Received: 27 June 2023

| Revised: 31 July 2023 | Accepted: 19 August 2023

DOI: 10.1111/cyt.13299

CASE REPORT

A case of lymphomatous pleural effusion fromangioimmunoblastic T-­cell lymphoma: The methodologyof cell transfer technique and immunocytochemistry on an
inadequate cytology specimen can potentially guide us to thecorrect diagnosis
Kinue Takebayashi1,2 | Rie Kadoguchi1,2 | Akihiro Shioya1,2,3 | Takeru Oyama1,3 |Sohsuke Yamada1,2,3
1

Department of Pathology, Kanazawa Medical University Hospital, Ishikawa, Japan2

Department of Pathology, Kanazawa Medical University Himi Municipal Hospital, Toyama, Japan3

Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Ishikawa, JapanCorrespondence
Sohsuke Yamada, Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 1-­1 Uchinada, Ishikawa 920-­0293, Japan.
Email: sohsuke@kanazawa-med.ac.jp
Keywords: angioimmunoblastic T-­cell lymphoma (AITL), cell transfer method, cytopathology, immunocytochemistry, pleural effusion

1|I NTRO D U C TI O N

immunocytochemistry could have most likely guided us to the correct cytological diagnosis.

Angioimmunoblastic T-­cell lymphoma (AITL), a diverse, but aggressive haematopoietic neoplasm of mature follicular helper T-­
cells, might be occasionally complicated with serous effusions.1,2

2|

C A S E PR E S E NTATI O N

However, lymphomatous effusion caused by AITL, accounting onlyfor less than 1% of all malignant effusions due to haematopoietic

An 84-­year-­o ld female presented with a chief complaint of ex-diseases, has been very rarely reported, because of the difficulty

ertional dyspnoea, due to progressive bilateral pleural effusions

on cytological diagnosis.1–­5 Malignant effusion of AITL often poses

detected by ambulatory chest X-­r ay. She had an unremarkablea diagnostically severe challenge to not only haematologists but

medical history. A subsequent chest computed tomography (CT)cytopathologists, since it is very hard to obtain the specific cyto-

scan incidentally revealed overt lymphadenopathy in the rightlogical findings, and its presence and is difficult to diagnose pre-­hilar and mediastinal regions, together with bilateral pleural effu-operatively. 2,3 Furthermore, there has been a description of asions. In addition, many cervical and intraperitoneal swollen andpatient with AITL presenting first with developing bilateral pleural

fused lymph nodes were generally identified on neck/abdominal

effusions, followed by systemic lymphadenopathies.6 In these con-CT, which prompted a thorough examination. The patient's labo-texts, early accurate diagnosis and a regimen of radical chemother-ratory studies showed variable inflammatory reactions: lactate

apy treatment might be able to improve the survival rates of AITL

dehydrogenase, 255 U/L; C-­reactive protein, 1.54 mg/dL; andpatients.

white blood cell count, 11,400/mm3 . Her tumour marker, serum

We report a case of AITL in which a complicated effusion wasrecognised first, and the cytological diagnosis was very difficult

soluble interleukin 2 receptor, was significantly increased up to4015 U/mL.

due to the insufficient/inadequate volume of submitted pleural ef-

The patient was first referred to the Department of Respiratory

fusion. However, the methodology of cell transfer technique andMedicine, where malignant lymphoma had not been suspected prior

The abstract of this paper was presented at the 64th Annual Spring Meeting of the Japanese Society of Clinical Cytology (in 2023).

Cytopathology. 2023;00:1–4.

wileyonlinelibrary.com/journal/cyt

© 2023 John Wiley & Sons Ltd.

