Secondary cutaneous Epstein-Barr virus-associated diffuse large B-cell lymphoma in a patient with angioimmunoblastic T-cell lymphoma: a case report and review of literature
https://doi.org/10.1186/1746-1596-7-7
© Yang et al; licensee BioMed Central Ltd. 2012
Received: 22 November 2011
Accepted: 19 January 2012
Published: 19 January 2012
Abstract
Only a few cases of extranodal Epstein-Barr virus (EBV)-associated B-cell lymphomas arising from patients with angioimmunoblastic T-cell lymphoma (AITL) have been described. We report a case of AITL of which secondary cutaneous EBV-associated diffuse large B-cell lymphoma (DLBCL) developed after the initial diagnosis of AITL. A 65-year-old Chinese male patient was diagnosed as AITL based on typical histological and immunohistochemical characteristics in biopsy of the enlarged right inguinal lymph nodes. The patient initially received 6 cycles of chemotherapy with CHOP regimen (cyclophosphamide, vincristine, adriamycin, prednisone), but his symptoms did not disappear. Nineteen months after initial diagnosis of AITL, the patient was hospitalized again because of multiple plaques and nodules on the skin. The skin biopsy was performed, but this time the tumor was composed of large, polymorphous population of lymphocytes with CD20 and CD79a positive on immunohistochemical staining. The tumor cells were strong positive for EBER by in situ hybridization. The findings of skin biopsy were compatible with EBV-associated DLBCL. CHOP-R chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab) was then administered, resulting in partial response of the disease with pancytopenia and suppression of cellular immunity. To our knowledge, this is the first case of cutaneous EBV-associated DLBCL originated from AITL in Chinese pepole. We suggest the patients with AITL should perform lymph node and skin biopsies regularly in the course of the disease to detect the progression of secondary lymphomas.
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Keywords
Background
Angioimmunoblastic T-cell lymphoma (AITL) is one of the most common subtypes of peripheral T-cell lymphomas, accounting for approximately 15-20% of all cases, or 1-2% of all non-Hodgkin lymphomas [1]. AITL is frequently accompanied by a polymorphic nature including fever, skin eruptions, polyclonal hypergammaglobulinemia, generalized lymphadenopathy and hepatosplenomegaly [2]. Histopathologically, the primary site of AITL is lymph node characterized by the effacement of the lymph node architecture, the increase of arborizing high endothelial venules and the infiltration of clear small- to medium-sized lymphocytes, along with the increase of B-immunoblasts that usually contain Epstein-Barr virus (EBV). AITL patients exhibit immunodeficiency secondary to the neoplastic process. Expansion of EBV-positive B cell is thought to be a consequence of underlying immune dysfunction [3]. In rare condition, secondary EBV-associated B cell lymphoma may occur together with AITL. However, to our knowledge, so far only 22 cases of AITL developed EBV-associated secondary B cell lymphomas have been described in English literature [4–14]. Herein, we report a case of secondary EBV-associated diffuse large B cell lymphoma occurring in the skin of a patient with lymph node AITL.
Case presentation
A 65-year-old Chinese male patient presented with a 6-month history of enlarged right inguinal lymph nodes without pain and fever and initially sought examination and treatment at our hospital in September, 2009. Physical examination revealed multiple enlarged lymph nodes easily identified in the right inguinal region, and the spleen was palpable 2 cm below the left costal margin without discrete masses or tenderness. Maculopapular eruptions could be found in the trunk. There was no remarkable edema and masses observed in the skin. The laboratory results including blood count, differential, liver and renal function were within the normal range. Eosinophilia and hypergammaglobulinemia were not observed. Computed tomography (CT) scan disclosed the enlargement of right inguinal and visceral lymph nodes, as well as hepatosplenomegaly. Test for EBV exhibited both viral capsid antigen (VCA) and EBV-associated antigen positive.
Histopathological findings of lymph node at the initial presentation. (A) The architecture of lymph node was effaced by a diffuse polymorphic infiltration composed of small- to medium-sized lymphoid cells, immunoblastic cells and scattered eosinophils around high-endothelial venules. (B) Multinucleated cells with eosinophilic nucleoli resembling Reed-Stemberg (RS) cells could be observed in the lymph node. (C) Immunohistochemical examination revealed that infiltrated small to medium-sized lymphoid cells were diffusely positive for CD3, but large immunoblast-like cells and RS-like cells were positive for CD20 (D) and CD30 (E).These larger cells were also positive for EBER by in situ hybridization (F).(A, H&E staining, with original magnification ×400; B, H&E staining, with original magnification ×600; C-E, immunohistochemical staining, with original magnification ×400; F, EBER-in situ hybridization, with original magnification ×400).
