Abstract
Angioimmunoblastic T-cell lymphoma (AITL) is a special subtype of
peripheral T-cell lymphoma with a poor prognosis, clinical
manifestations combinationed with immunohistochemistry, gene
rearrangement and so on can increase the diagnostic accuracy.
Introduction: Angioimmunoblastic T-cell lymphoma (AITL) is a
special subtype of peripheral T-cell lymphoma, Histopathological
examination is the main basis for the diagnosis of the disease, but due
to lack of specific pathological characteristics, the diagnosis is
challenging. The study has shown that combining immunohistochemistry and
gene rearrangement can increase the diagnostic accuracy.
Patient Concerns: A 56-year-old male patient was admitted to
the hospital due to skin redness and itching for 4 months.
Diagnoses: The patient was diagnosed with AITL with Hodgkin’s
lymphoma based on lymph node biopsy, immunohistochemistry, gene
rearrangement and positron emission tomography computer tomography
Keywords: follicular lymphoma, myelofibrosis,
immunohistochemistry, cytokines
Introduction
Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral
T-cell lymphoma with poor prognosis1 accounting for
1–2% of non-Hodgkin’s lymphoma and 15–20% of peripheral T-cell
lymphoma. The median age is approximately 65 years. The clinical
manifestations mostly include fever, weight loss, urticaria, papules,
red nodules, and skin lesions2 Due to the abnormal
proliferation activity of B cells, AITL is often accompanied by
autoimmune disorders, such as hemolytic anemia and
hypergammaglobulinemia. Studies have shown the Epstein-Barr virus (EBV)
to play an important role in the pathogenesis of AITL; EBV can stimulate
the activation of helper T cells, thereby leading to the occurrence of
tumors. While histopathological examination forms the basis for
diagnosis of the disease, the latter still remains challenging due to
the lack of specific pathological characteristics. The current study
suggested that combination of immunohistochemistry and gene
rearrangement can increase diagnostic accuracy. CD10 and CXCL13 are
specifically expressed in AITL and can be used as characteristic markers
for the diagnosis of AITL. The clonal rearrangement of IgH gene and TCRγ
would also be of great significance in the diagnosis.
Case Report
A 56-year-old man was admitted to the hospital with Hodgkin’s lymphoma.
The patient received ABVD and AVD chemotherapy, and all details of
unsatisfactory treatment effect were collected, wherefrom
angioimmunoblastic T-cell lymphoma and focal classical Hodgkin’s
lymphoma (compound lymphoma) were revealed. CD21 was found to shrink and
destroy the FDC network, CD20+; PAX-5+; CD3+; Ki-67+: 20 %–30%;
CD10–; BCL-6+; MUM-1+; PD-1+; CXCL-13-; CD30+; CD15-. Molecular
detection: TCRβDB+Jβ1/2 showed monoclonal rearrangement, and Vβ+Jβ2
showed oligoclonal rearrangement.
The patient was admitted to the hospital owing to skin redness and
itching for 4 months. Physical examination revealed extensive redness,
swelling, and rough skin on the head, neck, and limbs. There were
multiple enlarged lymph nodes in the right armpit and bilateral groin.
The largest one was approximately 4 cm in diameter, with a smooth
surface, no tenderness, and good mobility. The laboratory examination
results are presented in Table 1. At first, a proliferative disease of
the lymphatic system was suspected; a punch biopsy was performed, whose
histological diagnosis documented classic Hodgkin’s lymphoma,
lymphocyte-rich type, with molecular detection: EBER (+). In addition,
CD3+ lymphocytes occupied 96.1% , positively expressing CD3 and CD5,
whereas some expressed TCRrd, and a small number expressed CD8, as per
immunohistochemistry . Multiple organs with lymph node infiltration were
detected using radiological imaging. Interestingly, the patient
presented with skin redness. The patient completed the ABVD (doxorubicin
hydrochloride liposome 40 mg ivgtt d1, 15; bleomycin 10 mg/m2 iv d1, 15;
vindesine 4 mg iv d1, 15; dacarbazine 375 mg/m2 iv d1,15) chemotherapy,
followed by AVD in the second course. However, he tended to have a poor
performance status, and skin pruritus symptoms were aggravated.