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TAKEBAYASHI et al.

to thorough examination including CT scan or lymph node biopsy.

cytological and immunocytochemical re-­examination with regard toTherefore, clinicians submitted a small volume, only 10 mL, of yel-the atypical immature enlarged lymphoid cells. By using a cell trans-lowish and turbid pleural effusion for cytological examination. At

fer method,7 the atypical large, round to ovoid lymphocytes were

low to high magnification, its aspiration cytology showed small tospecifically immunopositive for CD3 and CD5 (Figure 1C,D). Addi-

rarely medium-­to-­large, round to ovoid lymphocytes having occa-

tional immunocytochemistry was not performed due to the insuffi-sionally prominent nucleoli (Figure 1A,B), admixed with a very small

cient/inadequate amount of submitted specimen.

number of atypical plasmacytoid cells (Figure 1A) and immature en-

Subsequently, a biopsy of the swollen inguinal lymph node waslarged lymphoid cells (Figure 1B). The background revealed variable

performed. Under low-­power view, the enlarged lymph node re-proportions of inflammatory cells, including neutrophils, eosinophils,vealed complete loss of follicles with focal extra-­nodal involvements

histiocytes, and plasma cells (Figure 1A,B), or scattered mesothelialof neoplastic cells (Figure 2A). The high-­power view showed a dif-cells. May-­Grünwald-­Giemsa stain identified a small number of en-fuse proliferation of overtly atypical medium-­to-­large lymphoid cells

larged blastoid lymphoid cells having irregularly shaped nuclei andhaving characteristically abundant clear cytoplasm, admixed with abasophilic cytoplasm (Figure 1B). Mitosis was very rarely seen. There

number of swollen high endothelial venules, and scattered eosino-

were no apparent apoptotic cells, Hodgkin/Reed-­Sternberg cells, orphils or plasma cells (Figure 2B). These aggregated atypical lymphoid

atypical irregular lymphocytes having clear to pale cytoplasm. Cy-cells were surrounding the high endothelial venules (Figure 2B). Mi-

tology of the pleural effusion initially diagnosed as likely suspicious

tosis was readily seen. On immunohistochemistry, the tumour cells

for a few neoplastic lymphocytes, not further specified, in which it

were overtly positive for CD3/5/4 (Figure 2C–­E) and weakly positive

was very hard to conclude the status as benign or malignant. Thefor bcl-­6, programmed death receptor-­1 (PD-­1) (Figure 2F,G) andcytological differential diagnoses included reactive inflammation

CD10, whereas they were negative for CD20. Moreover, the CD23-­(i.e., pleuritis), AITL, or plasmacytoma. We performed a careful

immunopositive follicular dendritic cell meshwork was irregularly

F I G U R E 1 The cytomorphological/immunocytochemical findings on aspirated pleural effusion specimens. (A) Clinicians submitted
a small volume, only 10 mL, of yellowish and turbid pleural effusion for cytological examination. The background revealed variable
proportions of inflammatory cells, including neutrophils, eosinophils, histiocytes, and plasma cells, or scattered mesothelial cells. Atypicalplasmacytoid cells having an irregularly enlarged nucleus (arrow) were very rarely seen (direct smear, Papanicolaou staining, ×400; scalebar = 50 μm). (B) May-­Grünwald-­Giemsa stain showed small to rarely medium-­to-­large, round to ovoid lymphocytes having occasionallyprominent nucleoli, admixed with a very small number of immature enlarged lymphoid cells (arrows). These blastoid cells contained irregular-­shaped nuclei and basophilic cytoplasm. There were no apparent apoptotic cells, Hodgkin/Reed-­Sternberg cells, or atypical irregularlymphocytes having clear to pale cytoplasm (direct smear, May-­Grünwald-­Giemsa staining, ×1000; scale bar = 20 μm). (C,D) We performed
a careful immunocytochemical re-­examination with regard to the atypical immature enlarged lymphoid cells. By using a cell transfer
method, the atypical large, round to ovoid lymphocytes (arrows)were specifically immunopositive for CD3 (C) and CD5 (D). Additional
immunocytochemistry was not examined due to the insufficient/inadequate amount of the submitted specimen (immunocytochemistry,
×1000; scale bars = 20 μm).

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TAKEBAYASHI et al.

