolute diagnostic tool in AITL (Went 2006). CXCL13 expression has been described in 29 of 29 AITL cases and in 30% of a subset of unspecified peripheral T-cell lymphomas with borderline features with AITL, while it was virtually absent in anaplastic large T-cell lymphomas and other unspecified peripheral T-cell lymphomas (Dupuis 2006). Two-colour immunostainings further showed CXCL13 immunoreactivity in the cytoplasm of atypical CD5-positive T cells that expressed CD10 (Dupuis 2006). CXCL13 immunoreactivity suggests a tumour derivation from follicular helper T-cells. Other markers for germinal centre T cells, such as SAP and PD-1, are expressed in 95% of AITL (Roncador 2007). Although further studies are needed, this distinct phenotype may prove to be a useful marker in the diagnosis of AITL. Non neoplastic CD8+ mature T cells are intermingled within the neoplastic infiltrate. Another characteristic is the dense meshwork of FDC highlighted with immunostaining with FDC markers, that is CD21, CD23 and CD35 (Figure 1) (Feller 1988; Weiss 1986). Interestingly, the neoplastic infiltrate is intimately associated to the FDC net. Most of the large immunoblasts, express B-cell markers, they may represent more than 25% of the cell population in up to 18% of cases (Lome-Maldonado 2002).
CD52 immunoreactivity is a relevant feature in some lymphoproliferative disorders where alemtuzumab (Mab-Campath), a humanized anti-CD52 monoclonal antibody, is being tested in prospective trials. In contrast with chronic lymphocytic leukaemia, CD52 expression is extremely variable among other haematological malignancies, mostly in T-cell lymphomas (Rodig 2006; Chang 2007; Piccaluga 2007). CD52 immunoreactivity was observed in 2 of 5 assessed cases of AITL (40%) (Rodig 2006). In situ hybridization for EBV EBER exhibits positive results in 50% of AILTs (Tan 2006). Cases with B-cell proliferations are more often EBV-positive and tend to show greater numbers of EBV-labelled cells. In cases with high numbers of EBV-labelled cells, the EBV staining pattern correlates with that of CD79a or CD20, consistent with an EBV-associated B-cell proliferation (Tan 2006). In cases with few numbers of labelled cells, the staining pattern for EBV is scattered and does not clearly correlate with that of B- or T-cell lineage markers.

Figure 1:

1_angioimmunoblastic
Angioimmunoblastic T-cell lymphoma. A) Prominent blood vessels are evident among the lymphoid cells (arrows). B) CD4 immunostaining highlights neoplastic cells around the arborizing blood vessels. C) A conspicuous number of interfollicular CD10+ cells is detected in the context of the neoplastic infiltrate. D) A CD21+ meshwork of dendritic cells extends from the vessels resembling “burn-out” germinal centres.

2.3 Genetic features

The presence of a monoclonal T-cell population can be confirmed in most but not all cases (Feller 1988; Kaneko 1988). Microdissection analysis have shown that clonal T-cell receptor genes (TCR) rearrangements are detected only among CD4+ cells, indicating that AILT derives from this population (Willenbrock 2001 ; Willenbrock 2005). In about 20% of cases, rearrangements of TCR are not detectable. It is unclear whether these cases lack clonal lymphocytic infiltrates, or whether they represent false negative results because of limited sensitivity of the Southern blot and/or PCR techniques applied. Another intriguing feature is the presence of an expanded monoclonal B-cell population in up to 30% of patients (Smith 2000). It is thought that these clones belong to EBV+ large B-immunoblasts that can be found in these patients (Weiss 1992; Anagnostopoulos 1992). In some cases, a B-cell clone can become dominant with the characteristics of the EBV driven lymphoprolipherations that are associated with immunosuppression. Chromosomal abnormalities are detected in the majority of AILT cases, 70% with conventional cytogenetics and 90% with FISH. Multiple different clones are found in up to 40% of cases. Trisomy 3 and 5 and an additional X chromosome are the most frequent cytogenetic abnormalities detected in AITL. There is a high incidence of individual metaphases with nonclonal abnormalities and of multiple, unrelated karyotipic clones (Schlegelberger 1990a; Schlegelberger 1990b; Schlegelberger 1996).
Recently reported studies on gene expression profiling strongly support that normal follicular helper T cells represent the normal counterpart of AITL, and suggest that the AITL spectrum may be wider than suspected, as a subset of CD30-negative unspecified peripheral T-cell lymphomas may derive from or be related to AITL (De leval 2007). The molecular profile of AITL is characterized by a strong microenvironment imprint (overexpression of B-cell- and follicular dendritic cell-related genes, chemokines, and genes related to extracellular matrix and vascular biology), and overexpression of several genes characteristic of normal follicular helper T cells, such as CXCL13, BCL6, PDCD1, CD40L, NFATC1. Overexpression of these genes was validated by immunohistochemistry in AITL (De leval 2007). A recent study showed that AILT and other unspecified peripheral T-cell lymphomas have rather similar gene expression profiling, possibly sharing common oncogenic pathways (Piccaluga 2007). AILT is closer to activated CD4(+), rather than to resting or CD8(+) lymphocytes, and several genes, including PDGFRA, REL, and vascular endothelial growth factor (VEGF), are deregulated in AILT. Interestingly, the VEGF is expressed not only by reactive cells, but also by neoplastic cells. These features provide new relevant information on AILT biology and new candidates for possible therapeutic targets such as PDGFRA (platelet-derived growth factor alpha) and VEGF (Piccaluga 2007).

