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19 July 2023 - Case of the Month #529

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Thanks to Dr. Hyunkyu Shin, Dr. Christian Schürch and Dr. Falko Fend, University Hospital and Comprehensive Cancer Center, Tübingen, Germany and Dr. Claudia Wickenhauser, University Hospital Halle (Saale), Germany for contributing this case and discussion and to Dr. Julie Feldstein, Histowiz.com, New York, New York, USA for reviewing the discussion.




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Case of the Month #529

Clinical history:
A 52 year old man with a neoadjuvantly treated gastrointestinal stromal tumor (GIST) of the stomach had a gastrectomy. In the histologic examination of the resected tumor, accumulations of discohesive large cells in cystic spaces of the regressively changed tumor bed of the GIST were noticed, as shown in the following images.

Histopathology images:




What is your diagnosis?

Click here for diagnosis, test question and discussion:


Diagnosis: EBV negative fibrin associated large B cell lymphoma (FA-LBCL) arising in cystic spaces of the regressive, neoadjuvantly treated gastrointestinal stromal tumor (GIST)


Test question (answer at the end):
Which of the following is a true feature of fibrin associated large B cell lymphoma (FA-LBCL)?

A. Distinguishing this tumor from chronic inflammation associated (CI-)LBCL has no clinical importance because both are inflammation      associated indolent neoplasms
B. The neoplastic cells are derived from germinal center B cells
C. This neoplasm is strongly associated with EBV infection with type III latency
D. This tumor is a highly aggressive lymphoid neoplasm due to its association with acute fibrous inflammation
E. With discohesive neoplastic cells, this tumor readily infiltrates pre-existing anatomic structure


Stains:
CD138

CD138

MUM1

MUM1

CD3

CD3

CD20

CD20

CD79a

CD79a


ALK

ALK

MYC

MYC

HHV8

HHV8

Kappa

Kappa

Lambda

Lambda


Cyclin D1

Cyclin D1

CD56

CD56

EBER

EBER

BCMA

BCMA




Discussion:
The 52 year old patient was initially diagnosed with a 20 cm sized gastrointestinal stromal tumor (GIST) of the stomach with high risk features in the biopsy specimen. In the histologic examination of the resected tumor after neoadjuvant chemotherapy, besides the residual GIST with spindled tumor cells, an infiltrate of noncohesive large cells arising in cystic spaces of the regressively changed GIST with extensive fibrin exudation was noticed. In the hematoxylin and eosin staining, the monotonous large neoplastic cells exhibited plasmablastic morphology with eccentrically located, partly binucleated nuclei with irregular nuclear membrane and distinct nucleoli. Immunohistochemically, the neoplastic cells were positive for MUM1, CD138, BCMA, lambda light chains, MYC and negative for CD19, CD79a, PAX5, CD30, ALK, HHV8, CD56, cyclin D1, EBER. In a FISH test, a translocation of MYC (8q24) was confirmed. In the next generation sequencing (NGS) analysis using an expanded Oncomine® lymphoma panel (Thermo Fisher), the following gene mutations with corresponding allele frequencies were found: MEF2B (38%), BTG1 (11%), KMT2D (11%), CXCR4 (9%). The case was submitted to the 21st EAHP-SH conference in Florence, Italy. Considering all the findings, the EAHP-SH workshop panel members classified this case as a fibrin associated large B cell lymphoma (FA-LBCL) arising in the neoadjuvantly treated GIST. The FA-LBCL was confined to the GIST and the tumor cells were not found elsewhere in the gastrectomy specimen. The patient is well and without evidence of lymphoma one year after resection.

FA-LBCL is a mature, large B cell lymphoma arising in confined, natural or acquired anatomical spaces, e.g., pseudocysts, in association with chronic fibrin deposition. Except for rare cases such as the one presented here, FA-LBCL is strongly associated with EBV infection and is often diagnosed incidentally due to its indolent and asymptomatic nature. Histomorphologically, FA-LBCL is comprised of the aggregates of large atypical lymphoid cells with irregular nuclear membrane and several prominent nucleoli in the background of fibrin exudation. Mitotic activity is brisk with a high proliferation index (Ki67/MIB1) of usually > 90%. An infiltration of pre-existing anatomic structure and mass formation must be absent, as these features differentiate FA-LBCL from LBCL with chronic inflammation (CI-LBCL). Immunohistochemically, FA-LBCL shows an activated B cell immunophenotype and so, pan B cell markers (CD19, CD20, CD22, PAX5, CD79a) are generally positive but CD10 is negative and MUM1 positive. BCL2, BCL6 and CD30 can be either positive or negative. In a minority of cases, FA-LBCL can exhibit plasmablastic morphology with positive CD138 and diminished positivity for pan B cell markers. Most cases demonstrate EBV infection with type III latency (EBER+, LMP1+, EBNA2+). Therefore, this case is unusual in two aspects: (1) the lack of EBV infection, which has been described in rare published cases (Virchows Arch 2020;476:647, Int J Surg Pathol 2022;30:39) and (2) the plasmablastic morphology and phenotype, since most cases show the phenotype of non germinal center B cell (GCB) DLBCL.

An important differential diagnosis of FA-LBCL is LBCL with chronic inflammation (CI-LBCL), particularly as these two entities cannot be distinguished simply based on histomorphology and immunophenotype. CI-LBCL is a more aggressive neoplasm with higher mortality than FA-LBCL, which is rather indolent. An infiltration into pre-existing anatomic structures or mass formation suggests CI-LBCL, while fibrin deposits are common in FA-LBCL. If the FA-LBCL exhibits plasmablastic morphology, it should be distinguished from plasmablastic lymphoma (PBL). PBL generally shows a distinct clinical context, e.g., HIV infection, tumor manifestations in the oral cavity and an obvious plasmacytic immunophenotype. Unlike FA-LBCL, LMP1 is not expressed in PBL.

In summary, the diagnosis of FA-LBCL is challenging due to its rarity and also the fact that it is usually incidentally diagnosed owing to clinical indolence. Furthermore, our case exemplifies an expansion of the concept of FA-DLBCL, based on its EBV negativity and plasmablastic phenotype. Pathologists should be aware of this entity, especially to differentiate from more aggressive neoplasms such as CI-LBCL and PBL demonstrating morphological similarity with FA-LBCL.

References:
WHO Classification of Tumours Editorial Board: Haematolymphoid Tumours, 5th Edition, 2023, Blood 2015;125:2323, Arch Pathol Lab Med 2016;140:1074, Am J Surg Pathol 2017;41:299, Am J Surg Pathol 2012;36:1074, Virchows Arch 2020;476:647, Int J Surg Pathol 2022;30:39

Test question answer:
C. This neoplasm is strongly associated with EBV infection with type III latency. Except for rare cases as presented here, FA-LBCL is consistently associated with EBV infection showing type III latency with LMP1 and EBNA2 positivity. Answer A is incorrect because CI-LBCL exhibits a more aggressive clinical course than FA-LBCL with similar morphology, so these two entities should be clearly distinguished. Answer B is incorrect because the neoplastic cells of FA-LBCL show an activated (nongerminal center) B cell phenotype (CD10-, BCL6+/-, MUM1+). Answer D is incorrect because FA-LBCL is an indolent lymphoid neoplasm, so it is often discovered incidentally during careful examination. Answer E is incorrect because this tumor is mostly confined to cystic or pseudocystic spaces without infiltration of pre-existing anatomic structures or mass formation.


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