# Atypical lymphoid proliferations associated with therapeutic intervention: a report of the 2024 EA4HP/SH lymphoma workshop

Ioannis Anagnostopoulos, Tanja Lakic, Olga Balague, Michiel van den Brand, Stefan Dirnhofer, Gorana Gasljevic, Camille Laurent, Maurilio Ponzoni, Leticia Quintanilla-Martinez, Birgitta Sander, et al.

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## To cite this version:

Ioannis Anagnostopoulos, Tanja Lakic, Olga Balague, Michiel van den Brand, Stefan Dirnhofer, et al. Atypical lymphoid proliferations associated with therapeutic intervention: a report of the 2024 EA4HP/SH lymphoma workshop. Virchows Archiv, 2025, 487 (2), pp.287 - 307. 10.1007/s00428-025-04197-0. inserm-05247301

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# Atypical lymphoid proliferations associated with therapeutic intervention: a report of the 2024 EA4HP/SH lymphoma workshop

Ioannis Anagnostopoulos¹ ID · Tanja Lakic² ID · Olga Balague³ ID · Michiel Van den Brand⁴,⁵ ID · Stefan Dirnhofer⁶ ID · Gorana Gasljevic⁷,⁸ ID · Camille Laurent⁹ ID · Maurilio Ponzoni¹⁰ ID · Leticia Quintanilla-Martinez¹¹,¹² ID · Birgitta Sander¹³ ID · James R. Cook¹⁴ ID

Received: 18 May 2025 / Revised: 14 July 2025 / Accepted: 15 July 2025 / Published online: 13 August 2025
© The Author(s) 2025

## Abstract

The challenging boundaries between neoplastic and reactive lymphoproliferations were discussed during the 2024 European Association for Haematopathology/Society for Hematopathology workshop in Dubrovnik, Croatia. Session 3 focussed on the atypical lymphoid proliferations associated with therapeutic interventions. Forty-four cases were submitted representing a broad spectrum of lymphoproliferative disorders (LPDs) encountered in the settings of immunosuppressive and immunomodulatory therapies, various interventions for solid tumor treatment, drug reaction with eosinophilia and systemic symptoms (DRESS), CAR T-cell therapy for B-cell lymphomas, Bruton tyrosine kinase inhibitors (BTKI) for SLL/CLL treatment, ABL-kinase inhibitor dasatinib, and COVID-19 vaccination. The cases of this session highlighted the importance of having sufficient clinical information including drug history and distribution of disease in order to achieve reliable diagnosis. Among LPDs associated with immunosuppressive and immunomodulatory therapies, the most challenging were T- and NK-derived infiltrates as they ranged from non-clonal to clonal. DRESS-associated lymphadenopathy exhibited variable histologic patterns with the most difficult differential diagnosis being with a T-cell lymphoma. LPDs observed after CAR T-cell therapy for B-cell neoplasms exhibited unexpected phenotypes resulting either from lineage switching/transdifferentiation, or from harvested T-cells already harbouring cancer-associated variants. Temporary interruption of BTKI treatment for CLL/SLL due to surgical procedures led to a “Pseudo-Richter transformation” that disappeared after reintroduction of therapy. Dasatinib led to a lymphadenopathy with a peculiar florid follicular hyperplasia that regressed after discontinuation of therapy. The findings of the few thoroughly studied COVID-19 vaccination associated lymphadenopathy cases reflected a disordered immune response. This report describes the most important features for diagnosis of these challenging cases.

**Keywords** Iatrogenic immunodeficiency · DRESS · CAR T-cell therapy · Pseudo-Richter transformation · Dasatinib lymphadenopathy · COVID-19 vaccination

## Introduction

Therapeutic interventions may be associated with a wide range of lymphoproliferative disorders (LPDs). The most widely studied are those arising in the setting of iatrogenic immunosuppression after solid organ or hematopoietic cell transplantation. It is also well known that immunosuppressive and immunomodulatory drugs administered for treatment of autoimmune and rheumatological diseases can affect the patient's immune system causing an immunodeficiency background. This iatrogenic immunodeficiency may be further aggravated by high patient's age associated with a

variable degree of immunosenescence [1]. In this immunodeficiency setting, a reactivation of latent Epstein-Barr virus (EBV) infection may also occur. These circumstances can lead to the development of a broad and heterogeneous spectrum of LPDs that encompasses a variety of lymphoid hyperplasias (follicular hyperplasia, progressive transformation of germinal centers, Castleman-disease-like changes, infectious mononucleosis-like hyperplasia, plasmacytic hyperplasia, other paracortical hyperplasias), some LPDs leading to an obliteration of underlying tissue architecture (polymorphic LPD, EBV+ mucocutaneous ulcer), as well as low grade and aggressive lymphomas [2]. The spectrum of iatrogenic immunodeficiencies and immune dysregulations is constantly expanding and includes settings of

<footnote>Extended author information available on the last page of the article</footnote>
multi-chemotherapy [3, 4], immune checkpoint and targeted regimens for solid cancers [5–7] and hematologic malignancies, chimeric antigen receptor (CAR) T-cell therapy for lymphomas [8], as well as next-generation immunosuppression in autoimmune and inflammatory diseases [9, 10].