3. DIAGNOSIS

3.1 Clinical presentation

AITL is a neoplasm of the elderly, the median patients age is 60-65 years, with an equal incidence in male and female. On diagnosis, almost all patients presents with advanced stage disease (stage III-IV). Rarely, the lymphoadenopathies are bulky; in about two-thirds of cases the most prominent manifestation of the disease is a combination of wide arrays of signs and symptoms suggesting a systemic disease: B-symptoms (70%), pruritus, skin rash (50%), hepatomegaly (50%) splenomegaly (79%), pleural effusion (37%), oedema (40%), ascites (25%) (Patsouris 1989; Frizzera 1974;Siegert 1995). In a significant proportion of patients autoimmune diseases can be detected, including: autoimmune hemolytic anemia, cold agglutinine anemia, vasculitis, polyarthritis, autoimmune thyroiditis (Dogan 2003). Among laboratory findings the most frequent on diagnosis are: anaemia, eosynophilia, hypergammaglobulinemia, autoantibodies, elevated lactate dehydrogenase serum levels, elevated eritrosedimentation rate, and bone marrow involvement.

3.2 Diagnostic criteria

The diagnosis of AITL is not always straightforward (Dogan 2003; Attygalle 2002). Clinical presentation can mimic infectious, inflammatory, autoimmune, or other lymphoid neoplasms, particularly Hodgkin’s disease. The diagnosis can only be achieved by lymph node biopsy and it should be underscored that the awareness of the clinical picture by the hemopathologist is of paramount importance. The lymph node architecture is often only partially effaced and there is not a single specific hallmark that can lead to the diagnosis. Histologically AITL may resemble a variety of disreactive or neoplastic conditions such as atypical T-zone hyperplasia, Castleman’s multicentric disease, Hodgkin’s lymphoma, large B-cell Lymphoma (Dogan 2003). Definite diagnosis is often difficult and can be tricky, particularly for a non experienced hematopathologist, leading to an error in initial diagnosis in about half of the cases (Attygalle 2002; Jaffe 1995). Therefore, fine needle aspiration or even a needle core biopsy do not constitute an appropriate diagnostic procedure when AILT is suspected. The recently reported aberrant expression of CD10 by the CD4 neoplastic clone may help the diagnosis (Yuan 2005). The expression of CXCL13 and PD1 in neoplastis cells could be helpful in differential diagnosis with some immunoreactive conditions like Still’s disease, where these molecules are expressed in normal CD4+ T-lymphocytes residing in the germinal centers. Molecular biology investigations are of value to monitor the minimal residual disease but their role for diagnosis is controversial. For instance, a TCR rearrangement cannot be demonstrated in up to 20% of AITL typical cases.

4. STAGING

4.1 Staging procedures

The staging work-up for AITL requires total-body computerized tomography, bone marrow trephine biopsy and a thorough examination of all suspected extranodal sites. Ascitic or pleural effusion, present in up 40% of cases and all extranodal suspected lesions should be cytologically or histologically confirmed whenever it is possible. At present time, there are no data on the sensitivity and accuracy of positron emission tomography (PET) in the staging of AITL.

4.2 Restaging and analysis of minimal residual disease

Restaging should include all diagnostic procedures positive at the time of diagnosis and initial staging. Minimal residual disease in AITL is currently detected by PCR analyzing the rearrangement of TCR genes. PCR amplification and sequencing of immunoglobulin heavy chain genes is advisable because it detects a gene rearrangement in 10% of cases (Feller 1988; Kaneko 1988). There are no clues about the clinical and prognostic value of a molecular remission.

5. PROGNOSIS

5.1 Natural history

AILT follows an aggressive clinical course and the results with the conventional chemotherapy are unsatisfactory. Although about two thirds of patients can achieve a complete remission, the median survival is less than three years and only 10-30% of patients are alive at five years from diagnosis. Patients often succumb to infectious complications. In addition, patients may develop expanded EBV-infected clones, that can lead to EBV-positive B-cell lymphomas in rare cases (Weiss 1992;Abruzzo 1993; Nathwani 1978). Actually, the overwhelming immune deregulations rather than tumor bulk is the leading problem and is responsible for most of the AILT-related mortality. Not surprisingly, there are many anedoctal reports of relapsed AILT patients who have responded to a variety of immunosuppressive therapy, such as low dose methotrexate/prednisone (Quintini 2001), cyclosporine, purine analogues (Ong 1996; Tsatalas 2001; Sallah 1996; Hast 1999), and thalidomide (Advani 1997; Takemori 1999; Dogan 2005).

