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Fibrin-associated large B-cell lymphoma: first case report within a cerebral artery aneurysm and literature review



Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is a rare Epstein-Barr virus (EBV) positive lymphoproliferative disorder included in the current World Health Organization (WHO) classification. It arises within fibrinous material in the context of hematomas, pseudocysts, cardiac myxoma or in relation with prosthetic devices. In these clinical settings the diagnosis requires an high index of suspicion, because it does not form a mass itself, being composed of small foci of neoplastic cells. Despite overlapping features with diffuse large B-cell lymphoma associated with chronic inflammation, it deserves a separate classification, being not mass-forming and often following an indolent course.

Case presentation

A 64-year-old immunocompetent woman required medical care for cerebral hemorrhage. Computed Tomography (CT) angiography identified an aneurysm in the left middle cerebral artery. A FA-DLBCL was incidentally identified within thrombotic material in the context of the arterial aneurysm. After surgical removal, it followed a benign course with no further treatment.


The current case represents the first report of FA-DLBCL identified in a cerebral artery aneurysm, expanding the clinicopathologic spectrum of this rare entity. A complete literature review is additionally made.

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In the current WHO classification, diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) is defined as an EBV-driven neoplasm, occurring in longstanding chronic inflammation in restricted spaces [1]. The prototype is pyothorax-associated lymphoma (PAL) arising in patients with a long history of pyothorax, following artificial pneumothorax as treatment for tuberculosis [1]. Recently, another EBV-related entity has been included among DLBCL-CI, but renamed fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) because it develops within fibrinous material [1].

It has been reported in association with pseudocysts, cardiac myxoma, valve prosthesis, fibrin thrombus, synthetic tube graft, hydrocele, metallic implants, and chronic subdural hematoma [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25]. Differently from PAL, it does not form masses, being composed of rare neoplastic cells and it represents often an incidental finding [1]. Whereas PAL follows an aggressive course, the majority of FA-DLBCL behave favorably and may not require therapies other than surgery. Rare cases with persistent or localized recurrent disease have been described [9]. Only one case with a poor outcome has been reported so far [24]. We present the first report of FA-DLBCL incidentally disclosed in a cerebral artery aneurysm, widening the clinicopathological spectrum of this rare entity.

Case presentation

A 64-year-old immunocompetent woman was referred to hospital for cerebral hemorrhage in left temporal-parietal region. CT angiography detected an aneurysm in the distal segment of left middle cerebral artery. Tiny fragments of brain tissue together with partially organized thrombus were surgically removed. Histologically, it was identified an artery, with an interrupted wall, occluded by thrombotic material (Fig. 1). Small foci of large atypical lymphoid cells (Fig. 1, inset; Fig. 2) were disclosed within thrombus. The cells were positive for PAX5 (Fig. 2, inset left), CD30 and MUM1 (Fig. 2, inset right) with partial expression of CD79α and CD20. The proliferative index (Fig. 3 a) was high (Ki67 about 90%). The cells expressed LMP-1 and were diffusely positive for EBV by in situ hybridization for EBV-encoded RNA (EBER) (Fig. 3, b). Clonal immunoglobulin heavy chain (IGH) rearrangement was detected. A fibrin-associated diffuse large B-cell lymphoma was diagnosed. Staging procedures (CT scan and bone marrow biopsy) were negative. Three months later, CT scan showed an almost complete hemorrhage resorption. No further treatment was given. The patient is alive, free of disease at 8 months from diagnosis.

Fig. 1

Low power view of artery with interrupted wall and containing thrombotic material (HE 4x); inset Rare atypical lymphoid cells lying within the thrombus are recognizable at high power view (HE 20x)

Fig. 2

High power detail of large lymphoid cells (HE 40x); inset left PAX5 positivity of lymphoid cells; inset right MUM1 expression of lymphoid cells

Fig. 3

High proliferative index (Ki67) (a); Epstein-Barr virus positivity in large-sized cells by in situ hybridization for EBV-encoded RNA (EBER) (b)

Discussion and conclusions

FA-DLBCL is a rare EBV-associated B-cell lymphoma included in the current WHO classification, in the chapter of DLBCL-CI [1]. Differently from DLBCL-CI, it is not mass-forming and therefore disclosed incidentally on histological evaluation of surgical specimens removed for other diseases [1]. Forty seven cases, including our, have been reported so far [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25]. Clinicopathological data are summarized in Table 1. It shows male predominance with a wide age range. No ethnic differences have been apparently identified so far [9]. All cases, except 2 [9], occurred in immunocompetent individuals, presenting with different symptoms, depending on the underlying conditions in which FA-DLBCL occurred.

Table 1 Demographic data, clinical data, and characteristics of reported cases of Fibrin-Associated Diffuse Large B-Cell Lymphoma

Cardiac myxoma represents one of the most frequent site of occurrence with 14 cases identified, whereas only occasional cases arose in atrial thrombi and within mixomatous valve degeneration. Some cases have been identified in association with prosthetic devices such as endovascular graft, cardiac valve prosthesis and metallic implant. Time from placement of devices to lymphoma diagnosis is extremely variable, ranging from 1 to more than 20 years. A rather frequent site of presentation is represented by pseudocysts, with a total of 10 cases, in different organs (adrenal gland, spleen, kidney, retroperitoneum, testis). Single descriptions at unusual sites as within testicular hydrocele, ovarian teratoma and testicular hematoma are also reported. The intracranial location appears to be rare, with only 4 cases within chronic subdural hematomas [9, 22,23,24] and 1 within an arachnoid cyst [25]. Our case represents the first report in a patient with a brain hemorrhage and incidentally identified within thrombotic material in a cerebral artery aneurysm. Notably in all cases evaluated (45/47) staging workup at diagnosis revealed no other sites of disease.