The major theme of the 2024 European Association for Haematopathology (EA4HP) and Society for Hematopathology (SH) workshop in Dubrovnik, Croatia, was “Exploring the boundaries between neoplastic and reactive lymphoproliferations”. A session was dedicated to atypical lymphoid proliferations associated with therapeutic intervention. Forty-four cases were submitted representing the challenges in the diagnosis of lymphoproliferations developing in association with the currently constantly expanding spectrum of therapeutic interventions. The cases were divided into the following thematic groups to illustrate not only the diagnostic challenges but also interesting biological features.

1. Lymphoid proliferations associated with immunosuppression or immunomodulatory therapy

2. Lymphoid proliferations associated with interventions for solid tumors

3. Drug reaction with eosinophilia and systemic symptoms (DRESS)

4. CAR T-cell therapy associated complications

5. Complications of SLL/CLL treated by Bruton tyrosine kinase inhibitors

6. Dasatinib associated lymphadenopathy

7. COVID-19 vaccination associated lymphadenopathy

8. Miscellaneous

## Lymphoid proliferations associated with immunosuppression or immunomodulatory therapy

The iatrogenic LPDs include a diverse spectrum of lesions arising in the setting of immunosuppressive or immunomodulatory drugs administered for many different underlying conditions. The most widely studied and best understood forms of iatrogenic LPDs, the post-transplant lymphoproliferative disorders (PTLDs), were specifically excluded from this session. The non-transplant related disorders, sometimes referred to as “other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD)” [11–14], may be divided into polymorphic versus monomorphic histologic categories, analogous to the classification of PTLDs. Details of the clinicopathologic findings in OIIA-LPD are limited, largely derived from case reports and small series. It is clear; however, that lesions associated with particular therapeutic agents may show specific characteristic findings. For example, LPDs arising in patients with autoimmune diseases (typically rheumatoid arthritis) treated with

methotrexate, are most commonly EBV-positive diffuse large B-cell lymphoma (DLBCL), polymorphic B-cell LPDs, or classic Hodgkin lymphomas (CHL) [12, 15, 16]. Patients receiving mycophenolate mofetil, which may be administered in the transplant setting or for autoimmune disease such as myasthenia gravis, are at particular risk for EBV-positive CNS DLBCL [17, 18] and cases of hepatosplenic T-cell lymphoma appear to be increased in patients with Crohn’s disease receiving anti-TNF agents together with thiopurines [13, 19, 20]. Further studies are needed to characterize the clinical spectrum of LPDs that arise in the setting of a rapidly growing list of agents, and the cases submitted to this session offer intriguing insights into these uncommon disorders.

Twelve cases of OIIA-LPD were submitted to this session, including 3 polymorphic B-cell LPDs, 5 cases of monomorphic B-cell LPDs, and 4 cases of T- or NK-cell LPDs. It should be noted that while the 2022 International Consensus Classification (ICC) maintains a separate diagnostic category for PTLDs versus OIIA-LPDs [21], the 5th edition WHO classification has eliminated PTLD as a distinct diagnostic category and instead groups all iatrogenic LPDs under one diagnostic umbrella with a recommended tripartite nomenclature specifying histologic pattern, viral status, and clinical setting [22, 23]. For the purposes of this workshop, all cases were classified using diagnostic criteria of both systems.

The 3 cases of polymorphic B-cell LPDs (Supplemental Table 1) were each EBV-positive and each were being treated with steroids for autoimmune disease. While some studies have reported an increased risk of lymphoma in patients receiving corticosteroids [24, 25], the precise role of steroid therapy in development of an LPD remains uncertain and difficult to separate from risks that may be associated with the underlying autoimmune disorder. Case LYWS-87 submitted by A. Sierra was a 21-year-old male with ulcerative colitis (UC), receiving vedolizumab and prednisone, who had a long history of poor response to other immunosuppressants. The patient developed ulcerated lesions of the colon, requiring subtotal colectomy, without adenopathy or other mass lesions. The colon contained multiple discrete ulcers with a heterogeneous infiltrate of small B- and T-lymphocytes, polytypic plasma cells, immunoblasts and scattered large atypical EBV-positive B-cells (Figure 1 A–E). Histologic classification of this lesion differed in the ICC and WHO5 systems. While each individual ulcer had features compatible with a diagnosis of an EBV-positive mucocutaneous ulcer (EBV-MCU), the diagnosis of EBV-MCU is restricted to solitary lesions in the ICC and the preceding WHO4R system, and the findings were therefore classified as a polymorphic EBV-positive B-cell LPD. The WHO5, in contrast, allows for a diagnosis of EBV-MCU with multiple lesions within one organ system. This patient was treated

<figure><img src="image_3.png" /></figure>
with reduction of immunosuppression and remained in
complete remission. Cases LYWS-323 from G. Lukose and
LYWS-453 from M. B. Pereira each presented with ade-
nopathy and lymph node biopsy disclosed a polymorphic
background with scattered EBV-positive cells, which were
Reed-Sternberg like (LYWS-323) or of centroblastic mor-
phology (LYWS-453). Clinical follow-up was not available
in these latter two cases.

