88-year-old Female with Lymphadenopathy. Faizi Ali, MD

Transcription

1 88-year-old Female with Lymphadenopathy Faizi Ali, MD

2 Clinical History A 88-year-old caucasian female presented to our hospital with the complaints of nausea, vomiting,diarrhea, shortness of breath and lower quadrant pain. P/E: Extensive cervical and intra-abdominal lymphadenopathy on palpation, Bibasilar crackles and Right sided pleural effusion on auscultation and 2+ pitting bilateral lower extremity edema.

3 Clinical History. Vitals: BP: 161/79 mm/hg, Pulse:80/min with regular rate and rhythm, RR: 18/min CBC: Mild Normocytic hypochromic anemia with Hg: 11.1 g/dl Plt: 250 b/l WBC: 15.5 B/L A comprehensive metabolic panel showed BUN 34 mg/dl, creatinine 2.1mg/dL, Na+ 129 mmol/l, ( ) K+ 4.2, total proteins 9.1g/dL( ) albumin 1.7( ) and globulins 7.4 g/dl( ). Cardiac enzymes were normal

4 Clinical History Pt. also developed acute renal failure which was thought to be obstructive secondary to extensive intra-abdominal periaortic lymph nodes near renal hilum. PMH : Negative for DM,MI,CHF or any kidney disease. PSH: Cholecystectomy and appendectomy 30 years ago.

5 Clinical History. Finally, a left cervical lymph node biopsy was performed to rule out lymphoma.

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11 CD-20

12 CD-3

13 CD-43

14 CD-4

15 CD-8

16 CD-10

17 CD-20

18 IMS Other: CD-5 Focally positive Plasma Cell: Focally positive Kappa: focally positive Lambda: focally positive

19 Immunophenotype Aberrant T-cell population expressing CD-2, CD-4, CD-5, CD-7, CD-10 and lacking CD-3, CD-8, CD-56, CD-57. Increased Plasma cells at 20% with bright CD-19 and CD-38 expression without light chain restriction.

20 Diagnosis Angioimmunoblastic T-cell Lymphoma

21 BM Bx

22 BM Bx

23 BM Bx Summary: Bone marrow plasmacytosis (25%-35%) with no immunophenotypic evidence of light chain restriction.

24 NHL--Incidence Diagnosis % of total cases 1. Diffuse large B cell 33% Mediastinal 2% 2. Follicular 22% Grade 1 10% Grade 2 6% Grade 3 6% 55% 3. Marginal zone 9% 4. CLL/SLL 7% 5. Mantle cell 6% 6. Burkitt 3% 80% 7. Lymphoplasmacytic 1% 8. T and NK neoplasia 12% Other types 7% Non-Hodgkin s lymphoma classification project, 1997

25 Incidence of Peripheral T-cell Lymphoma Subtypes Diffuse Large B- cell Follicular Lymphoma Marginal Zone B-cell Peripheral T-cell Lymphoma CLL/SLL

26 W.H.O. classification of mature T-cell and NK-cell neoplasms (2001) Leukemic/Disseminated T-cell PLL T-cell LGL leukemia Agrressive NK leukemia Adult T-cell leukemia/lymphoma Cutaneous Mycosis fungoides Sezary syndrome 1 cutaneous ALCL Lymphomatoid papulosis Blastic NK cell lymphoma Other Extranodal Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Nodal Angioimmunoblastic lymphoma (2%) Peripheral T-cell lymphoma, unspecified (3.7%) Anaplastic large cell lymphoma (2.4%)

27 Angioimmunoblastic T-cell Lymphoma Definition: Peripheral T cell lymphoma characterised by systemic disease, a polymorphous infiltrate involving lymph nodes, with a prominent proliferation of high endothelial venules and follicular dendritic cells.

28 AILT.History Initially thought to be an abnormal reactive process, a disorder of immune regulation showing angioimmunoblastic lymadenoapthy, with an increased risk of progression to lymphoma. Later defined as a form of peripheral T-cell lymphoma arising as de novo.

29 Epidemiology Occurs in middle aged and elderly pts. with equal incidence in males and females. One of the more common specific subtypes of peripheral T-cell neoplasms, accounting 15-20% of Peripheral T cell lymphomas 1-2% of all non-hodgkin lymphomas

30 Etiology Epstein-Barr Virus (EBV) is found in majority of cases (75%) However, most of the EBV positive cells are B-cells.