After the diagnosis of AITL, the patient received 6 cycles of chemotherapy with CHOP regimen (cyclophosphamide, vincristine, adriamycin, and prednisone), but his symptoms did not disappear. The patient was followed up without any treatment for nearly one year after completing the whole chemotherapy courses. There was no further complaint from the patient during the follow-up period. In April, 2011, nineteen months after initial diagnosis the patient was readmitted to our hospital due to presentation of multiple plaques and nodules on the skin. Skin examination showed irregular plaques and nodules ranging from 0.5 to 2.5 cm in diameters in the trunk and extremities. CT scan revealed multiple enlargements of right inguinal and visceral lymph nodes as well as hepatosplenomegaly. Bone marrow aspiration was normal. The skin biopsies were performed in the skin lesion located at the left upper arm.
Histological findings of skin lesion. (A) Low power view of skin lesion showed diffuse infiltration of lymphoid cells in dermal and subcutaneous tissue without epidermotropism. (B) Large atypical lymphoid cells with prominent nucleoli were observed in the skin lesion. Atypical large lymphoid cells were stained positively with CD20 (C) and CD79a (D). However, CD3 positive cells in skin lesion were small lymphocytes with scattered distribution (E). (F) Most of atypical large cells were positive for EBER by in situ hybridization. (A, H&E staining, with original magnification ×40; B, H&E staining, with original magnification ×400; C-E, immunohistochemical staining, with original magnification ×400; F, EBER-in situ hybridization, with original magnification ×400).
After diagnosis, the patient received a cycle of R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and achieved a partial response. However, pancytopenia and suppression of cellular immunity were observed. The patient refused further treatment of R-hyperCVAD regimen (rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and was discharged from hospital. The further following up was not performed due to contact loss of the patient.
Angioimmunoblastic T-cell lymphoma (AITL) was previously regarded to be an atypical reactive process. In 1974, Frizzera et al. firstly termed it as "angioimmunoblastic lymphadenopathy with dysproteinemia (AILD)" [15], of which AILD was described as a reactive lymphoproliferative disorder of T lymphocytes [16]. AITL was considered as a malignant transformation of AILD, but the histological distinguishing AITL from AILD was quite difficult. In the past, the presence of clusters of cells with abundant clear cytoplasm was regarded as one of the most important morphological criteria and used to distinguish AITL from AILD. However, subsequent molecular and cytogenetic studies revealed that clonal TCR gene rearrangement and chromosomal abnormalities were identified in the majority of AILD [17, 18], which indicated most cases previously diagnosed as AILD actually represented AITL. In 2001, WHO classification of tumor of hematopoietic and lymphoid tissue suggested AITL was most likely to arise as a peripheral T-cell lymphoma. As both terms of AITL and AILD were in common use, they could be used interchangeably in clinics. However, some researchers argued that a few cases of AILD with atypical or oligoclonal proliferation might precede the development of AITL, and should be classified as a distinct entity of preneoplastic process [19, 20]. Although debate remained, we considered AILD might represent the existence of stages in the development of AITL rather than independent disease entities.
Although the pathogenesis of AITL remains unclear, it is currently thought to most likely derived from germinal-center T-helper cells (TFH) [21]. The primary site of AITL is lymph node and virtually all patients present with generalized lymphadenopathy. Histological examination of the lymph nodes exhibits nearly complete effacement of the follicular architecture, a mixed lymphoid infiltrate, and numerous high endothelial venules in an expanded T-cell zone. In some cases, the lymph nodes show diffuse obliteration of their architecture by lymphoid infiltration consisting of lymphocytes, immunoblasts, plasma cells, and histiocytes, together with numerous high endothelial venules surrounded by an expanded network of follicular dendritic cells. Immunohistochemically, the neoplastic cells express most pan T-cell antigens such as CD2, CD3 and CD5. The majority of the proliferating cells are CD4 positive or, less often, CD8 positive [3]. Attygalle et al. demonstrated that CD10 was a phenotypic marker, which specifically identified the tumor cells of 90% of AITL [22]. Dorfman et al. reported that programmed death-1 (PD-1), a member of the CD28 costimulatory receptor family, is expressed by germinal center-associated T cells in AITL [23]. De Leval et al. indicated tumor cells in AITL could overexpress CXCL13, which is the characteristic of normal TFH cells [21]. These researchers suggest those immunophenotypes are helpful to distinguish AITL from atypical paracortical hyperplasia and other peripheral T-cell lymphomas as well as diagnosing extranodal dissemination. In our case, not only histological examination of lymph node demonstrated a morphological characteristic of AITL, but also the presence of T-cell linage with aberrant CD4 and CD10 expression identified in neoplastic cells by immunohistochemical staining which also strongly supported a diagnosis of AITL at initial lymph node biopsy.