Of 5 cases of monomorphic B-cell OIIA-LPD (Sup-
plemental Table 2), 2 were EBV-positive DLBCL (EBV+
DLBCL) with a diffuse proliferation of large EBV-positive
B-cells with a non-germinal center phenotype. Case LYWS-
474 submitted by S. Bhavsar was a patient receiving azathio-
prine for autoimmune hepatitis, who developed an EBV+
DLBCL involving liver, lung, bone, and mediastinal lymph

nodes, while LYWS-359 submitted by Louis Carrillo was a
CNS EBV+ DLBCL in a patient receiving mycophenolate
and hydroxychloroquine for mixed connective tissue disease
(Figure 1 F–I). Azathioprine and mycophenolate have been
each used for many years as immunosuppressant medica-
tions for solid organ transplants and for treatment of autoim-
mune disorders and carry known risks of iatrogenic LPDs
[11, 12, 18]. Case LYWS-379 presented by B. Shah was a
patient with a 10-year history of chronic plaque psoriasis,
who developed an EBV+ CHL within several months of
starting guselkumab, an anti-IL-23 monoclonal antibody.
The data available to date suggest that guselkumab is not
associated with an increased risk of lymphoma [26], but
patients with plaque psoriasis are at an increased risk of lym-
phoma overall including cutaneous T-cell lymphomas and

<figure><img src="image_4.png" /><figcaption>**Fig. 1** Iatrogenic B-cell lymphoproliferative disorders. Case LYWS-87 (images courtesy of A. Sierra) showed multiple colonic lesions (A) with a heterogeneous infiltrate of small lymphocytes, immunoblasts, and scattered large atypical cells (B). The infiltrate contained numerous CD20 positive cells (C) with a well-defined rim of small CD3 positive cells at the base (D). An EBER in situ hybridization</figcaption></figure>

stain highlighted scattered positive Reed-Sternberg-like cells (E). In
case LYWS-359 (images courtesy of L. Carrillo), a patient receiving
mycophenolate and hydroxychloroquine for mixed connective tissue
disease developed a CNS mass (F) which was composed of sheets
of large atypical cells (G) expressing CD20 (H). An EBER in situ
hybridization stain was diffusely positive (I)
<figure><img src="image_5.png" /><figcaption>**Fig. 2** Iatrogenic T-cell lymphoproliferative disorder. In case LYWS-473 (images courtesy of X. Wu), ascites fluid and HLH developed in a patient with a history of CLL and Richter's transformation placed on everolimus. The cytology cell block showed a monomorphic population</figcaption></figure>

of small lymphocytes (A), which were positive for CD3 (B) and PD1 (C). The T-cells included few CD4 positive cells (D) with numerous CD8 positive cells (E)

CHL [27]. The role of other prior immunosuppressive therapies in contributing to the development of this lymphoma, if any, is uncertain. This case illustrates the difficulty in determining the role of a specific agent in promoting lymphomagenesis, especially for relatively new agents with limited data. LYWS-388 from S. Tian was an EBV+ DLBCL arising in the setting of a prior grade 3 A follicular lymphoma with focal EBV-positive areas. It is possible that the CHOP therapy administered in this case contributed to the eventual emergence of the EBV+ DLBCL, but insufficient materials were available for the panel to completely assess the relationships between these samples. Finally, case LYWS-234 submitted by G. Parecki was a patient receiving methotrexate on-and-off for 10 years for eosinophilic granulomatosis with polyangiitis and asthma who developed a pulmonary marginal zone lymphoma. EBER studies demonstrated few scattered positive cells, consistent with background EBV reactivation. It should be noted that diffuse EBV positivity can be seen in rare extranodal marginal zone lymphomas as a PTLD or OIIA-LPD [28, 29], but this is distinct from the few, scattered EBER positive cells that characterize EBV reactivation. Distinguishing background EBV reactivation from a truly EBV positive lymphoma or polymorphic EBV+ LPD may be important for clinical management.

Four submitted cases represented EBV-negative T-cell or NK-cell proliferations arising in patients receiving

immunosuppressive or immunomodulatory therapy (Supplemental Table 3). Case LYWS-124 from R. L. King was an EBV+ DLBCL arising in a patient receiving multiple immunosuppressive therapies for Crohn's disease. Following R-CHOP treatment, the patient was diagnosed with an EBV- peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). PCR studies of both samples showed that the PTCL T-cell clone was not detectable in the EBV+ DLBCL sample, arguing that these represent independent processes and raising the possibility that chemotherapy may have contributed to development of the PTCL. The three remaining cases were examples of unusual T-cell or NK-cell proliferations arising in the setting of etanercept, vedolizumab, and everolimus therapies (LYWS-193, LYWS-287, and LYWS-473, respectively). Case LYWS-193 from J. Sidhu was a patient with rheumatoid arthritis treated with methotrexate and etanercept, a TNF inhibitor. Within 2 months of beginning etanercept, the patient developed severe influenza A with adenopathy, and lymph node biopsy showed a somewhat depleted lymph node with a monotonous infiltrate of small CD4+ T-cells that coexpressed PD1, CD57, and CD200 but were negative for other TFH markers. As this non-canonical-TFH proliferation was not clonal by PCR, the panel favored a diagnosis of an atypical T-cell proliferation rather than an overt lymphoma and the patient died soon after biopsy. Case LYWS-287 submitted by L. M. R. Gjerdrum was a 77-year-old male receiving vedolizumab, an α4β7 integrin antibody for
Crohn's disease, who developed a chronic NK-cell lymphopro-
liferative disorder (absolute lymphocyte count 5–10 × 10⁹/L).
NGS studies showed no STAT3 mutations, but mutations in
TET2 and TNFAIP3 were present, and it was difficult to deter-
mine if these represented somatic mutations in the lymphocytes
versus background clonal myeloid elements. In case LYWS-473
submitted by X. Wu, a 79-year-old man with a history of CLL
with CHL-type Richter transformation treated with multiple
chemotherapy regimens was placed on everolimus and soon
developed pancytopenia, hemophagocytic lymphohistiocytosis
(HLH), and ascites. A cytology cell block of the ascites fluid
showed a proliferation of monomorphic small lymphocytes that
were predominantly CD8 positive with PD1 expression (Fig-
ure 2). Despite the presence of a clonal population by PCR, the
review panel favored a diagnosis of an atypical clonal T-cell
proliferation rather than lymphoma. PD1 expression is charac-
teristic of exhausted cytotoxic T-cell proliferations [30–32], but
it is difficult to determine whether this proliferation was second-
ary to the lymphoma, HLH, or therapy, or any combination
thereof. These cases illustrate the complexity of attempting to
determine the contribution of these therapeutic agents to T- or
NK-cell proliferations, especially for newer therapeutic agents
where relatively little data exists in the literature.

