Abstract
Background/Aim: Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is frequently associated with the Epstein-Barr virus (EBV) and manifests as non-mass-forming microscopic lesions within fibrin-rich lesions. Herein, we describe the cytological features of FA-DLBCL. Case Report: A 72-year-old man presented with a large retroperitoneal cystic mass that was treated by cyst aspiration and laparoscopic excision. Individually dispersed large, atypical cells in a necrotic background contained scant cytoplasm and hyperchromatic nuclei with irregular nuclear contours, frequent karyorrhectic debris, and mitotic figures. A fibrinous exudate with necrotic material attached to the inner surface of the cystic mass contained large, atypical cells that were individually scattered or arranged in small clusters. These were positive for cluster of differentiation 20 and Epstein-Barr virus-encoded RNA in situ hybridization. Conclusion: We cytologically characterized FA-DLBCL as large, atypical cells that were individually scattered or arranged in small clusters in a necrotic background. To the best of our knowledge, we revealed the cytological features of FA-DLBCL.
Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is a neoplasm of large B-cells that is incidentally found at sites of chronic fibrin deposition (1). It is an unusual form of DLBCL associated with chronic inflammation (DLBCL-CI) (2). Like DLBCL-CI, FA-DLBCL involves the proliferation of Epstein-Barr virus (EBV) infected large B-cells located in restricted anatomical spaces that afford protection against the immune system (3). However, FA-DLBCL should perhaps be regarded as a non-malignant or pre-malignant lymphoproliferative disorder rather than malignant DLBCL-CI (4) because it is indolent with the potential for a surgical cure (5). Fibrin-associated DLBCL manifests as non-mass-forming, microscopic lesions within fibrin-rich lesions (2, 6). Owing to its rarity and unique clinical presentation, FA-DLBCL poses significant diagnostic challenges for practicing pathologists. To the best of our knowledge, the cytological features of FA-DLBCL have not been published. This report describes the cytological features of FA-DLBCL in liquid-based preparation (LBP) and conventional smear (CS) specimens for the first time. Our findings improve the understanding of this rare entity and offer insights for pathologists facing decisive cytological diagnoses.
Case Report
The Institutional Review Board at Kyung Hee University Hospital (Seoul, Republic of Korea) reviewed and approved the study protocol (protocol number: 2023-05-039). A 72-year-old man presented with a large, retroperitoneal cystic mass that was incidentally detected during a regular health screening. The patient denied a history of pancreatitis, trauma, or malignancies. Laboratory findings revealed serum lactate dehydrogenase levels within the normal range. Abdominopelvic contrast-enhanced computed tomography revealed an 8-cm, unilocular, thick-walled cystic mass located between the para-aortic area and the left renal hilum (Figure 1A). The cystic wall was not enhanced, whereas the density of the inner portion was homogeneous and low, indicating a fluid-filled, unilocular cystic lesion. No intramural solid lesion was evident. Complete laparoscopic excision of the retroperitoneal mass was performed. Cystic fluid that was immediately aspirated after surgical excision was sent to the pathology department for cytological examination.
Imaging and gross findings of fibrin-associated diffuse large B-cell lymphoma arising in retroperitoneal pseudocyst. (A) Abdominopelvic computed tomography image reveals large, unilocular, thick-walled, fluid-filled cystic mass (yellow arrow) in left retroperitoneum. (B) The resected specimen shows unilocular cyst with thick fibrous wall, with inner surface partially covered with yellow-to-brown, mud-like, fibrinous exudate and necrotic material. (C) The exudate and necrotic material are gently detached from the inner surface, and cell block is prepared using pelleted necrotic material.
Grossly, the resected specimen was a unilocular cyst with a thick fibrous wall. The inner surface of the wall was partially covered with a yellow-to-brown, mud-like, fibrinous exudate and necrotic material (Figure 1B). The exudate and necrotic material were gently detached from the inner surface of the cyst, and a cell block was prepared from pelleted fibrinous and necrotic material (Figure 1C). The resected specimen was macroscopically examined by board-certified pathologists and submitted for histological examination.