F I G U R E 2 The histological/immunohistochemical findings on the tissue of swollen inguinal lymph node. (A) Under low-­power view, theenlarged lymph node revealed complete loss of follicles with focal extra-­nodal involvements of neoplastic cells (H&E staining, ×40). (B) The
high-­power view showed a diffuse proliferation of overtly atypical medium-­to-­large lymphoid cells having characteristically abundant clear
cytoplasm, admixed with a number of swollen high endothelial venules, and scattered eosinophils or plasma cells. These aggregated atypicallymphoid cells were surrounding the high endothelial venules (H&E staining, ×200). (C-­H) On immunohistochemistry, the tumour cells wereovertly positive for CD3 (C), CD5 (D), and CD4 (E), and were weakly positive for bcl-­6 (F) and PD-­1 (G), while the CD23-­immunopositive
follicular dendritic cell meshwork (H) was irregularly expanding (immunohistochemical stainings, ×100; insets, ×400).
expanding (Figure 2H). The Epstein–­Barr virus-­encoded small RNAs

inadequate volume, lymphomatous effusion caused by AITL couldin situ hybridisation stain was completely negative for lymphoma

be considered as one of the differential diagnoses. Besides, immuno-cells. Based on the above features, we finally made a conclusive

cytochemical staining to detect CD3/5/4 should be performed withdiagnosis of systemic AITL accompanied by lymphomatous pleuralthe use of a cell transfer method. In fact, re-­examination of our caseeffusions. One and half months later, the patient died with exacer-allowed us to focus on a very small number of atypical medium-­to-­bating dyspnoea, before treatment was started with chemotherapy.

large, round to ovoid lymphocytes, which were not seemingly appreciated at the time of the initial diagnosis.

3|DISCUSSION

According to the first and largest series regarding lymphomatous
effusion related to AITL, most recently published by Li et al, 2 twopatterns of cytomorphology have been proposed, even though they

It is well known that AITL could be complicated with not only serous

also consider that the challenging cytological diagnosis of AITL ef-effusions but rarely with lymphomatous effusion.1,2 However, therefusion reveals a significantly broad spectrum, mimicking a variety

are only a few case reports in which detailed cytological examinationof reactive and/or neoplastic processes. Li et al's “pattern 1” shows

has been described.3,4 We did not find any case reports or studies

small to medium-­sized ovoid to irregular lymphocytes varying inin which effusion AITL cells were identified by the methodology ofthe number of apoptotic cells or mitoses, without any evidence ofcell transfer technique and immunocytochemistry. When compli-Hodgkin/Reed-­Sternberg cells. On the other hand, “pattern 2” re-cated effusion is first recognised, and the cytological diagnosis of aveals the appearance of characteristic Hodgkin/Reed-­Sternberg

few atypical lymphoid cells is very difficult due to the insufficient/cells having multi-­lobated nuclei, together with medium-­sized ovoid

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TAKEBAYASHI et al.

to irregular lymphocytes, and prominent apoptotic features and nu-C O N FL I C T O F I N T E R E S T S TAT E M E N Tmerous mitotic figures. Based on these descriptions, the cytologicalNo conflicts of interest are declared.

findings of the present AITL case would be consistent with pattern
1, since we were not able to recognise any Hodgkin/Reed-­Sternberg

DATA AVA I L A B I L I T Y S TAT E M E N T

cells, and there were no remarkable apoptotic or mitotic activities.

There is no sharing of data in connection with this manuscript.

