Hematology

Angioimmunoblastic T cell lymphoma

Angioimmunoblastic T cell lymphoma

What every physician needs to know:

Angioimmunoblastic T cell lymphoma (AITL) presents in older patients and the median age at diagnosis is approximately 60. There is a slight male predominance. Patients often present with a variety of unusual signs and symptoms. Along with adenopathy, generalized rash is common as are fevers and night sweats. Patients will often develop associated autoimmune phenomenon such as hemolytic anemia, arthritis, and thyroid abnormalities. Rarely the disease will spontaneously remit, more commonly it follows a very aggressive course.

Often several biopsies are needed to establish the diagnosis and AITL can mimic many infectious and autoimmune conditions. Many patients will have a concomitant, Epstein Barr early RNA positive clonal B cell infiltrate. This can lead to a misdiagnosis of acute Epstein-Barr virus (EBV) infection or misdiagnosis of an EBV-associated B cell lymphoma.

Are you sure your patient has angioimmunoblastic T cell lymphoma? What should you expect to find?

AITL is generally a rapidly progressive disease. The most common sign is palpable lymphadenopathy, present in the vast majority of patients. The lymphadenopathy can wax and wane, which can initially lead to the clinical impression of a non-neoplastic disorder. Hepatomegaly and splenomegaly are also very common. The majority of patients will have "B" symptoms including fevers, night sweats, and/or unintentional weight loss. An intermittent, morbilliform cutaneous eruption on the trunk is common though a more diffuse, pruritic, maculopapular rash can occur. The rash is usually an epiphenomenon of the lymphoma and morphologic evidence of cutaneous involvement is rarely demonstrable on skin biopsy. Less common but well described signs and symptoms include polyarticular arthritis, pleural effusion, and ascites.

AITL is generally associated with a variety of laboratory abnormalities that are not commonly observed with other lymphomas. Angioimmunoblastic T cell lymphoma with dysproteinemia (AILD) syndrome is characterized by AITL with any of the following:

  • polyclonal hypergammaglobulinemia,

  • a positive direct antiglobulin (Coombs') test,

  • plasmacytosis in the peripheral blood.

Associated autoimmune phenomenon such as vasculitis, hypo or hyperthyroidism, arthritis with or without a detectable rheumatoid factor, immune thrombocytopenic purpura, and hemolytic anemia are commonly described. In addition to a positive Coombs' test, patients may also have cold agglutinins or cryoglobulinemia with or without rash and anemia. Peripheral neuropathy can occur, even without direct neurologic involvement. Patients may develop a sensory neuropathy or a motor neuropathy similar to chronic inflammatory demyelinating polyneuropathy. Uveitis may rarely occur.

Other common, though less specific, laboratory abnormalities occurring in AITL include an elevated lactic acid dehydrogenase (LDH) level, elevated beta-2 microglobulin, elevated erythrocyte sedimentation rate, lymphopenia, anemia, thrombocytopenia, and hypoalbuminemia. Hypereosinophilia is also common.

Beware of other conditions that can mimic angioimmunoblastic T cell lymphoma:

AITL mimics many other neoplastic and non-neoplastic conditions as a result of a diverse constellation of signs and symptoms associated with the disease. The two most common categories of disease confused with AITL are rheumatologic and infectious.

Rheumatologic categories of disease commonly confused with AITL

AITL can be confused with a variety of rheumatologic conditions because of the associated skin rash, arthritis, serositis, hypergammaglobulinemia and eosinophilia.

To further complicate matters, a skin biopsy can show a non-specific lymphocytic and/or mononuclear cell infiltrate as seen in rheumatologic conditions. Occasionally there will be an inflammatory infiltrate with vascular proliferation mimicking vasculitis. Also, patients will often have a positive rheumatoid factor or cryoglobulinemia. Less commonly, there may be anti-nuclear antibodies or anti-smooth muscle antibodies.

