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Corresponding author at: Division of Cardiology, Cardiovascular and Aortic Center, Saiseikai Fukuoka General Hospital, 1-3-46 Tenjin, Chuo-ku, Fukuoka 810-0001, Japan.
Adult T-cell leukemia/lymphoma (ATLL) is a mature peripheral T-cell neoplasm caused by human T-cell leukemia virus type I (HTLV-1) infection. Besides the oncogenic property, HTLV-1 causes HTLV-1-associated myelopathy/tropical spastic paraparesis and certain inflammatory diseases via a complex host immune response to latent virus infection. Cardiac involvement of ATLL is rare, with the majority of cases being disclosed in postmortem autopsy in patients with advanced subtypes. We herein report the case of a 64-year-old female patient with indolent chronic ATLL with severe mitral regurgitation. Although the condition of ATLL was stable, dyspnea on exertion gradually progressed over the course of three years and echocardiography revealed marked thickening of the mitral valve. Finally, the patient experienced hemodynamic collapse with atrial fibrillation and underwent surgical valve replacement. The removed mitral valve was grossly edematous and swollen. A histological examination revealed a granulomatous reaction mimicking the active phase of rheumatic valvulitis, with the infiltration of ATLL cells that were immunohistochemically positive for CD3, CD4, FoxP3, HLA-DRα, and CCR4. The postoperative course was uneventful, with the exception that Sjögren's syndrome was noted. The history of rheumatic fever was unclear, and such unique valvular pathology was presumably related to autoimmune mechanisms associated with HTLV-1 infection.
Learning objective
We report a case of chronic adult T-cell leukemia/lymphoma (ATLL) with isolated valvular infiltration with a unique histology of granulomatous reaction. Human T-cell leukemia virus type I infection may accelerate autoimmune reactions and cardiac inflammation, irrespective of indolent clinical subtype. Among ATLL cases, possible progression of valvular insufficiency and heart failure in patients with cardiac symptoms should be carefully evaluated.
Adult T-cell leukemia/lymphoma (ATLL) is a hematopoietic neoplasm of mature peripheral T lymphocytes associated with human T-lymphotropic virus type1 (HTLV-1) infection. The southern part of Japan, sub-Saharan Africa, and the Caribbean are known to be major endemic regions [
]. HTLV-1 causes latent virus infection. There are one million HTLV-1 carriers estimated in Japan, and 4–5 % of HTLV-1 carriers will develop ATLL in their lifetime. The tumorigenicity of HTLV-1 is counterbalanced by the host immune response and thus the clinical manifestations of HTLV-1 infected individuals are diverse [
]. ATLL is classified into four subtypes (acute, lymphoma, chronic, and smoldering) according to the Shimoyama classification, with the respective subtypes accounting for 50.8 %, 24.9 %, 13.8 % and 10.5 % of cases in a recent Japanese nationwide survey [
Besides the oncogenic property, HTLV-1 causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in 0.25–4 % of patients and also certain inflammatory diseases via a complex host immune response to latent virus infection [
]. Potential associations between HTLV-1 infection and the onset of Sjögren's syndrome, arthritis, polymyositis, and systemic lupus erythematosus have been reported [
]. Only a few cases of indolent ATLL have been reported to show isolated valvular involvement with a favorable prognosis after surgical valve replacement [
Adult T-cell leukemia/lymphoma revealed by a surgically cured cardiac valve lymphomatous involvement in an iranian woman: clinical, immunopathological and viromolecular studies.
]. We herein report the case of a patient with chronic ATLL who received valve replacement for severe valvular insufficiency. Histology revealed a unique granulomatous reaction mimicking the active phase of rheumatic valvulitis, with ATLL cell infiltration.
Case report
The patient was a 64-year-old woman who had been diagnosed with asymptomatic chronic ATLL 5 years previously. Cardiac enlargement was indicated on chest X-ray 3 years previously. She visited our hospital because of recent progressive worsening of shortness of breath. Her blood pressure was 116/76 mmHg and heart rate was 83 bpm, and regular. A physical examination showed no lower extremity edema; however, marked peripheral coldness was observed. Electrocardiography showed sinus rhythm, first-degree atrioventricular block, and complete right bundle branch block. Chest X-ray showed a markedly enlarged cardiothoracic ratio (79 %), without pleural effusion. Transthoracic echocardiography (TTE) revealed severe mitral regurgitation (MR; vena contracta 6.0 mm, regurgitant volume 90 mL, effective regurgitant orifice area 0.57 cm2) with marked thickening of the mitral valve and moderate aortic regurgitation (AR; pressure half time, 244 msec; vena contracta, 5.5 mm) (Fig. 1). TTE also revealed moderate tricuspid regurgitation. The blood test showed high white blood cell count 12,000/μL (neutrophils 66 %, lymphocytes 27.3 %, monocytes 5.6 %, eosinophils 0.5 %, basophils 0.6 %) and elevated aspartate amino transferase (229 U/L), and alanine amino transferase (352 U/L). Her blood hemoglobin and N-terminal prohormone of brain natriuretic peptide levels were 11.6 g/dL and 1558 pg/mL, respectively.