Cystic fluid aspirates were processed using both LBP and CS. Papanicolaou staining of the LBP specimens revealed individually dispersed, large, atypical cells on a necrotic background (Figure 2A). The cells possessed hyperchromatic nuclei with irregular contours, vesicular chromatin, and inconspicuous nucleoli (Figure 2B). A few tumor cells contained a moderate amount of bluish-pale amphophilic cytoplasm, whereas most viable tumor cells possessing scant cytoplasm showed apparent naked nuclei. Karyorrhectic debris (Figure 2C) and mitotic figures (Figure 2D) were frequently noted. The necrotic background consisted mainly of amorphous pale material and a few scattered karyolytic tumor cells. Small non-neoplastic lymphocytes, histiocytes, and red blood cells were not evident. The overall cytological features of the CS specimens were similar to those of the LBC specimens. However, viable tumor cells, apoptotic bodies, or mitotic figures were more difficult to identify in the SC specimens because these features were scant and distributed widely throughout the slide (Figure 2E and F). Although a few microscopic areas had scattered hemosiderin pigments, no blood was evident in the background.
Cytological features of fibrin-associated diffuse large B-cell lymphoma. (A) Liquid-based preparation (LBP) reveals several large, atypical cells individually dispersed in a necrotic background. (B) The large, atypical cells possess hyperchromatic nuclei with irregular nuclear contour and scant cytoplasm. (C) Karyorrhectic debris (yellow arrows) is observed (D) Mitotic figures (blue arrows) are also abundant. (E and F) Conventional smear reveals amorphous necrotic material and some karyorrhectic debris (green arrows). Compared with LBP, viable tumor cells are scant in conventional smear. A-F, Papanicolaou staining. Original magnification: A, 200×; B-F, 600×.
Histologically, hematoxylin and eosin (H&E) staining revealed heavy infiltration of the thick fibrous wall of the cystic mass by lymphocytes and plasma cells. Numerous secondary lymphoid follicles contained germinal centers. The epithelial lining was absent, but the inner surface was partially covered with fibrinous and necrotic material. Large, atypical cells were individually dispersed or arranged in small clusters in a few small areas of fibrinoid necrosis (Figure 3A). Consistent with this finding, H&E staining of the cell block sections revealed several foci of densely or loosely aggregated atypical lymphoid cells in a background of fibrinoid necrosis (Figure 3B). In line with these cytological features, the atypical lymphoid cells possessed scant cytoplasm and hyperchromatic nuclei with irregular nuclear contours, vesicular chromatin, and inconspicuous nucleoli (Figure 3C). Mitotic figures and karyorrhectic debris were abundantly found. We performed immunohistochemical staining using a panel of antibodies and EBV-encoded RNA in situ hybridization (EBER-ISH). Immunostaining revealed that the atypical lymphoid cells were positive for cluster of differentiation 20 (CD20), multiple myeloma oncogene 1, B-cell lymphoma 6, and EBER-ISH (Figure 3D), but negative for CD3, CD10, and human herpes virus 8. Non-neoplastic lymphocytes infiltrating the cystic wall comprised mixed B- and T-cell populations and were negative for EBER-ISH, indicating that tumor cells had not infiltrated the cystic wall. The final pathological diagnosis was FA-DLBCL arising in a retroperitoneal pseudocyst. The patient underwent no further treatment and is currently alive without evidence of disease at six months after surgery.
Histological features of fibrin-associated diffuse large B-cell lymphoma. (A) The cystic wall consists of dense fibrosis and lymphoplasmacytic infiltration with secondary lymphoid follicles (blue arrows). The inner surface contains some scattered large, atypical cells (yellow arrow) within fibrinous exudate. (B) The cell block section also shows loosely aggregated, large, atypical cells (yellow arrow) in a background of fibrinoid necrosis. (C) The atypical cells have hyperchromatic, pleomorphic nuclei with irregular nuclear contours and scant cytoplasm. Apoptotic bodies are evidently visible (green arrows). (D) The tumor cells have nuclear immunoreactivity for Epstein-Barr virus-encoded RNA in situ hybridization. Staining method: A-C, hematoxylin and eosin staining; D, immunostaining. Original magnification: A, 40×; B, 100×; C, 400×; D; 200×.