Lymphoid proliferations associated
with interventions for solid tumors

Five cases submitted to this session represented LPDs aris-
ing in patients being treated for solid tumors (Supplemental
Table 4). LYWS-23 submitted by T. Tousseyn was a patient
with *EGFR* mutated adenocarcinoma of the lung, who was
treated with chemotherapy and an anti-EGFR agent and devel-
oped a T-cell lymphoma with TFH phenotype and only focal
scattered EBV positive cells, and LYWS-173 from N. Demko
was a patient with esophageal adenocarcinoma, who devel-
oped an EBV+ polymorphic LPD arising after chemotherapy.
Chemotherapy for solid tumors is increasingly recognized
as contributing to development of an iatrogenic LPD [3, 4],
although the clinical history should be thoroughly examined

for any coexisting immunodeficiency, autoimmune disorder,
or immunosuppressive medications, which may also promote
development of an LPD. The EBV+ polymorphic B-cell LPD
in case LYWS-173 was similar to lesions typically arising in
the setting of immunosuppression. The T-cell lymphoma in
case LYWS-23, in contrast, is largely similar to that which
might arise in an immunocompetent host, and it is difficult in
such cases to determine to what extent prior chemotherapy
truly promoted the development of the lymphoma.

Two cases were examples of LPDs arising in patients treated
with anti-PD1 checkpoint inhibitors. Only rare examples of
clonal lymphoproliferative disorders have been reported in
patients with checkpoint inhibitor therapy [7], which are gener-
ally thought to act by increasing immunocompetence via restor-
ing activity of exhausted T-cells [33, 34]. Case LYWS-375
submitted by I. Anagnostopoulos was an EBV+ polymorphic
B-cell LPD in a patient receiving pembrolizumab for colorectal
carcinoma with microsatellite instability (MSI) due to deficient
DNA mismatch repair. LYWS-286 from A. Szumera-Cieckie-
wicz was a patient receiving nivolumab for *BRAF* mutated mel-
anoma who developed subcutaneous masses. Biopsy showed
an EBV negative lymphoid proliferation with morphologic and
phenotypic features consistent with a diagnosis of a subcuta-
neous panniculitis-like T-cell lymphoma. However, cases of
panniculitis-like infiltrates have also been reported as immune-
related adverse events in patients receiving checkpoint inhibi-
tors [35, 36], and there was insufficient material for molecular
studies in this case to confirm T-cell clonality, such that the
review panel was unable to render a definitive diagnosis.

Finally, case LYWS-423 submitted by M. Merzianu
was a 96-year-old man with a 15-year history of multiply
recurrent melanoma as well as a parotid area follicular lym-
phoma, which had been diagnosed on fine needle aspirate
and had not been treated. The melanoma was treated with
intralesional talimogene laherparepvec (T-VEC), a modi-
fied herpes simplex virus intended to infect and lyse mela-
noma cells, stimulating an anti-tumoral immune response.
A biopsy performed to assess response after 6 weeks (Fig-
ure 3) showed no evidence of melanoma, but diffuse sheets
of kappa monotypic plasma cells were present with a normal

<figure><img src="image_6.png" /><figcaption>**Fig. 3** Iatrogenic lymphopro-
liferative disorder following
treatment for solid tumor. Case
LYWS-423 (images courtesy
of M. Merzianu) was a patient
with melanoma who received
intralesional talimogene laher-
parepvec. Follow-up biopsy
showed a diffuse infiltrate (A)
composed of mature plasma
cells (B) with monotypic kappa
light chain expression</figcaption></figure>
(CD19 positive, CD56 negative) phenotype. PCR studies showed a clonal B-cell receptor rearrangement with clonal amplicons that did not match the prior follicular lymphoma. The pattern of findings suggested a clonal but reactive plasmacytic proliferation secondary to T-VEC therapy, possibly involved in treatment response [37].