Histologically all cases were remarkably similar and found incidentally, being composed of microscopic foci of large lymphoid cells, embedded within fibrin and not invading adjacent tissue structures. Most cases had a non-germinal center B-cell phenotype and high proliferative index. A strong association with EBV infection is present; as 41/43 evaluated were positive for EBV by EBER-ISH. Notably a type III EBV latency profile, with positivity for LMP-1 and Epstein-Barr nuclear antigen-2 (EBNA-2) was found in most cases (18/22 tested). Type III latency of EBV infection is the hallmark of lymphoproliferative disorders arising in the setting of severe immunosuppression. EBV-infected cells expressing EBNA-2 do not survive in immunocompetent individuals, because destroyed by cytotoxic T-lymphocytes. As patients with FA-DLBCL are immunocompetent, it has been assumed that the restricted environment where FA-DLBCL occurs, allows the EBV-infected B-cells to escape T-cell surveillance [9]. Clonal immunoglobulin rearrangement was identified in most cases evaluated. None of the cases tested by fluorescence in situ hybridization (FISH) showed c-MYC, BCL6 and/or BCL2 rearrangements or amplifications: a rather striking difference from PAL, presenting MYC amplification in 80% of cases [9]. Clinical course of FA-DLBCL is commonly indolent. Remarkably of 36 cases with available follow-up, 30 pursued a benign course, with no evidence of disease from 1 to 130 months. Treatment is variable, although surgery alone often represents the treatment of choice. Sixteen/30 cases were treated with surgery alone, 11 with surgery plus chemotherapy, 1 with surgery plus radiotherapy, 1 with surgery plus immunotherapy, and 1 with surgery plus chemotherapy and radiotherapy. All cases arising within pseudocysts behaved favorably. Local recurrences or persistent disease were seen only in isolated cases in which the primary disease had arisen either within an atrial myxoma (1) or at sites of previous vascular graft (2) [9]. The recurrent or persistent disease presented close to the site initially involved. Two/3 patients died of thromboembolic disease and 1 is alive with stable and localized disease. It has been hypothesized that FA-DLBCL arising at cardiac or vascular sites can recur or persist more easily than cases occurring in sites more amenable to complete surgical removal [9]. Kameda et al reported the unique case with an aggressive course, occurring in an elderly patient within a chronic subdural hematoma observed conservatively [1, 24]. Seven months later, a de novo brain mass developed beneath the hematoma [24]. After surgical removal, the neoplasm within the subdural hematoma appeared consistent with FA-DLBCL and the brain mass was an EBV-positive DLBCL [24]. The authors hypothesized that the lymphoid process developed in the hematoma before infiltrating the brain parenchyma [24]. Once the lymphoma infiltrates outside the subdural hematoma, the prognosis becomes poor [1]. FA-DLBCL shares similarities with breast implant-associated anaplastic large B-cell lymphoma (BIA-ALCL), although the latter is a T/null lymphoma, not EBV-related [1]. Both entities portend a worse prognosis, when infiltrate the surrounding tissues outside the restricted space of origin.

Our case arose in a previously unreported setting, being identified in a cerebral artery aneurysm of a patient with a brain hemorrhage. The disease was totally confined within thrombotic material occluding the artery. After surgical removal, it pursued a benign course with no additional treatment.

In conclusion, FA-DLBCL is a rare EBV-related lymphoproliferative disorder, arising within fibrinous material in different clinical settings. Intracranial location is very rare. This represents the first report within a cerebral artery aneurysm. Diagnosis can be tricky, being FA-DLBCL not mass-forming and composed of tiny neoplastic foci. Clinical behavior is mostly indolent. The limited number of FA-DLBCL reported so far makes difficult to draw definitive conclusion regarding the best treatment. Further cases with longer follow-up would help to adopt the most appropriate therapeutic options for each individual patient.

Availability of data and materials

All the original data supporting our research are described in the Case presentation section and in the figures’ legends.



Breast implant-associated anaplastic large B-cell lymphoma


Computed Tomography


Diffuse large B-cell lymphoma associated with chronic inflammation


EBV-encoded RNA


Epstein-Barr virus


Fibrin-associated diffuse large B-cell lymphoma


Pyothorax-associated lymphoma


World Health Organization


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The authors have no financial ties to disclose.

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ZaM wrote the manuscript and performed literature review; AS performed histopathological examination and designed the study; MM studied the patient; GV, MG, DL, FOG, MMP performed literature review; ZiM was involved in review, editing and validation of the manuscript. All authors have read and approved the manuscript.

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Correspondence to Maurizio Zizzo.

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Zanelli, M., Zizzo, M., Montanaro, M. et al. Fibrin-associated large B-cell lymphoma: first case report within a cerebral artery aneurysm and literature review. BMC Cancer 19, 916 (2019).

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  • Fibrin
  • B-cell
  • Lymphoma
  • Epstein-Barr virus