Any of these laboratory abnormalities can be falsely interpreted as confirming a rheumatologic disease in what otherwise seems to be an appropriate clinical context. Also, AITL will transiently respond to prednisone started empirically for a presumed rheumatologic disorder providing false reassurance that the diagnosis of a rheumatologic condition is correct.

Infectious categories of disease commonly confused with AITL

AITL can also be confused with a variety of infections. The rapid onset of fevers and night sweats can often suggest infection, a diagnosis that can be falsely supported by non-specific laboratory tests such as polyclonal hypergammaglobulinemia, lymphopenia, and/or an elevated erythrocyte sedimentation rate. Non-specific cutaneous eruptions are also common in infection, particularly viral infections. Skin biopsies in AITL can demonstrate necrotizing granulomas with abundant histiocytes and eosinophils mimicking a viral exanthem or other infectious etiology.

AITL can spontaneously wax and wane which can be further suggestive of an infectious etiology. Also, patients with AITL seem to have some degree of endogenous immune suppression and can present with concomitant pneumonia, sinusitis, and other common infections with transient improvement in symptoms when the offending infection is treated with antibiotics.

Patients can also present with varicella or less commonly opportunistic infections such as Pneumocystis jiroveci. The presence of P. jiroveci in a patient with lymphopenia, constitutional symptoms, disseminated lymphadenopathy, and rash can lead to a false impression of acute human immunodeficiency virus (HIV) infection. False positive HIV antibody tests can occur as can false positive RPRs (rapid plasma reagin test). Viral hepatitis antibody tests can also be falsely positive, leading to misdiagnosis particularly in patients who present with hepatomegaly and cryoglobulinemia. More sensitive tests, such as polymerase chain reaction tests (PCR), however, can eliminate the possiblility of active HIV infection or viral hepatitis as a cause of the patient's symptoms.

The association of AITL with a clonal, EBV positive B cell infiltrate can lead to a false diagnosis of acute EBV infection especially since EBV can also cause rash, constitutional symptoms, lymphadenopathy, and hepatosplenomegaly. Many lymphomas are initially misdiagnosed as tuberculosis or cat scratch disease though an exposure history and if need be specific testing for these agents should rapidly exclude them as diagnostic possibilities.

Other hematological malignancies commonly confused with AITL

AITL can be confused with a number of other hematologic malignancies. The presence of hypergammaglobulinemia, anemia, elevated beta-2 microglobulin, hypoalbuminemia and plasmacytosis can initially suggest multiple myeloma.

Also, patients with AITL may have hypercalcemia from marrow involvement or from peripheral conversion of vitamin D to its active form. They may also have renal insufficiency from dehydration as a result of general debilitation or concomitant infection. This can further suggest a diagnosis of multiple myeloma, a misperception that can be exacerbated by the finding of an increased number of plasma cells in the bone marrow. However, a serum protein electrophoresis demonstrating polyclonal gammaglobulins and peripheral blood flow cytometry or clonality tests from a bone marrow biopsy demonstrating that the plasma cells are polyclonal can all be used to help rule out multiple myeloma.

The presence of an EBV positive, clonal population of B cells can lead to a misdiagnosis of B cell non-Hodgkin lymphoma, particularly T cell/histiocyte rich, diffuse large B cell lymphoma (DLBCL) which can have a similar presentation with acute onset of fevers, night sweats and weight loss with associated hepatosplenomegaly. The T cells in T cell/histiocyte rich DLBCL should be polyclonal, however, and should not have exclusively a T follicular helper cell immunophenotype unlike in AITL where the T cells will be clonal (although clonality cannot always be demonstrated and lack of clonality should not be relied upon exclusively to rule out a diagnosis of AITL).

Similarly, an EBV+ clonal process with a dense T cell infiltrate can suggest a diagnosis of Hodgkin lymphoma. However, the EBV+ cells in AITL are generally CD20 positive which is less common in Hodgkin lymphoma and the cells should not express CD15 or CD30 as they generally will in Hodgkin lymphoma. To further confuse matters, patients with AITL can occasionally develop true EBV positive B cell non-Hodgkin lymphomas.