Furthermore, Yamagata et al have reported the cytological findingsof lymphomatous effusion resulting from AITL, revealing the appear-I N FO R M E D C O N S E N T

ance of atypical plasma cells varying in size and shape, such as cells

Written informed consent was obtained from the patient for theirthat were irregularly enlarged and/or with two nuclei.5 The present

anonymised information to be published in this article.

case is most likely in agreement with the above features.
The expressions of follicular helper T-­cell markers, including PD-­
1, CD10, bcl-­6 or CXCL-­13, are very useful for the definitive diag-ORCID
Sohsuke Yamada

https://orcid.org/0000-0003-2662-0024

nosis of lymphomatous effusion caused by AITL, according to thefirst case report diagnosed by cell block immunohistochemistry.3 InREFERENCES

addition, when submitted effusion is sufficiently available for var-

1. Li J, Zhao S, Zhang W, et al. Serous effusions diagnostic accuracy
for hematopoietic malignancies: a cyto-­histological correlation.
Front Med (Lausanne). 2020;7:615080.
2. Li J, Zhu X, Deng X, et al. Angioimmunoblastic T-­cell lymphoma diagnosed from serous effusion by integration of cytologic features
and ancillary studies. Am J Clin Pathol. 2023;159(4):379-­394.
3. Furumai H, Nakazato Y, Machida H, et al. Cytological features andimmunohistochemical findings related to lymphomatous effusion inan angioimmunoblastic T-­cell lymphoma patient: case report. Diagn
Cytopathol. 2021;49(8):964-­967.
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2021;49(12):E462-­E466.
5. Yamagata T, Okamoto Y, Yamagata Y, et al. Angioimmunoblastic
lymphadenopathy with dysproteinaemia accompanied by pleuraleffusion. Respirology. 2005;10(1):124-­127.
6. Hosoki K, Okada S, Ichinohasama R, Yamaguchi M, Uchiyama B,Maeyama T. Angioimmunoblastic T-­cell lymphoma developed withlymphocytic pleural effusion. Intern Med. 2007;46(11):739-­742.
7. Kawasaki M, Shioya A, Takata M, et al. A case of bone metastasis ofhepatocellular carcinoma: Mallory hyaline bodies can lead to the correct cytological diagnosis. Diagn Cytopathol. 2023;51(2):E70-­E74.

ious examinations, clinicians/cytopathologists should perform not
only immunohistochemistry but flow cytometry or next-­generation
sequencing studies.7 In fact, flow cytometry can also play a key rolefor confirmation of the final diagnosis of AITL effusion, after rulingout the differential diagnoses (including B-­cell lymphoma, Hodgkinlymphoma, natural killer lymphoma, other T-­cell lymphomas, poorly
differentiated carcinoma, or malignant melanoma). Nevertheless,because of the insufficient/inadequate amount of submitted pleural effusion in the current case, only 10 mL, we were never able to
make cell block sections or perform additional immunocytochemistry. Therefore, we cytopathologists have to suggest taking a larger
volume of specimen to clinicians, in order to obtain an accurate andcorrect diagnosis of malignant effusion of AITL. Actually, suspicionof AITL effusion requires a multidisciplinary approach, since we havemore or less realised the limitations of cytomorphologically conclusive diagnosis.
AU T H O R C O N T R I B U T I O N SSohsuke Yamada and Kinue Takebayashi participated in the conception of the case study and writing of the manuscript. Sohsuke Yamada, Kinue Takebayashi, Rie Kadoguchi, Akihiro Shioya, and Takeru
Oyama performed the clinical imaging and/or cytological/pathological/immunocytochemical interpretation of this tumour lesion. All ofthe authors have read and approved the final manuscript.
AC K N OW L E D G M E N T S
We would like to thank the native English-­speaking scientific doctor,
Mr. Brian Quinn, as the official English Editor of Japan Medical Communication, and the Clinical Research Support Office, KanazawaMedical University, Japan, for their expert English editing, technicalassistance, and helpful comments.

How to cite this article: Takebayashi K, Kadoguchi R, ShioyaA, Oyama T, Yamada S. A case of lymphomatous pleural
effusion from angioimmunoblastic T-­cell lymphoma: The
methodology of cell transfer technique andimmunocytochemistry on an inadequate cytology specimen
can potentially guide us to the correct diagnosis.
Cytopathology. 2023;00:1-4. doi:10.1111/cyt.13299