Discussion
Herein, we described a rare case of FA-DLBCL arising in a retroperitoneal pseudocyst. Ho et al. (7) summarized 87 patients with FA-DLBCL. Their literature review revealed that patients with FA-DLBCL had many types of underlying medical conditions, such as cardiac myxoma, thrombus, hematoma, aneurysms, prosthetic valves, breast implants, and cystic lesions at various locations (8-12). The mechanism of FA-DLBCL development in these lesions remains unknown. However, chronic inflammation in a fibrin-rich micro-environment probably plays a critical role in type III EBV latency (13). Like our patient, 95.4% of previously published FA-DLBCL cases were related to EBV (7), supporting that FA-DLBCL is an EBV-associated large B-cell lymphoma.
The underlying lesion in most patients with FA-DLBCL consists solely of the disease site at initial presentation. Unlike other types of malignant lymphomas, systemic dissemination or lymph node enlargement is not evident in FA-DLBCL. Because these tumors present as microscopic lesions, visible mass formation is unusual (14). For these reasons, most FA-DLBCLs are diagnosed only after pathological examination of the underlying lesions. Awareness of the pathological features of FA-DLBCL as well as prior knowledge of the disease entity is required for accurate diagnoses. The approximal surface of fibrin-rich areas, such as the inner surface of the cystic wall and the outer surface of myxomas or thrombi are sites where FA-DLBCL is usually detected. The possibility of other primary lymphomas or secondary systemic lymphoma should be considered if tumor cells involve non-fibrin-rich tissues (5, 15). The numbers of tumor cells widely vary among patients. Therefore, as many tissue sections as possible should be examined, given that the underlying lesions usually show only mud-like fibrinous and necrotic material. In this study, both the cell block made from the material attached to the inner cystic surface and the tissue sections obtained from the cystic wall helped us to arrive at an accurate diagnosis. Some sections contained a few small clusters of tumor cells. Non-neoplastic cellular components were absent, which facilitated tumor cell identification.
To the best of our knowledge, this is the first report to describe the cytological features of FA-DLBCLs in cystic fluid aspirates. Finding a tumor cell population in cytology specimens supports the rationale for diagnosis of FA-DLBCL based on cystic cytological findings. The characteristic morphological features of FA-DLBCL were evident in cytology specimens, including tumor cells possessing large, atypical nuclei with frequent mitotic figures, apoptotic bodies, and scant cytoplasm in a necrotic background (5). Despite the scant cellularity of FA-DLBCL and the diffuse necrotic background, mitotic figures and apoptotic bodies were readily identifiable, supporting a diagnosis of malignant tumors. However, a few viable tumor cells were easier to find with LBP than with CS. Most FA-DLBCLs arise in cystic lesions, prosthetic joints, and breast implants, which can be analyzed using fine-needle aspiration cytology. Therefore, cytological examination of such underlying lesions can be the first non-invasive step to obtain a diagnosis of FA-DLBCL.
In summary, we described the cytological features of FA-DLBCL in cystic fluid aspirates. We also noted the characteristic morphological features of FA-DLBCLs in matched tissue sections. Co-existing FA-DLBCL should be suspected during pathological examination of apparently benign cystic lesions if mud-like fibrinous and necrotic material and large, atypical lymphoid cells with mitotic figures and apoptotic bodies are found in a background of fibrinous necrosis. An accurate diagnosis of FA-DLBCL requires a comprehensive examination of the suspected lesion.
Acknowledgements
This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIT) (RS-2023-00240480 and 2023R1A2C2006223).
Footnotes
Authors’ Contributions
All Authors made substantial contributions to the conceptualization and design of the study; collection, interpretation, and validation of the data; administration of the project; drafting of the manuscript; revising the draft critically for important intellectual content; and providing final approval of the version to be published.
Conflicts of Interest
The Authors have no conflicts of interest or financial relationships to declare regarding this study.
- Received December 21, 2023.
- Revision received January 22, 2024.
- Accepted January 23, 2024.
- Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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