Fig. 1Mitral regurgitation and aortic regurgitation on transthoracic echocardiography (apical four-chamber view and parasternal long-axis view). (A) Irregular thickening of mitral valve (arrow) and dilated left atrium (LA). (B) Color flow imaging demonstrating severe mitral regurgitant jet into the LA. (C) Mitral valve and aortic valve on parasternal long-axis view. (D) Color flow imaging demonstrating moderate aortic regurgitation.
LV, left ventricle; RA, right atrium; RV, right ventricle; Ao, aorta.
Left ventricular end-diastolic and end-systolic diameter was 53/35 mm with preserved ejection fraction (60 %), and the thickness of interventricular septum and left ventricular posterior wall was 10/9 mm, respectively.
Coronary angiography showed no significant stenosis. Right heart catheterization revealed the following: mean pulmonary capillary wedge pressure, 25 mmHg; cardiac index, 1.4 L/min/m2; and SvO2, 44.9 %. Left ventriculography revealed severe MR (Sellers IV). Moreover, the patient developed paroxysmal atrial fibrillation with rapid ventricular response leading to cardiogenic shock. Under general anesthesia, mitral valve replacement (Medtronic MOSAIC 27 mm, Minneapolis, MN, USA), aortic valve replacement (Medtronic MOSAIC ULTRA 21 mm), tricuspid valve plasty (Carpentier Edwards Physio-Tricuspid 26 mm, Irvine, CA, USA), and Maze surgery were performed urgently.
Grossly, the resected mitral valve was thickened with edematous and dark brownish appearance with irregular surface (Fig. 2A ). Histology revealed diffuse infiltration of lymphoid cells, histiocytes, and a relatively small number of polymorphonuclear leukocytes in the fibrotic leaflets (Fig. 2B-D). Immunohistochemistry revealed that the majority of infiltrating lymphoid cells are positive for CD3 (pan-T cells) but not CD20 (pan-B cells). These CD3-postive lymphoid cells were also positive for CD4, FoxP3, HLA-DRα, and CCR4, consistent with ATLL infiltration (Fig. 2E, F). Moreover, small granulomatous lesions with the accumulation of histiocytes were scattered in valvular tissue with multinuclear giant cells, mimicking Aschoff nodules in active-stage rheumatic valvulitis (Fig. 2C). Although the vegetation was not noted grossly, small fibrinous aggregation equivalent to non-bacterial thrombotic endocarditis (NBTE) was sporadically observed.
Fig. 2Histology of the mitral valve. (A) Gross appearance (atrial view). Three segments of anterior mitral leaflet (AML: A1-A3) and posterior mitral leaflet (PML) are indicated. (B) Low-power view of AML shows diffuse infiltration of lymphoid cells. (C) High-power view of AML. Small granulomatous lesion with multinuclear giant cells (dotted circle). (D) High-power view of AML. Mixed infiltration of lymphoid cells, histiocytes, and a small number of polymorphonuclear leukocytes are seen. (B-D) Hematoxylin and eosin staining. Immunohistochemical staining for CD3 (E) and CCR4 (F) in the same part as panel D.
The aortic valve was tricuspid with a floppy appearance; however, focal thickening was present at the commissure without fusion (Fig. 3A ). Histologically, the aortic valve showed mild fibrous thickening, some myxomatous degeneration, and calcification (Fig. 3B) with infiltrating ATLL cells and small granulomatous lesions (Fig. 3C-F).
Fig. 3Histology of the aortic valve. (A) Gross appearance (aortic side view). Left and right coronary cusps (LCC, RCC) and noncoronary cusp (NCC) are indicated. (B) Low-power view of LCC shows severe calcification. (C) Medium-power view of LCC shows scattered small granulomatous lesions (dotted circles). (D) High-power view of NCC shows a small granulomatous lesion (dotted circle) and multinuclear giant cell (arrow). (E) Medium-power view of RCC shows diffuse infiltration of lymphoid cells. (B-E) Hematoxylin and eosin staining. (F) Immunohistochemical staining for CD3 in RCC.
The patient was discharged on postoperative day 23 after an uneventful postoperative course. However, she complained about dry mouth and a blood test revealed a 1280-fold increase in anti-SS-A antibodies. Minor gland lip biopsy findings were consistent with Sjögren's syndrome. At one year after surgery, there have been no other lymphomatous manifestations and her chronic ATLL has been carefully managed without chemotherapy.
Discussion
Approximately 10 % of ATLL cases show cardiac involvement [
]. O'Mahony et al. reported 8 cases of cardiac involvement among 112 ATLL patients. Almost all involved acute ATLL which required chemotherapy, with invasion of multiple organs in addition to the heart. Distinct cardiac manifestations (e.g. pericardial effusion and tumor nodules) are usually observed at autopsy [
]. Cardiac invasion is generally considered to occur in the advanced stage of unfavorable subtypes of ATLL and have a poor prognosis. In contrast, Gabarre et al. reported a case of chronic ATLL with isolated valvular involvement that showed a favorable prognosis without chemotherapy at least 2 years after the surgical replacement of the aortic and mitral valves [
Adult T-cell leukemia/lymphoma revealed by a surgically cured cardiac valve lymphomatous involvement in an iranian woman: clinical, immunopathological and viromolecular studies.