Which individuals are most at risk for developing angioimmunoblastic T cell lymphoma

AITL is the second most common T cell lymphoma in Europe and the third most common in North America. AITL accounts for 1-2% of cases of non-Hodgkin lymphoma overall. AITL predominantly affects older individuals, with a median age at diagnosis of approximately 60. There is a slight male predominance. There are no identified genetic or environmental risk factors.

As with most lymphomas, patients who are chronically immunosuppressed such as those who have undergone organ transplantation or patients who are infected with HIV seem to be at higher risk. Patients with autoimmune disorders, particularly those on chronic immunosuppression, may also be at higher risk though the association between autoimmune disorders and B cell lymphomas is better defined.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

An excisional lymph node biopsy and/or bone marrow biopsy is the preferred way to establish a diagnosis. Biopsy of one or both of these sites provides enough tissue to evaluate morphology and immunohistochemistry as well as tissue to perform more sensitive tests such as flow cytometry, cytogenetics, and T cell receptor gene rearrangement studies.

A skin biopsy may show morphologic evidence of AITL but is very often non-specific. A core biopsy of a lymph node may be adequate as long as there is enough tissue to send the aforementioned ancillary tests. However, a core biopsy increases the likelihood of having insufficient material to perform all necessary tests which can increase the possibility of misdiagnosis or a non-diagnostic specimen. A fine needle aspiration is almost never sufficient to confidently make the diagnosis of AITL.

A complete blood count to evaluate for anemia or thrombocytopenia from direct marrow involvement or from autoimmune mechanisms is quite useful. The presence of lymphopenia and eosinophilia can further suggest a diagnosis of AITL, though these findings are nonspecific.

Patients should have a comprehensive metabolic profile to assess for liver function and renal function, which can be impaired by AITL. Hyperbilirubinemia, particularly indirect hyperbilirubinemia, can suggest autoimmune hemolysis. Abnormalities in renal or liver function may also affect chemotherapy selection and/or dosing. Hypoalbuminemia is common in AITL, but nonspecific. All patients should have a serum protein electrophoresis with immunoelectrophoresis. If a patient with AITL has hypergammaglobulinemia the gammaglobulins should be polyclonal. The presence of a monoclonal gammopathy could suggest a diagnosis of B cell non-Hodgkin lymphoma or a plasma cell dyscrasia. An elevated LDH can result from the lymphoma itself and/or ongoing hemolysis and can be used to monitor the response to treatment of both. A normal LDH does not rule or definitively establish the diagnosis of lymphoma but LDH is a very useful adjunctive test nonetheless. Beta-2 microglobulin is also frequently elevated and can be used, though is not required, to monitor response to therapy.

An HIV test is recommended for all newly diagnosed patients since HIV is a risk factor for lymphoma. Testing for viral hepatitis B and C (and rarely A) is also helpful, particularly since these patients often have hepatomegaly and, less frequently, cryoglobulinemia.

Patients should also have a direct anti-globulin (Coombs) test to assess for possible autoimmune hemolysis and tests of thyroid function since concomitant, AITL induced thyroid disease may require specific therapy. Serum levels of phosphate, uric acid, calcium, and potassium should be measured to assess for spontaneous tumor lysis syndrome and should be followed particularly early in therapy when the risk of tumor lysis syndrome is highest.

A test for rheumatoid factor is not required and is only necessary if rheumatoid arthritis is being seriously considered in the differential diagnosis. It is more important to be aware of the diagnostic pitfalls resulting from a falsely positive rheumatoid factor in AITL.

Helpful pathology tests

AITL generally has the immunophenotype of a follicular helper T cell andexpresses CD10, BCL-6, CXCL13, and PD-1.