31 Clinical Features Pt.s usually present in advanced stage disease, with Generalized lymphadenopathy Hepatosplenomegaly Skin rash with pruritis, and fever Pleural effusions, ascites and or edema. Bone marrow commonly involved on biopsy Lab findings include: Polyclonal hypergammaglobulinemia, hemolytic anemia, positive rheumatoid factor and anti-smooth muscle antibodies.

32 Pathologic Features Partially effaced LN architecure with regressed or absent follicles in most cases. Arborizing vasculature Atypical T-lymphocytes with clear cytoplasm Scattered B-immunoblasts Plasmacytosis, eosinophils Increased number of follicular dendritic cells Rare cases have follicular hyperplasia

33 Immunophenotypic features Extensive FDC CD21+meshwork surrounding high endothelial venules (HEV) CD4+, CD10+, BCL-6+ T-cells Scattered large B-cell blasts, usually EBV+ Polyclonal plasma cells

34 Grading Grading of AILT is generally not peformed but increase in T-cell immunoblast may be observed over time.

35 Origin of AITL. Kim et al,2004 Revealed for the first time the unique gene expression pattern of GC-Th cells in comparison with other CD-4+ subsets. CXCL13, a critical chemokine for B-cell entry to lymphoid follicles, is one of the most highly up-regulated genes in GC-Th cells (but not in other T cells).

36 Grogg et al 2005, Blood Angioimmunoblastic T-cell lymphoma: a neoplasm of germinal-center T-helper cells? We have read the paper by Kim et al 1 recently published in Blood with great interest. The study reports the gene-expression profile of germinalcenter T-helper (GC-Th) cells and identifies genes differentially expressed by G-C-Th cells compared with other T-cell subsets.

37 Grogg et al 2005, Blood Based on this observation, we investigated the expression of CXCL13 in AITL. We stained paraffin sections of 29 AITL lymph-node biopsies using a monoclonal antibody against CXCL13 (Clone 53610; R&D Systems, Minneapolis, MN) and standard immunohistochemical methods. All cases were previously characterized by immunohistochemical studies that documented expression of CD3 and CD4 by the tumor cells. CD10 was expressed in 22 cases. We observed striking cytoplasmic expression of CXCL13 by the vast majority of the tumor cells (> 80%) in 25 (86%) of 29 AITL cases studied.

38 Copyright 2005 American Society of Hematology. Copyright restrictions may apply. Figure 1. CXCL13 expression in AITL Grogg, K. L. et al. Blood 2005;106:

39 Kadin and Kikuchi et al Hum Pathol. 1999;30: Bcl-6 expression in reactive follicular hyperplasia, follicular lymphoma, and angioimmunoblastic T-cell lymphoma with hyperplastic germinal centers: Heterogeneity of intrafollicular T-cells and their altered distribution in the pathogenesis of angioimmunoblastic T- cell lymphoma

40 CXCL 13 and Germinal Center Th cells GC Th cells express CD10 and Bcl-6 GC Th cells express CXCL 13 CXCL 13 causes induction and proliferation of follicular dendritic cells CXCL 13 is involved in B-cell recruitment to LN s and activation of B-cells CXCL 13 is required for the adhesion and arrest of B-cells on HEV s

41 Angioimmunoblastic T-cells Express CD10 Dogan et al.blood 2002

42 Angioimmunoblastic T-cell Lymphoma Is a disease of germinal center derived T-cells (Th cell)

43 Genotypic Analysis of AILT Summary of 95 cases from 6 studies Elaine Jaffee TCR Rearrangement 70/95 (74%) Why is clonal TCR not detected in all cases? CD10+ T-cells may represent a minority of cells present in some cases Some cases may be misdiagnosed Differential diagnosis of atypical paracortical hyperplasia and AILT a problem, especially in older series Small false negative rate by PCR

44 Genotypic Analysis of AILT Summary of 95 cases from 6 studies lgh R 12/95 (13%) Why does a T-cell lymphoma contain clonal B-cell expansion? B-cell/ plasma cell proliferation is a constant feature of AITL Expansion of EBV+ B-cells may lead to B-cell clones

45 EBV + cells nearly universally found, and are CD20+ B-cells

46 Prognosis and Predictive Factors Clinical course is aggressive with a median survival < 3 years High risk of infectious complications with treatment which makes delivery of aggressive chemotherapy difficult.

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48 The Doctrine of T-cell Lymphoma according to Rumsfeld there are known knowns; there are things we know we know. We also know there are known unknowns; that is to say we know there are some things we do not know. But there are also unknown unknowns the ones we don t know we don t know. Donald H. Rumsfeld (February 12, 2002)