], similarly to the present case. Thus, cardiac involvement possibly occurs in any subtype of ATLL, irrespective of clinical stage, and is not always indicative of a poor prognosis. Furthermore, valvular tissue may be relatively vulnerable to ATTL infiltration [
Adult T-cell leukemia/lymphoma revealed by a surgically cured cardiac valve lymphomatous involvement in an iranian woman: clinical, immunopathological and viromolecular studies.
]. Our patient's peripheral blood data showed chronic ATLL for five years. CT showed no lymphadenopathy or other organ invasion. This is a rare case of isolated valvular involvement that was successfully removed by surgery in the setting of chronic ATLL. To date, there have not been any specific features of the valvular surgery reported in chronic ATLL cases.
The valvular tissue histology showed diffuse ATLL cell infiltration, which was confirmed by immunohistochemistry for CD3, CD4, FoxP3, HLA-DRα, and CCR4 [
in: Swerdlow S.H. Campo E. Harris N.L. Jaffe E.S. Pileri S.A. Stein H. WHO classification of tumours of haematopoietic and lymphoid tissues (revised 4th edition). IARC,
Lyon2017: 363-367
]. Tax is essential for initiating the malignant transformation of infected cells, while HBZ suppresses apoptosis to maintain the transformed cells and to promote viral replication [
]. HBZ balances the function of Tax; however, both regulatory factors promote inflammatory pathways (e.g. Tax activates NF-κB, a transcriptional factor that plays central mediatory role of inflammation; HBZ induces the unstable expression of FoxP3, resulting in interferon-γ secretion) [
This may be the first report of a unique granulomatous reaction mimicking the active phase of rheumatic valvulitis. We observed small histiocytoid granulomas with multinuclear giant cells that were equivalent to Aschoff nodules (Figs. 2C, 3C, D). We considered the possible pathogenesis. First, granulomatous reaction may be generated by local inflammatory activation by ATLL infiltration. Accordingly, cutaneous non-necrotizing and non-infectious granulomas are reported to be associated in some ATLL cases [
]. However, there are no reports of granulomatous reaction with ATLL infiltration in valvular tissue. Second, although the previous group A Streptococcus infection was not completely excluded in our case, accelerated granulomatous inflammation by ATLL may be considered to cause rheumatic valve disease mimicking cardiac lesions. Cross-reactivity between streptococcal proteins and cardiac epitopes has been proposed as a trigger of autoimmunity. The prominence of CD4-positive T-cells has been demonstrated in rheumatic cardiac lesions. Proinflammatory cytokines [e.g. interleukin-1 (IL-1), IL-6, and TNF-α] are associated with the progression of Aschoff nodules [
]. The predominance of CD4-positive ATLL cells and activated cytokines might accelerate rheumatic inflammation. Third, Sjögren syndrome was associated in the present case. Collagen vascular disease is a systemic chronic inflammatory disease that is possibly associated with NBTE (i.e. Libman Sacks endocarditis). However, granulomatous reactions are rarely seen in NBTE. In addition, antiphospholipid antibody was negative in the present case. Sjögren's syndrome has been also known as a potential risk of B-cell lymphomas, however secondary T-cell lymphoma was rarely reported [
]. Therefore, the unique valvular pathology of our case may be related to complex autoimmune mechanisms. Further study is needed to clarify the inflammatory responses in HTLV-1-infected individuals.
Conclusion
We observed a unique histology of granulomatous valvulitis with ATLL cell infiltration in a patient with chronic ATLL. The ATLL activity was dissociated from the progression of valvular disease. Thus, host-specific autoimmunity may have been associated. Cardiac involvement of ATLL is rare; however, careful examination and regular echo in follow-up may facilitate early detection, especially in indolent clinical subtypes.
Declaration of competing interest
None.
References
Imaizumi Y.
Iwanaga M.
Nosaka K.
Ishitsuka K.
Ishizawa K.
Ito S.
Amano M.
Ishida T.
Uike N.
Utsunomiya A.
Ohshima K.
Tanaka J.
Tokura Y.
Tobinai K.
Watanabe T.
et al.
Prognosis of patients with adult T-cell leukemia/lymphoma in Japan: a nationwide hospital-based study.
Adult T-cell leukemia/lymphoma revealed by a surgically cured cardiac valve lymphomatous involvement in an iranian woman: clinical, immunopathological and viromolecular studies.
in: Swerdlow S.H. Campo E. Harris N.L. Jaffe E.S. Pileri S.A. Stein H. WHO classification of tumours of haematopoietic and lymphoid tissues (revised 4th edition). IARC,
Lyon2017: 363-367
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