These markers are not typically co-expressed on other T cell lymphomas although isolated increased PD-1 expression has been observed in reactive T cell infiltrates in viral lymphadenitis and approximately 60% of cases of peripheral T cell lymphoma, not otherwise specified (PTCL, NOS). The lymphoma cells are usually CD4 positive and generally express one or several other T cell markers (CD2, CD3, CD5, CD7). The T cell receptor gene will be clonally rearranged in up to 90% of patients and many patients will have a clonal B cell population as well.

Either the B or T cells can be EBV or human herpes virus 6 (HHV 6) positive though the pathophysiologic implication of this is unclear. The neoplastic cells are usually surrounded by high endothelial venules that give the disease its name. These venules are typically surrounded by follicular dendritic cells expressing CD21, CD23, and CD35. There is no pathognomonic cytogenetic abnormality though trisomy 3, trisomy 5, and +X seem to be the most common. AITL can be confused with a subset of PTCL, NOS that exhibits a follicular growth pattern and exhibits a t(5;9)(q33;q22) involving ITK and SYK.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of angioimmunoblastic T cell lymphoma?

Computed tomography (CT) scans of the chest, abdomen, and pelvis are useful both for establishing the diagnosis and staging the extent of lymphoma. Widespread or bulky adenopathy is more suggestive of lymphoma than carcinoma, infectious, or inflammatory conditions.

Positron emission tomography (PET) scanning is not generally helpful in making the diagnosis since inflammatory conditions and other cancers that present in a similar fashion to AITL will often be 2-[18F] fluoro-2-deoxy-D-glucose (FDG) avid. PET can be useful as a baseline to assess disease burden and during and immediately after treatment to assess response though this remains to be validated.

CT scans of the neck are optional but most disease in the neck can be followed adequately by palpation. CT or magnetic resonance imaging (MRI) of the head/brain is only necessary if there are signs or symptoms of central nervous system (CNS) involvement since AITL rarely affects the CNS. A lumbar puncture is only necessary if there are neurologic symptoms suggestive of CNS involvement since AITL rarely directly affects the CNS even though it can cause a paraneoplastic neuropathy.

If you decide the patient has angioimmunoblastic T cell lymphoma, what therapies should you initiate immediately?

There is no imaging test that will definitively establish or definitively exclude a diagnosis of AITL. A tissue biopsy is mandatory. Once the diagnosis of AITL is definitively established patients should be treated with chemotherapy unless they have comorbidities that preclude chemotherapy administration.

If patients are very symptomatic corticosteroids such as prednisone or dexamethasone can be initiated in the interval between the diagnostic biopsy and the receipt of the results. Before initiating corticosteroids in this setting the clinician must be confident that enough tissue was obtained for the pathologist to perform all necessary tests to establish the diagnosis since corticosteroids could obscure the results of a future biopsy if the initial biopsy did not yield sufficient material to establish a diagnosis.

If the patient has signs of active tumor lysis syndrome they should be hydrated and initiated on allopurinol. In rare circumstances rasburicase may be necessary if the uric acid is very high. A general guideline would be to consider rasburicase if the initial uric acid is over 10 or there is evidence of uric acid induced nephropathy such as an otherwise unexplained elevation in creatinine in the presence of hyperuricemia.

More definitive therapies?

More definitive therapies

Patients with AITL should be encouraged to participate in well designed clinical trials since we have comparatively scant data to guide treatment choices.

Outside of the context of a clinical trial, some patients will respond to prednisone or even cyclosporine though most are treated with anthracycline-based chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone).

In a study comparing CHOP to prednisone the complete remission (CR) rate was 64% with CHOP compared to 29% with prednisone with a median survival of 19 months in patients receiving CHOP compared to 11 months in those receiving prednisone.

A recent retrospective analysis suggested that the addition of etoposide to CHOP (CHOEP) may be beneficial in patients under the age of 60 with a normal LDH level and such a strategy is reasonable to consider.

