The patient is a 69 year old male who presented to the hospital with a 3-month history of drenching night sweats, weight loss, fatigue, and generalized lymphadenopathy. He also endorsed a very itchy rash all over his body. He denied smoking. There was no other relevant social or family history.
Physical examination confirmed diffuse lymphadenopathy, hepatosplenomegaly and a mild diffuse skin rash. Notably, there was a 2.5 cm level-1 lymph node palpated in the left neck. This was subsequently biopsied.
Biopsy of the level-1 neck lymph node revealed a 2.3 x 1.5 x 1.2 cm mass pink-tan and firm mass. Sectioning revealed a glossy white-tan cut surface. H&E staining revealed a polymorphic lymphocytic infiltrate of in the interfollicular zones. The infiltrating lymphocytes ranged from small to large cells with abundant cytoplasm, eosinophils, and plasma cells. There was also a notable increase in the number of high endothelial vessels lined by lymphocytes with irregular nuclear borders and clear cytoplasmic zones.
Further characterization by immunohistochemical staining showed the majority of the interfollicular cells to be CD3 and CD5 expressing T cells. These were a mix of CD4 and CD8 positive cells but with marked CD4 predominance. CD7 appeared positive in a smaller population of T-cells compared to CD3 (consistent with loss of this pan-T-cell marker). Varying numbers of the interfollicular cells were positive for CD10, BCL-6, CXCL-13, and PD-1 with a strong positivity for ICOS, phenotypically consistent with an expansion of Tfh (T-follicular helper cell) cells.
Interspersed between the T cells were numerous CD20 positive cells with prominent nucleoli that also revealed CD30 positivity. CD21 staining revealed expanded follicular dendritic cell meshworks. EBER ISH was positive in a rare subset of cells. Kappa and lambda ISH showed an increased number of polytypic plasma cells.
Flow Cytometry showed the presence of a small population of T-cells that were CD4 positive but CD3 negative. There was no evidence of B-cell clonality. TCR-G PCR was positive.
A final diagnosis of Angioimmunoblastic T-cell lymphoma (AITL) was rendered.
AITL is a relatively rare neoplasm of mature T follicular helper cells, representing about 1-2% of all non-Hodgkin lymphomas. It is; however, one of the more common subtypes of peripheral T-cell lymphomas, accounting for 15-30% of this subgroup. The condition was first reported in 1974 in Lancet as a non-neoplastic abnormal immune reaction1. It was first recognized as a distinct clinical entity in in 1994 in the Revised European American Lymphoma Classification2. The disease shows a geological preference to Europe (28.7%) over Asia (17.9%) and North America (16%). AITL occurs primarily in middle aged and elderly individuals and shows a slight predominance of males over females.
The disease has a strong association with EBV infection, but the neoplastic T-cells are almost always EBV negative, creating an interesting question of EBV’s function in the etiology of AITL. AITL most often presents late in the disease course with diffuse systemic involvement, including hepatosplenomegaly, lymphadenopathy and other symptoms such as rash with pruritis and arthritis. Lab findings include cold agglutinins, rheumatoid factor and anti-smooth muscle antibodies. There also tends to be immunodeficiency secondary to the neoplastic process. The clinical course of AITL is variable, but the prognosis is poor, with the average survival time after diagnosis being < 3 years. The histological features and genetic findings have not been found to impact clinical course.
Microscopically, AITL presents with either partial or total effacement of the normal lymph node architecture with perinodal infiltration. The cells of AITL are small to medium-sized lymphocytes with clear to pale cytoplasm, distinct cell membranes and very minimal cytological atypia. These cells often congregate around the high endothelial venules. The T-lymphocytes are present in a largely polymorphous inflammatory background of other lymphocytes, histiocytes, plasma cells and eosinophils. There are 3 overlapping sub-patterns of AITL. The first of these is similar to a reactive follicular hyperplasia, and can only be distinguished from normal hyperplasia by use of immunohistochemical stains to differentiate the neoplastic cells from normal reactive cells. The second pattern has retained follicles, but they show regressive changes. The third pattern has completely or sub totally effaced. These three patterns seem to be on a spectrum with one another, given that progression from the first to the third pattern has been seen on consecutive biopsies in the same patient.
Cytologically, AITL cells express pan-T-cell markers including CD2, CD3 and CD5 and the vast majority are CD4 positive. CD3 may be quantitatively decreased or absent by flow cytometry. There are a variable number of CD8 positive T-cells. The tumor cells also show the immunophenotyping of normal T follicular helper cells including CD10, CXCL13, ICOS, BCL6 and PD1 in 60-100% of cases. CXCL13 and CD10 are the most specific, whereas PD1 and ICOS are the most sensitive.
- Horne, C., Fraser, R., & Petrie, J. (1974). Angio-Immunoblastic Lymphadenopathy With Dysproteinemia. The Lancet, 304(7875), 291. doi:10.1016/s0140-6736(74)91455-x
- Harris, N.l. “A Revised European-American Classification of Lymphoid Neoplasms: a Proposal from the International Lymphoma Study Group.” Current Diagnostic Pathology, vol. 2, no. 1, 1994, pp. 58–59., doi:10.1016/s0968-6053(00)80051-4.
- Swerdlow, Steven H. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer, 2017.
- “Angioimmunoblastic T Cell Lymphoma.” Pathology Outlines – PathologyOutlines.com, http://www.pathologyoutlines.com/topic/lymphomanonBAITL.html.
-Zachary Fattal is a 4th year medical student at the Central Michigan University College of Medicine. He is pursuing a career in pathology and has a special interest in hematopathology, cytopathology and blood bank/transfusion medicine. You can follow him on Twitter @Paraparacelsus.
–Kamran M. Mirza, MD, PhD, MLS(ASCP)CM is an Assistant Professor of Pathology and Medical Education at Loyola University Health System. A past top 5 honoree in ASCP’s Forty Under 40, Dr. Mirza was named to The Pathologist’s Power List of 2018. Follow him on twitter @kmirza.