Immunohistochemical examination of the skin revealed CD20 +, PAX-5 +,
CD3 +, Ki-67 + (20–30%), CD10-, BCL-6 +, MUM-1 +, PD-1 +, CXCL-13-,
CD30 +, and CD15-(Fig. and 1,2). TCRβDB+Jβ1/2 showed monoclonal
rearrangement, and Vβ+Jβ2 showed oligoclonal rearrangement upon
molecular examination with PTPRD gene mutation. Pathological diagnosis
was non-Hodgkin peripheral (mature) T-cell lymphoma, prone to
angioimmunoblastic T-cell lymphoma. Due to the angioimmunoblastic T-cell
lymphoma with Hodgkin’s lymphoma, it was decided that the patient would
be followed-up with EDOCH chemotherapy; however, unfortunately, he died
of lung infection.
Discussion
AITL is a special subtype of peripheral T-cell lymphoma that originates
from follicular helper T cells (TFH), often with fever, night sweats,
weight loss, lymphadenopathy, skin rash, and other clinical
manifestations3 Skin involvement is one of the most
common extranodal manifestations of the disease4 Due
to the heterogeneity of AITL, most cases do not get diagnosed until
weeks or months after the onset of symptoms.
While the diagnosis of AITL relies on lymph node biopsy, some patients
may be diagnosed after 2–3 lymph node biopsies. The pathological
features include the destruction of lymph node structure, the tumor
cells being mainly of medium size, the cytoplasm being lightly stained
or transparent, the nucleus being generally round or oval, and the cell
being atypical . In the background of inflammatory cells, such as
eosinophils, lymphocytes, and plasma cells, large cells of varying
numbers are scattered. The TFH phenotype is positive for CD3, CD4, and
CD105 Most CD5 and CD7 expression are
absent6 CD30 is found in 20% of
patients7 Cytoplasmic CXCL13 is almost uniformly
expressed, and is specific for AITL8 TFH expression of
PD-1, ICOS, BCL-6, and CD200 can be distinguished from that in benign
lymphoproliferative diseases and PTCL subtypes. Approximately 60% of
patients have TCR gene rearrangements, as seen in TCβ, TCD, and TCG
rearrangements, whereas some patients have IgH gene rearrangements. In
recent years, with advanced research on genomics, AITL has been found to
have higher TET2, RHOA, IDH2, and DNMT3A mutations, especially TET2
mutations, which are related to poor prognosis9However, AITL currently lacks a systematic method of identification, and
hence its diagnosis is still challenging.
The occurrence of AITL is highly correlated with EBV infection.
EBV-infected B cells can transmit EBV protein signals on their surface
to T cells through major histocompatibility complex II (MHCII) molecules
when TFH cells interact with B cells. Cells up-regulate the expression
of CD ligands, provide antigen and costimulatory signals for T cell
activation, and promote the secretion of chemokine
CXCL1310 which subsequently leads to B cell
activation. Laforga et al11 had proposed the
hypothesis that EBV promotes the proliferation of B cells in AITL. They
believed that due to the effect of EBV, CD8-positive T cells are
immunosuppressed, leading to oversight of EBV-positive B cells.
EBV-infected B cells lose control and may be polyclonal, oligoclonal, or
monoclonal. If the immunoglobulin structure is broken, B cells can have
three outcomes: 1. proliferation resembling that of RS cells; 2.
proliferation resembling that in CHL; or 3. it might develop into CHL.
In the 2008 edition of the ‘WHO Classification of Tumors of
Hematopoietic and Lymphoid Tissues’, RS-like cells were mentioned, for
the first time, to be seen in early AITL12; AITL and
CHL also have lymph node structure destruction, and plasma cell, tissue
cell, and other inflammatory cell infiltration, in addition to a
correlation with EBV infection13 thereby confirming
the dependence of AITL and CHL on immunophenotypes only. The
immunophenotype of CHL includes CD15+, CD30+, PAX-5 weakly positive,
CD3-, CD20- (mainly), CD45-, and CD79a-, which combined with RS cells,
help in the diagnosis14,15 CHL and AITL are two types
of lymphoma with extremely different prognoses. While CHL has good
prognosis, with a 5-year overall survival (OS) rate >
80%16 AITL has poor prognosis. A retrospective
analysis had found (after CHOP chemotherapy in elderly patients with
AITL) the CR rate to be 25%, and the median OS to be only 14.9 months.
At present, ABVD is the first-line treatment for CHL, and most patients
benefit from it. However, AITL progresses rapidly with high mortality
rate. Therefore, patients with newly diagnosed lymphoma should be
verified based on clinical phenotype, pathological morphology, and
immunohistochemistry for better and successful.
The Key Clinical Message
Clinical manifestations combinationed with immunohistochemistry, gene
rearrangement can increase the diagnostic accuracy of lymphoma.