5.2 Prognostic factors

Although AITL is a very aggressive neoplasm, the clinical outcome of the patients varies considerably, with rapid fatal course in some patients, and durable remission in others. A number of presenting clinical features, age, stage, B-symptoms, rush/pruritus, oedema, ascites, lactate dehydrogenase, haemoglobin (Siegert 1995) and cytogenetic findings (Schlegelberger 1996) have been reported to be significantly related to survival. However, the currently available staging systems and prognostic scores proved to be inadequate when applied to AITL cases. Up to 90% of AITL patients present an advanced stage and comprehensibly Ann Arbor staging system is insufficient in distinguishing different prognostic groups (Pautier 1999). The International Prognostic Index (IPI) failed in identifying groups with different prognosis (Lee 2003; Rudiger 2002). The PIT score, recently proposed for PTCL-NOS (Gallamini 2004), has not yet been applied to AITL series. Further, the presence or absence of TCR rearrangements or absence and presence focal or sheet-like proliferations of immunoblasts do not discriminate patients with different outcomes (Lome-Maldonado 2002; Lee 2003). Recently, in a small series of cases, it has been found that increased levels of vascular endothelial growth factor-A gene expression in both lymphoma cells and vascular cells, are related to the extranodal involvement and survival time (Zhao 2004).

6. TREATMENT

6.1 Standard-dose anthracycline-containing chemotherapy

The standard therapeutic option for patients with AITL has not yet been clearly established. Randomized clinical trials that evaluate the effectiveness of different therapeutic modalities in AITL are lacking. There are only two trials focused on therapy of AITL, one prospective non-randomized and one retrospective. These studies accrued patients mostly before the 1990, and reflect the attitude of hematologist at that time of considering AITL a disreactive non neoplastic albeit often fatal disease. AITL patients showing stable disease received monotherapy with prednisone whereas those presenting with aggressive disease, or patients at release received combination chemotherapy. The remission rate was significantly higher in the chemotherapy group (29% vs. 64%) while no differences were detected in overall survival and disease-free survival, with a median overall survival of 15 months (Siegert 1992). In another trial, 33 patients received CHOP-like therapy (28 patients as first-line and 8 patients after prednisone). Sixty percent of patients achieved a complete remission but the outcome was poor with a relapse rate of 56% and a median overall survival of 36 months (Schetelig 2003).

6.2 High-dose therapy

An EBMT-base survey reported on the impact of high-dose chemotherapy (HDCT) and autologous hematopoietic stem-cell transplantation in patients with AITL. HDCT was given as part of 1st-line therapy in 48% of 29 cases and as 2nd/3rd-line in 52%. There was one treatment-related death; with a median follow-up of 5 years the overall survival and event-free survival was 44% showing that AITL is susceptible to HDCT and should be considered at least in selected cases (Schetelig 2003).

6.3 Other therapeutic approaches

Several case reports deal with the activity of immunosuppressive therapy or immunomodulatory drugs on AITL. Partial or even long lasting complete remissions have been described in patients who received as first-line or salvage therapy, interferon, cyclosporine, low-dose methotrexate and prednisone, thalidomide, 2-clorodeoxyadenosine, and fludarabine (Siegert 1991; Strupp 2002). The activity of thalidomide is intriguing in the light of its antiangiogenetic properties (Zhao 2004). Alemtuzumab (Mab-Campath), a humanized monoclonal antibody anti-CD52 antigen, with a substantial activity against T-cell lineage lymphomas, has recently been tested in a phase II trial (Gallamini 2007), in association with CHOP. The combination Campath-CHOP produces a high remission rate with considerable but manageable toxicity. In fact, complete remission was achieved in 17 (71%) of 24 treated patients. At a median follow-up of 16 months (5-42), 14 patients were alive, nine had died from progressive disease and one from pneumonia at day +198 while in remission. So far, 13 were disease-free, with an overall median duration of response of 11 months. The most frequent side effect were grade 4 neutropenia and CMV reactivation. Major infections were J-C virus reactivation, pulmonary invasive aspergillosis, Staphylococcus sepsis, and pneumonia (Gallamini 2007). CD52 expression variability (see item 2.2) suggests that target validation on a case-by-case basis will likely be necessary to guide the rational analysis of alemtuzumab therapy (Rodig 2006; Piccaluga 2007).

6.4 Which therapy outside a controlled trial?

Although it is difficult to establish firm guidelines regarding the optimal therapeutic regimen for AITL, it can be recommended that an anthracycline-containing regimen must be employed as first line therapy, on a type 3 level of evidence. High-dose chemotherapy can be offered to young fit AITL patients, as second- line therapy or as consolidation of the first remission, on a type 3 level of evidence. Prednisone and immunosuppressive or immunomodulatory drugs such as thalidomide, cyclosporine, or methotrexate can produce a very good palliation of the disease or even durable remission and must be considered, as suitable for individual clinical use, in patients unfit for standard therapy.

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Dr. Andrés Ferreri (Associate Editor)
San Raffaele Scientific Institute – Milan, Italy
mail: ferreri.andres@hsr.it

Dr. Emilio Iannitto (Author)
University of Palermo – Italy
mail: eiannitto@tin.it

Prof. Hans Kreipe (Reviewer)
Medizinischen Hochschule – Hannover, Germany
mail: Kreipe.Hans@MH-Hannover.DE