Clinicopathological features of patients with AITL-developed secondary EBV-associated B cell lymphoma described in present and previous reports
caseNo. | Authors (yr.) | Age/sex | Tumor site | Interval (mo) | Histotype of BCL* | Treatment | Clinical Outcome | ||
---|---|---|---|---|---|---|---|---|---|
AITL | BCL | AITL | BCL | ||||||
1 | Abruzzo LV (1993) [4] | 46/M | LN | SK | 26 | Large-cell immunoblastic type | Cyclophosphamide | N/D | Died of multiorgan failure |
2 | Park S (2002) [5] | 55/F | LN | LN | 48 | BCL | CHOP | CHOP-R | CR and alive 12 mo later |
3 | Xu Y (2002) [6] | 48/F | LN | LN | 0 | DLBCL | CHOP and ESHAP | CR and relapsed a few months later | |
4 | Zettl A (2002) [7] | 68/M | LN | ST | 34 | DLBCL | Observation | Glucocorticoids | Died 4 mo later of tuberculosis |
5 | 47/M | LN | LN | 29 | DLBCL | CC; BMT | CC; involved field radiation | Died 3 mo later of Aspergillus pneumonia | |
6 | 61/M | LN | LN | 96 | Plasmacytoma | N/Av | N/Av | Alive with disease 24 mo later | |
7 | Hawley RC (2006) [8] | 69/F | LN | SK | 56 | DLBCL | CHOP | R-hyperCVAD | Died 54 mo later |
8 | Attygalle AD (2007) [9] | 28/M | LN | BM | 24 | DLBCL | CHOP | Gemcitabine | No response and died 3 mo later |
9 | 60/F | LN | LN | 8 | DLBCL | CHOP | CHOP-Et | No response and died 3 mo later | |
10 | 59/M | LN | LN | 8 | DLBCL | N/Av | CC | PR and alive with disease 68 mo later | |
11 | 72/M | LN | LN | 84 | DLBCL | N/Av | N/Av | N/A | |
12 | 78/F | LN | LN | 0 | DLBCL | Thalidomide | PR | ||
13 | Willenbrock K (2007) [10] | 76/F | LN | LN | 8 | DLBCL | N/Av | N/Av | N/Av |
14 | 46/F | LN | BM | 5 | DLBCL | N/Av | N/Av | N/Av | |
15 | 84/M | LN | LN | 0 | DLBCL | N/Av | N/Av | N/Av | |
16 | 72/M | LN | LN | 0 | DLBCL | N/Av | N/Av | N/Av | |
17 | 65/M | LN | LN | 0 | CD30-positive BCL | N/Av | N/Av | N/Av | |
18 | 60/F | LN | LN | 0 | DLBCL | N/Av | N/Av | N/Av | |
19 | Weisel KC (2008) [11] | 59/M | LN | DB and lung | 11 | DLBCL | Fudarabine+ CHOP | N/D | Died 2 weeks later |
20 | Takahashi T (2010) [12] | 66/F | LN | Ileum | 24 | DLBCL | THPCOP CHASE | N/D | Died 1 mo later of respiratory failure |
21 | Skugor ND (2010) [13] | 36/F | LN | LN | 11 | DLBCL | FED | CHOP-R and stem cell transplantation | CR |
22 | Huang J (2011) [14] | 64/M | LN | LN | 47 | DLBCL | IHOP | CHOP-R | Alive with disease 13 mo later |
23 | Present case | 65/M | LN | SK | 19 | DLBCL | CHOP | CHOP-R | PR |
The presence of large immunoblast cells and scattered RS-like cells in AITL might create diagnostic confusion with other neoplastic condition of lymphoid tissue. The main differential diagnoses include classical Hodgkin lymphoma (cHL) and T cell/histiocyte-rich large B-cell lymphoma (THRLBCL). THRLBCL is characterized by a limited number of scattered, large, atypical B cells embedded in a background of abundant T cells and frequently histiocytes. Immunohistochemically, large atypical cells express pan B-cell markers and no expression of CD30, and are lack of EBV infection. The background of THRLBCL is composed of variable number of CD68-positive histiocytes and CD3-, CD5-positive small T cells rather than CD4-, CD10- and CXCL13-positive small to medium-sized TFH cells. Numerous high endothelial venules surrounded by an expanded network of follicular dendritic cells highlighted by CD21 and CD23 will be useful to distinguish AITL form THRLBCL. In this present case, an interesting finding was the presence of occasional CD30 and EBV-positive RS-like cells within inflammatory background of lymph node. This histological finding was similar to the morphological feature of cHL. However, recognition of cytologic atypia or immunophenotypic aberrancy in the background T cells is critical for making the differential diagnosis between AITL and cHL.
In conclusion, secondary B-cell lymphoma in AITL is rare. Herein we report the first case of cutaneous EBV-associated DLBCL sequential to AITL in Chinese patients. Extranodal involvement by secondary lymphoma in the patients with AITL might imply a poor prognosis. Therefore, clinicians should keep in mind that there is a possibility of sequential development of B-cell lymphoma after AITL. It is necessary to perform lymph node and skin biopsies regularly to detect the progression to secondary lymphomas for patients with AITL.
Consent
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Declarations
Authors’ Affiliations
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