## Drug reaction with eosinophilia and systemic symptoms (DRESS)

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a form of severe cutaneous delayed-type hypersensitivity drug reaction that is often characterized by lymphadenopathy and eosinophilia that may raise concern for a lymphoproliferative disorder [38–41]. DRESS is uncommon overall but has been reported to represent up to 23% of cutaneous drug reactions in hospitalized patients, and mortality rates in the US have been estimated to be approximately 5%. The diagnosis of DRESS is based on a pattern of clinical, laboratory, and pathologic findings with different organizations proposing varyingly rigorous sets of diagnostic criteria (Table 1) [40–42]. Antibiotics represent the most common category of inciting drugs, although a very wide range of agents have been implicated including anticonvulsants, anti-inflammatory agents, antivirals, and iodine containing contrast medium, among many others. In addition to hematologic abnormalities that may include eosinophilia and/or atypical lymphocytosis, systemic symptoms may include dysfunction of the liver, kidneys, lung, or heart, although

almost every organ system has been reported to be involved [38, 39]. Systemic symptoms may be severe, or even fatal due to organ failure. HHV6 reactivation has been associated with DRESS [38, 39, 43], although the role of HHV6 in the development of DRESS remains controversial and HHV6 is not detectable in all cases. HHV6 reactivation defines typical DRESS using Japanese consensus criteria but it is not required for a diagnosis of DRESS in other systems. Treatment typically consists of withdrawal of the offending agent and steroid therapy with a prolonged taper to decrease the risk of relapse.

Six cases of DRESS were submitted to this session (Supplemental Table 5). Implicated drugs included antibiotics in 4 cases while one patient received doxazosin and bendroflumethiazide (LYWS-32 from D. Pisani) and one received a combination of thalidomide, sulfasalazine, and traditional Chinese medicine (LYWS-86 submitted by Y. Li). Lymph node biopsies were performed in 5/6 cases, highlighting the propensity of DRESS to raise clinical concern for a lymphoproliferative disorder. Four different histologic patterns have been described in DRESS lymph nodes, three of which were illustrated in the submitted cases (Figure 4): reactive paracortical hyperplasia (LYWS-86 from Yu Li and LYWS-208 from J. V. Alves De Castro), Kikuchi-like (LYWS-203 submitted by A. Saglam), angioimmunoblastic T-cell lymphoma-like (LYWS-107 submitted by S. El Hussein and LYWS-297 submitted by J. R. Cook), and Hodgkin-like (not identified in this cohort). All cases were reported to show retention of the pan-T-cell-antigens studied, and PCR studies for T-cell clonality were performed in three cases, with

<table><caption>**Table 1** Diagnostic criteria in the initial report of DRESS by Bouquet et al., and criteria employed by subsequent investigators</caption><thead><tr><th>Bocquet et al. [40]</th><th>Japanese Consensus Group [42]</th><th>RegiSCAR [41]</th></tr></thead><tbody><tr><td>1. A cutaneous drug eruption</td><td>1. Maculopapular eruption developing &gt;3 weeks after starting a limited number of drugs</td><td>1. Acute skin eruption</td></tr><tr><td>2. Systemic involvement by lymphadenopathy ≥2 cm in diameter or hepatitis (transaminase ≥2 times upper limit of normal) or interstitial nephritis or interstitial pneumonitis or carditis</td><td>2. Prolonged clinical manifestations 2 weeks after discontinuation of the causative drug</td><td>2. Fever (&gt;38 °C)</td></tr><tr><td>3. Hematologic abnormalities: eosinophilia ≥1.5×10<sup>9</sup>/L or presence of atypical lymphocytes</td><td>3. Fever (&gt;38 °C)</td><td>3. Lymphadenopathy at ≥2 sites</td></tr><tr><td rowspan="7">Required: All 3 elements</td><td>4. Liver abnormalities (alanine aminotransferase &gt;100 U/L)</td><td>4. Involvement of at least one internal organ</td></tr><tr><td>5. Leukocyte abnormalities (at least 1 present): Leukocytosis (&gt;11×10<sup>9</sup>/L)<br/>Atypical lymphocytosis (&gt;5%)<br/>Eosinophilia (&gt;1.5×10<sup>9</sup>/L)</td><td>5. Lymphocytosis or lymphocytopenia</td></tr><tr><td>6. Lymphadenopathy</td><td>6. Peripheral eosinophilia</td></tr><tr><td>7. HHV-6 reactivation</td><td>7. Thrombocytopenia</td></tr><tr><td>Required: All criteria (typical) or the first 5 (atypical)</td><td>Required: At least 3. A scoring system is also applied to classify degree of certainty.</td></tr></tbody></table>

<figure><img src="image_7.png" /></figure>
<figure><img src="image_8.png" /><figcaption>**Fig. 4** Patterns of lymph node histology in DRESS syndrome. Case LYWS-297 (images courtesy of J.R. Cook) showed an angioimmunoblastic T-cell lymphoma-like pattern with architectural effacement, vascular proliferation, and a proliferation of small lymphocytes and occasional larger cells (A). Case LYWS-203 (images courtesy of A. Saglam) exhibited a Kikuchi-like pattern with areas of neutrophil-</figcaption></figure>

polyclonal results in each case. Immunohistochemistry for HHV6 was performed by the submitter of LYWS-208 and by the review panel in additional three cases, and 2/4 (50%) were positive.

In light of the potentially fatal complications of DRESS, timely recognition of this diagnosis is critical for patient management [38, 39]. The heterogeneity of lymph node morphology makes the correct diagnosis challenging, and some cases may raise concerns for a T-cell neoplasm, especially TFH lymphoma. PCR studies were polyclonal in all cases studied, which may provide some reassurance in routine practice, but ultimately establishing the correct diagnosis requires correlation with the clinical findings and the time course since initiation of drug therapy.