More aggressive regimens such as MegaCHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone) and VIP-reinforced ABVD (etoposide, ifosfamide, cisplatin, doxorubicin, bleomycin, vinblastine, dacarbazine) have not proven beneficial. The clonal B cell population noted in some patients with AITL generated interest in adding the anti-CD20 antibody rituximab to CHOP in this patient population. A European randomized trial comparing CHOP to R-CHOP was stopped early due to a lack of benefit with the addition of rituximab.

CHOP has also been combined with the anti-VEGF antibody bevacizumab based upon the highly vascular nature of AITL and sporadic reports of responses to bevacizumab in patients with relapsed/refractory AITL. A randomized trial comparing CHOP to CHOP plus bevacizumab was stopped early due to excess toxicity, particularly cardiac toxicity, in the bevacizumab arm.

Post-remission therapies

High dose chemotherapy and autologous stem cell transplantation in first remission may improve the durability of response in AITL. Although this approach has never been studied in a randomized fashion a retrospective trial of 146 patients suggested a benefit to autologous transplantation. The overall survival (OS) of patients undergoing autologous transplant was 67% at 24 months and 59% at 48 months. Not surprisingly, patients who had achieved a complete response prior to transplant had superior outcomes with a progression-free survival (PFS) of 70% at 24 months and 56% at 48 months compared to patients with chemosensitive disease but not a CR at the time of transplant who had a progression-free survival of 42% at 24 months and 30% at 48 months. Predictably, patients who had chemorefractory disease at the time of transplantation had the worst outcome with a progression-free survival of 23% at 24 and 48 months.

Patients who are medically fit and who achieve a complete remission with front-line therapy should be considered for autologous transplantation in first remission. Patients who achieve a partial remission (PR) or who do not respond to initial chemotherapy should be treated with additional salvage chemotherapy and should be considered for autologous transplantation if they subsequently achieve a complete response. These patients may benefit from an allogeneic transplant rather than an autologous transplant though this remains to be proven and autologous transplant is still generally preferred. Patients should not undergo transplantation if they do not have chemosensitive disease. Patients who never achieve a response better than a PR should be considered for allogeneic transplantation.

Relapsed/refractory disease

Patients who fail to achieve an initial CR or who relapse after an initial CR require salvage therapy if their medical condition otherwise permits. As with upfront treatment, patients should be offered participation in well designed clinical trials since the optimal therapy in this setting remains undefined.

The only drug specifically approved by the U.S Food and Drug Administration (FDA) to treat relapsed/refractory peripheral T cell lymphoma (PTCL) is the antifolate pralatrexate, which has a response rate of 27% with a median duration of response of just over 9 months in all histologies though the response rate in AITL was under 10%. Thus, in patients with an adequate performance status and hematologic reserve, combination therapy should be considered prior to single agent therapy. Gemcitabine is a particularly active drug in T cell lymphomas in general and is often combined with platinum drugs (increasingly oxaliplatin though historically cisplatin) with or without corticosteroids.

Other salvage regimens utilized in aggressive lymphomas such as ICE (ifosfamide, carboplatin and etoposide) and DHAP (cytosine arabinoside, cisplatin and dexamethasone) are also reasonable to consider. Patients who did not undergo autologous transplant in first remission and who subsequently enter a complete remission should be offered autologous transplantation although the data is conflicting as to whether or not autologous transplantation is beneficial in this setting.

Patients who have failed a prior autologous transplantation who subsequently remit should be offered allogeneic transplantation if they are suitable candidates and a donor is available. Retrospective data has suggested that allogeneic transplantation is effective in patients with AITL who have a chemosensitive relapse or primary refractory disease that subsequently responds to additional therapy. In a European registry study, the relapse rate at 2 and 3 years after allogeneic transplantation was estimated as 16% and 20% respectively. The relapse rate was lower in patients developing chronic graft-versus-host disease (cGVHD), suggesting a graft versus lymphoma effect. PFS and OS rates were 62% and 53% and 66% and 64% at 1 and 3 years, respectively. Not surprisingly, OS and PFS were significantly better in chemotherapy-sensitive patients.

The optimal type of transplantation in patients with relapsed or refractory disease remains unknown and is the subject of an ongoing randomized trial. A reasonable approach in patients with chemosensitive disease is to offer autologous transplantation if no autologous transplantation was performed in first remission and reserve allogeneic transplantation for patients who fail autologous transplantation either in first or subsequent remissions. Patients who do not achieve at least a PR with salvage therapy should not generally be offered transplantation since most data would suggest that the outcomes are poor in this setting.

Cyclosporine may be effective in patients who fail chemotherapy or are not chemotherapy candidates. Most data is limited to case reports but there is reasonable evidence that cyclosporine administered at a dose of 3 - 5 mg/kg PO bid for 6 - 8 weeks and gradually tapered by 50 mg every 1 - 3 weeks depending on response and toxicity can be effective.

A number of agents are currently being studied or have been studied in relapsed/refractory PTCL. These include the histone deacetylase (HDAC) inhibitor romidepsin. In a large phase II trial, romidepsin had an overall response rate of 38% with a median duration of response of approximately 9 months. Although the numbers are small, only one of the 6 patients with AITL in this study responded to romidepsin treatment. Belinostat, another HDAC inhibitor, has a response rate of 22% based upon a small phase I/II trial in T cell lymphoma. Registration studies for both agents are ongoing. The fusion protein denileukin diftitox, the anti-CD52 antibody alemtuzumab, and the anti-CD4 antibody zanolimumab are all being evaluated in AITL. Pentostatin has a response rate of approximately 20% in T cell lymphomas in general, though large scale studies specific to AITL are lacking. None of the aforementioned agents are approved by the FDA for the treatment of AITL.

What other therapies are helpful for reducing complications?

Pegfilgrastim or filgrastim are useful in most patients receiving combination chemotherapy to decrease the chance of febrile neutropenia.

Patients with a high disease burden or elevated uric acid should be initiated on allopurinol for the first 10-14 days of the first cycle of chemotherapy and should be monitored for tumor lysis syndrome. Rarely, rasburicase may be necessary if the patient has severe spontaneous or treatment induced tumor lysis syndrome.

Patients receiving pralatrexate require folic acid and vitamin B12 supplementation.

Patients receiving trimethoprim/sulfamethoxazole or probenecid concomitantly with pralatrexate may be at increased risk of pralatrexate induced toxicity and should be monitored accordingly or the drugs should be held if it is safe to do so.

What should you tell the patient and the family about prognosis?

AITL can occasionally spontaneously remit, though almost never does so permanently.

The complete remission rate with CHOP is 64% with a median survival of 19 months. The 5 year overall survival is 32% with a 5 year failure free survival of 18%. Survival is dependent on the International Prognostic Index (IPI) score. OS at 5 years is 56% with an IPI of 0 or 1 while it drops to 26% with an IPI of 4 or 5. Similarly, failure free survival at 5 years is 34% with an IPI of 0 or 1 but only 16% with an IPI of 4 or 5. Patients who haven't relapsed by year 5 are likely cured.

Autologous transplantation in first remission may improve survival, with an OS of 56% at 4 years in patients transplanted in first CR. Allogeneic transplantation can be curative in a select group of patients, including those who relapse after autologous transplantation, though the relative value of allogeneic compared to autologous transplantation early in the disease course remain to be defined and are the subject of ongoing randomized trials. Patients and family members should also be aware that individuals with AITL can occasionally develop aggressive B cell lymphomas, likely as a result of additional mutations in the EBV positive, clonal B cell population that often occur concomitant with AITL.

What if scenarios.

In general, dose density and dose intensity matter in potentially curable lymphomas including AITL. Every attempt should be made to maintain chemotherapy at full dose and on time. Patients with AITL may present with high fevers and a sepsis-like clinical picture. If a thorough search for infectious causes is unrevealing chemotherapy can be initiated in this setting as treating the lymphoma will often reverse these symptoms.