## CAR T-cell therapy associated complications

Adoptive cellular therapy using CARs has altered the landscape of cancer immunotherapy. CAR T-cells are genetically modified autologous T-cells manufactured to express a CAR gene. The efficacy of CAR T-cells has been proven in patients with relapsed/refractory B-cell derived malignancies, including acute lymphoblastic leukemia (B-ALL) [44], mantle cell lymphoma (MCL) [45], multiple myeloma (MM)

poor necrosis (B) and HHV6 positive cells detected by immunohistochemistry (C). A reactive paracortical hyperplasia-like pattern was illustrated in LYWS-208 (images courtesy of A. Flaifel) with expanded paracortical regions (D) containing small lymphocytes with scattered large transformed cells (E)

[46], and different entities of large B-cell lymphoma (LBCL) [47]. Despite the remarkable therapeutic efficacy of CAR T-cell therapies, there are several known complications. Besides those associated with the direct receipt of CAR T-cells or from the cytotoxic and immunosuppressive regimens that accompany such a treatment like cytokine release syndrome, neurotoxicity syndrome, cytopenias and infections, there are complications requiring haematopathological expertise for clarification of therapy resistance and for characterization of post-infusion malignancies. In addition, pathology laboratories are expected to play a role in monitoring the phenotype, persistence, and tumour infiltration properties of CAR T-cells and the tumour microenvironment for factors that might predict CAR T-cell therapy success. In the workshop, five cases were submitted dealing with CAR T-cell therapy complications: two cases associated with CAR T-cell resistance (LYWS-88 and LYWS-262), and three cases with neoplastic and non-neoplastic T-cell proliferations (LYWS-172, LYWS-186, and LYWS-93).

## Resistance to CAR T-cell therapy

Despite frequent durable remissions induced by this biologically active immunotherapy in haematologic malignancies, over half of the patients show a lack of response or eventually
relapse [48] [49, 50]. Available evidence suggests that resist-
ance to CAR T-cells is multifactorial and influenced by fac-
tors related not only to the target but also to the effector cells.
Antigen loss in tumor cells is one of the major mechanisms of
resistance and can occur through various mechanisms, such
as gene mutations, deletions, rearrangements, epigenetic
modifications, lineage switching also referred to as transdif-
ferentiation, in which sequential neoplasms with apparent dif-
ferent lineages exhibit evidence of derivation from a common
ancestor clone, and trogocytosis, in which CAR T-cells gnaw
away antigen from the target cells. Following CAR T-cell
therapy, the antigen-negative subclones within a heteroge-
neous tumour population can be selected and expanded by
immune pressure followed by additional clonal evolution.
The frequency and impact of antigen loss varies depending
on the target antigen, disease entity, and patient population.
The CD19-negative relapse rate ranges from 18% to 25% for
pediatric B-ALL and 7% to 9% for adult B-ALL patients [50]
and between 20% and 50% for LBCL in different clinical tri-
als/studies [47, 49] while the frequency of de facto BCMA
loss in MM is largely unknown [51].

Regarding the mechanisms for CD19 resistance in B-ALL,
the most common one represents mutations in exons 2–5 of
the *CD19* gene [52, 53]. Another mechanism is lineage switch
from B-ALL to acute myeloid leukaemia, which has been
observed in approximately 7% of patients [54]. The findings
regarding CD19 resistance in LBCL have so far shown that
mutations in the *CD19* gene appear to be an uncommon phe-
nomenon. A non-invasive study of a large number of relapsed/
refractory LBCL patients receiving anti CD19-CAR T-cells
identified that alterations of multiple classes of genes, particu-
larly those defining B-cell identity (*IRF8*, *PAX5*), involved in
immunoregulation (*CD274*), shaping immune microenviron-
ment (*TMEM30A*) and in *TP53*, were associated with resist-
ance [55], whereas somatic mutation mediated CD19 loss
was a relatively uncommon mechanism of resistance. The
only one comparable tissue-based study analysed sequential
samples from nine LBCL patients prior and post anti-CD19
CAR T-cells. While the histopathologic features were mostly
retained at relapse in 7/9 patients with the exception of fre-
quent loss of one or several B-cell-characteristic molecules,
the remaining two cases exhibited a dramatic phenotypic shift
with reduction of B-cell-characteristic molecules and emer-
gence either of T-cell, or histiocytic markers [56]. None of the
post CAR T-therapy samples harboured *CD19* gene mutations,
while new pathogenic variants were acquired after therapy
including mutations triggering the PI3K pathway or associated
with tumor aggressiveness (*KRAS*, *INPP4B*, *SF3B1*, *SYNE1*,
*TBXL1XR1*). A further resistance mechanism identified in that
study is the occurrence of transdifferentiation in two cases as
mentioned above. Both cases had similar cytogenetic abnor-
malities as the original LBCL with similar IGH rearrange-
ments indicating clonal relatedness. The in-depth analysed

post CAR T tumour with aberrant T-cell phenotype showed
an acquired *PAX5* mutation and reduced mRNA expression
of most B-cell genes with increased methylation of their pro-
moter. There are also two additional case reports on transdif-
ferentiation of B-cell neoplasms after CAR T-cell therapy into
either a sarcoma or a poorly differentiated neoplasm [57, 58].
Both reported on similar findings as Laurent et al. [56] by
showing an acquisition of gene mutations post CAR T-cell
therapy with subsets not usually seen in lymphoid malignan-
cies and in the case of sarcoma a hypermethylation and silenc-
ing of the B-cell programming genes. Regarding the mecha-
nism for resistance in MM, several reports demonstrated a rare
occurrence of a homozygous *BCMA* gene deletion resulting in
loss of BCMA expression [59, 60]

The two workshop cases fitting to CAR T-cell therapy
resistance (LYWS-88 submitted by E. Fenu, and LYWS-
262 presented by A. Torabi) further expand our knowledge
regarding transdifferentiation as an escape mechanism from
immunotherapy pressure (Figure 5). The first case regards an
8-year-old female with B-ALL that relapsed multiple times
despite treatment by two different protocols and a matched
sibling bone marrow transplant (BMT). She received CD19-
targeting CAR T-cell therapy followed by a second unrelated
BMT but remained MRD-positive and developed extramed-
ullary lesions, which were treated with a PD-1 inhibitor. One
month after CAR T-cell infusion, a BM biopsy and flow
cytometry were negative for B-ALL, but there was a minute
focus of atypical spindled cells within the periosteum. A
subsequent BM biopsy showed an infiltrate of pleomorphic
cells with irregular nuclei, prominent nucleoli, and ample
cytoplasm. The cells expressed CD68, CD163, and CD11c
leading to the diagnosis of histiocytic sarcoma. NGS analy-
sis detected the same IGH, IGK, and IGL sequences as the
B-ALL proving clonal relatedness. In addition, comparative
analysis with the B-ALL revealed the acquisition of new
mutations in the histiocytic neoplasm thus confirming trans-
differentiation of B-ALL to a histiocytic sarcoma. This is
apparently the first case of B-ALL that showed a transdif-
ferentiation to a sarcoma. The second case was a man in
early 50s initially diagnosed with a follicular lymphoma
grade 1–2 in a lymph node biopsy and DLBCL in the staging
BM biopsy. After DA-EPOCH-R chemotherapy, a lympho-
blastic transformation of the lymphoma was observed. Due
to critical disease progression, he received anti-CD19 CAR
T-cells. After an initial response, PET/CT scan showed
multiple bone and soft tissue tumours. Biopsies showed a
small round blue cell tumour that only expressed CD56 and
p53 while being negative for an array of B-cell- and T-cell
markers as well as for TdT markers for epithelial and neu-
roendocrine differentiation. FISH identified the presence
of the *IGH::BCL2* that was also present in all lymphoma
manifestations prior to CAR T-cell therapy and NGS iden-
tified acquisition of gene mutations when compared with

<figure><img src="image_9.png" /></figure>
LYWS-88

B-ALL

<figure><img src="image_10.png" /></figure>

CD19 CAR T-cells

<figure><img src="image_11.png" /></figure>

One month later
**Histiocytic sarcoma**

<figure><img src="image_12.png" /></figure>

CD163
CD11c

<figure><img src="image_13.png" /></figure>

B-ALL and sarcoma: identical IGH, IGK and IGL sequences

Overlapping and novel mutations
Post CAR T-cell therapy

LYWS-262

Follicular lymphoma
Lymphoblastic Transformation

<figure><img src="image_14.png" /></figure>

CD19 CAR T-cells

<figure><img src="image_15.png" /></figure>

Two months later
**Undifferentiated neoplasm**

<figure><img src="image_16.png" /></figure>

CD56

<figure><img src="image_17.png" /></figure>

All lesions: identical IGK rearrangements
FISH positive for IGH:BCL2 t(14;18)

Overlapping and novel mutations post
CAR T cell therapy

**Fig. 5** Transdifferentiation in CAR T-cell treated B-cell lymphomas. Overview of the histological, immunophenotypic and molecular findings of LYWS-88 submitted by E. Fenu and LYWS-262 (images courtesy of A. Torabi) with resistance to anti CD19 CAR T-cell therapy due to trans-differentiation of treated neoplasms
the specimens prior to therapy, while some mutations were no longer detectable. Interestingly, *CD19* and *PAX5* genes were intact in this case. This case thus represents a transdif- ferentiated transformed follicular lymphoma following CAR T-cell therapy.

## Secondary T-cell lymphomas after CAR T-cell therapy

This main potential long-term risk is currently under the US- Food and Drug Administration (FDA) scrutiny [61] docu- mented by the report of a “Serious Risk of T-cell malignancy following BCMA-Directed or CD19-Directed Autologous CAR T-Cell Immunotherapies”. Notably, this report sug- gests that some of the T-cell lymphoma cases after CAR T were “CAR-positive” highlighting a potential association between CAR transduction and transformation. Available data suggest that the risk of a second primary malignancy is not higher than expected among patients with substan- tial previous exposure to chemotherapy [62]. The 20 to 25 reported cases of T-cell lymphoma are, however, attracting particular interest due to the possibility of a direct causal link to CAR T-cell therapy. Among the cases for which ade- quate data are available, the lymphomas manifested within 2 years post-infusion. In cases for which genetic sequencing has been performed, the CAR transgene has been detected in the malignant clone, which indicates a direct causal link [61, 63–65].