Patients with AITL can develop aggressive B cell lymphomas so repeat biopsy is essential if there is a suspicion for disease recurrence. A de novo aggressive B cell lymphoma may be treated differently than a recurrence of AITL, most notably by the addition of the anti-CD20 antibody rituximab to the treatment regimen. Patients who are treated for AITL and develop an aggressive B cell lymphoma are generally treated with rituximab containing salvage chemotherapy regimens (e.g., R-ICE or R-DHAP) followed by autologous transplantation (if not previously performed for AITL and if the patient is a suitable candidate) or even allogeneic transplantation if a previous autologous transplant was performed.

Pathophysiology

AITL is derived from follicular helper T cells that are genetically and molecularly distinct from T cells giving rise to other T cell lymphomas. Although trisomy 3, trisomy 5, and +X are common cytogenetic findings none are pathognomic and the role of these cytogenetic changes, if any, in the pathobiology of the disease remains undefined.

The tumor cells in AITL frequently express EBV and HHV 6 and these same viruses are often found in a clonal B cell infiltrate associated with AITL. Again, the pathophysiologic link between these viruses and the development of AITL remains undefined. Investigators have postulated that the clonal B cells support the growth of the tumor cells though targeting the B cells with the monoclonal anti-CD20 antibody rituximab has not provided a therapeutic benefit.

Gene expression profiling of AITL has demonstrated overrepresentation of genes involved in cell-to-cell communication and adhesion, immune response, vascular biology, and the extracellular matrix. Other investigators have demonstrated that expression of molecular products involved in immune tolerance and high expression of receptors or cell-adhesion molecules that mediate proliferative signals, including platelet derived growth factor receptor alpha (PDGFRα) and platelet derived growth factor receptor beta (PDGFRβ), were associated with a poor prognosis independent of the IPI. Conversely, transcripts that have inhibitory effects on myeloid cell functions, that are associated with B cells, or that encode members of the ribosomal protein synthesis pathway were independently associated with a good prognosis. The pathophysiologic implications of these findings remain to be defined and these findings have not yet led to the development of individualized treatment approaches.

What other clinical manifestations may help me to diagnose angioimmunoblastic T cell lymphoma?

As mentioned in preceding sections, AITL should be considered in any patient presenting with a constellation of lymphadenopathy, rash, autoimmune phenomena, and/or systemic symptoms (fevers, night sweats, weight loss).

What other additional laboratory studies may be ordered?

Females of reproductive age should undergo a serum or urine pregnancy test if chemotherapy is contemplated since most chemotherapeutics are teratogenic, particularly if given in the first trimester.

Males should be counselled about sperm banking and warned that many men will be transiently infertile as a result of the disease itself, especially if they have "B" symptoms such as night sweats and unintentional weight loss.

If anthracycline based chemotherapy is planned patients should have an assessment of left ventricular function by either echocardiogram or multi-gated acquisition (MUGA) scan.

A lumbar puncture for cell count, differential, cytology, flow cytometry, protein, and glucose is only necessary if there is clinical or radiographic evidence of CNS involvement. Lumbar puncture is not otherwise warranted given the AITL does not commonly affect the central nervous system.

Serologies for viral hepatitis B are helpful prior to chemotherapy that includes prednisone since reactivation or worsening of hepatitis B can occur in this setting. Suppressive therapy for hepatitis B may be required.

Patients at high risk for prior tuberculosis exposure should have a purified protein derivative (PPD) test placed prior to chemotherapy as reactivation can occur and suppressive therapy may be needed.

What’s the evidence?

Murad, N, Mounier, N, Briere, J. "Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the Group d'Etude des Lymphomes de l'Adulte (GELA) trials". Blood. vol. 111. 2008. pp. 4463-70.

[The largest and best series examining the clinical characteristics of AITL.]

Lachenal, F, Berger, F, Ghesquières, H. "Angioimmunoblastic T-cell lymphoma: clinical and laboratory features at diagnosis in 77 patients". Medicine (Baltimore). vol. 86. 2007 Sep. pp. 282-9.

[A very nice description of the presenting features of AITL.]

Park, BB, Ryoo, BY, Lee, JH. "Clinical features and treatment outcomes of angioimmunoblastic T-cell lymphoma". Leuk Lymphoma. vol. 48. 2007. pp. 716-22.

[A comparatively large study evaluating the natural history of AITL.]

Krenacs, L, Schaerli, P, Kis, G, Bagdi, E. "Phenotype of neoplastic cells in angioimmunoblastic T-cell lymphoma is consistent with activated follicular helper T cells". Blood. vol. 108. 2006. pp. 1110-11.

[Important paper describing derivation of AITL from T follicular helper cells.]

Attygalle, AD, Chuang, SS, Diss, TC. "Distinguishing angioimmunoblastic T-cell lymphoma from peripheral T-cell lymphoma, unspecified, using morphology, immunophenotype, and molecular genetics". Histopathology. vol. 50. 2007. pp. 498-508.

[Helps establish diagnostic criteria distinguishing AITL from the more common PTCL, NOS.]

Iqbal, J, Weisenburger, DD, Greiner, TC. "Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma". Blood. vol. 115. 2010. pp. 1026-1036.

[Examines the use of molecular techniques to provide diagnostic and prognostic information in PTCL and AITL.]

Schmitz, N, Trumper, L, Ziepert, M. "Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group". Blood. vol. 116. 2010. pp. 3418-25.

[Evidence that CHOP is still largely standard therapy of choice; suggests addition of etoposide to CHOP may be useful in a subset of patients.]

Siegert, W, Agthe, A, Griesser, H. "Treatment of angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma using prednisone with or without the COPBLAM/IMVP-16 regimen. A multicenter study. Kiel Lymphoma Study Group". Ann Intern Med. vol. 117. 1992 Sep 1. pp. 364-70.

[Early study suggesting an advantage to chemotherapy over prednisone alone.]

Kyriakou, C, Canals, C, Goldstone, A. "High-dose therapy and autologous stem-cell transplantation in angioimmunoblastic lymphoma: complete remission at transplantation is the major determinant of Outcome-Lymphoma Working Party of the European Group for Blood and Marrow Transplantation". J Clin Oncol. vol. 26. 2008 Jan 10. pp. 218-24.

Kyriakou, C, Canals, C, Finke, J. "Allogeneic stem cell transplantation is able to induce long-term remissions in angioimmunoblastic T-cell lymphoma: a retrospective study from the lymphoma working party for the European group for blood and marrow transplantation". J Clin Oncol. vol. 27. 2009. pp. 3951-58.

[The two studies listed above are the major studies establishing the current role ofautologous and allogeneic stem cell transplantation in AITL.]

Advani, R, Horwitz, S, Zelenetz, A, Horning, SJ. "Angioimmunoblastic T cell lymphoma: treatment experience with cyclosporine". Leuk Lymphoma. vol. 48. 2007. pp. 521-25.

Dang, NH, Pro, B, Hagemeister, FB. "Phase II trial of denileukin diftitox for relapsed/refractory T-cell non-Hodgkin lymphoma". Br J Haematol. vol. 136. 2007 Feb. pp. 439-47.

Gallamini, A, Zaja, F, Patti, C. "Alemtuzumab (Campath-1H) and CHOP chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial". Blood. vol. 110. 2007 Oct 1. pp. 2316-23.

Zinzani, PL, Musuraca, G, Tani, M. "Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma". J Clin Oncol. vol. 25. 2007 Sep 20. pp. 4293-7.

Mercieca, J, Matutes, E, Dearden, C, MacLennan, K, Catovsky, D. "The role of pentostatin in the treatment of T-cell malignancies: analysis of response rate in 145 patients according to disease subtype". J Clin Oncol. vol. 12. 1994. pp. 2588-93.

[The five studies listed above are the significant studies that established apotential role for their respective therapeutic agents in AITL.]
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