Case LYWS-172 presented by D. Gratzinger revealed another scenario that can lead to a secondary T-cell lym- phoma after CAR T-cells, namely that the harvested T-cells already harbour cancer associated variants (Figure 6). The patient, a 59-year-old woman with a history of psoriasis and eosinophilic fasciitis treated with steroids, methotrexate, and mycophenolate-mofetil, developed an EBV+ DLBCL. As R-CHOP and RGemOx chemotherapy led only to an incom- plete response, the patient received CD19 CAR T-cell ther- apy. One month post infusion pancytopenia, increasing EBV titre and clinical findings consistent with HLH, prompted a BM biopsy. This showed an infiltration by large T-cells that were EBV+ in the EBER in situ hybridization and exhib- ited an aberrant T-cell immunophenotype (CD2+, CD3+/-, CD7+, CD5-, CD4+, TCR silent, CD56-, CD57-), while no expression of B-cell-characteristic antigens was detectable. The patient was diagnosed with an EBV+ T-cell lymphoma associated with HLH. PET-CT showed widespread nodal and BM disease burden and the patient passed away from disease shortly thereafter. To clarify a possible CAR T-cell derived lymphoma, several investigations were performed (flow cytometry profiling of the bone marrow specimen for surface CAR protein, single cell RNA-seq for CAR vector transgene RNA, quantitative PCR for detection of integrated CAR vector DNA and overlapping 120 bp probes against the

entire CAR vector) all leading to negative results. A possible transdifferentiation of DLBCL to T-lineage was excluded by comparison of clonal IG and TCR rearrangements, chro- mosomal abnormalities and acquired somatic mutations. Then the question was addressed, whether a clinically occult T-cell lymphoma had been unmasked by CAR T therapy of DLBCL. Review of the original biopsies failed to identify a cytologically abnormal T-cell population; the T cells in the background exhibited a low proliferative activity and the dominant clone type of the T-cell lymphoma was detectable at an extremely low level in the DLBCL biopsy specimen, well below the level of routine detection or overt lymphoma. Single-cell DNA sequencing data indicated that the founder population of DLBCL and T-cell lymphoma was present in the haematopoietic stem cells, which contained mutations in *TET2* and *DNMT3A* and propagated them into the com- mon lymphoid and myeloid progenitors. EBV activation due to immune suppression was probably a common event in both lymphomas but one that led to unique subsequent mutations and structural variations that ultimately resulted in the mature neoplasms [66]. An obvious question is whether clonal haematopoiesis that is rather common in the age group of patients undergoing CAR therapy poses a criti- cal risk factor for development of lymphoma. As thousands of CAR recipients that must have harboured pre-existing clones have not developed lymphoma, there is considerable reassurance that there is no substantial risk for secondary haematolymphoid malignancies.

## Unusual T-cell proliferations after CAR T-cell therapy

The first case (LYWS-93, submitted by P. Kaur) could not be classified by the review panel. The patient, a 31-year-old male with a transformed follicular lymphoma and multiple osseous lesions, received CD19 CAR T cells and presented 6 months later with a large left lower extremity 20 cm mass. Biopsy showed a diffuse infiltration of skeletal muscle by highly proliferative (Ki67 80%) small T cells (CD3+, CD2+, CD5+, CD8+). The mass resolved spontaneously 3 months later. As no tissue was available for further studies, one could only speculate whether it represented a delayed CAR T-cell response or an unusual T-cell lymphoprolifera- tive disorder. The second case (LYWS-186, submitted by J. Harris) was a 74-year-old man with relapsed/refractory MM who developed 2 weeks post-BCMA CAR T cell infu- sion hyperleucocytosis with absolute lymphocytosis and 2 months post-infusion with an altered mental status. Periph- eral blood and cerebrospinal fluid contained CD4+ T cells with variable CD7 expression without evidence of clonal- ity. Flow cytometry disclosed that they represented an unu- sually sustained CAR T-cell expansion. Ongoing diarrhea (3.5 months post-infusion) prompted GI biopsies showing absent plasma cells and chronic epithelial injury mimicking

<figure><img src="image_18.png" /></figure>
<figure><img src="image_19.png" /><figcaption>**Fig. 6** Secondary T-cell lymphoma after CAR T-cell therapy of a B-cell lymphoma. Schematic presentation of the findings in case LYWS-172 (images courtesy of P. L. Bulterys) illustrating the paral-</figcaption></figure>

lel development of EBV-positive diffuse large B-cell lymphoma and EBV-positive T-cell lymphoma from a common haematopoietic progenitor cell population

CVID. RNA-scope disclosed that the T cells in the lamina propria also corresponded to anti-BCMA CAR T cells, thus representing another case of the rarely observed immune effector cell-associated enterocolitis [67]. It might be possible that eradication of BCMA-positive long-lived IgA plasma cells in gut mucosa is involved in pathogenesis. Both cases underline the need for reliable and standardized methods to detect CAR T cells in pathology laboratories. Table 2 presents an overview for various currently available techniques.

## Complications of SLL/CLL treated by Bruton tyrosine kinase inhibitors

Bruton tyrosin kinase inhibitors (BTKIs) are being widely used as an efficacious therapy for patients with small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL). Such medication is administered as continuous therapy until unacceptable toxicity or disease progression/transformation occur. Richter transformation of CLL/SLL into aggressive lymphoma occurs in 2%–10% of patients [69] and has been described as
<table><caption>**Table 2** Summary of the currently available methods for detection of CAR T cells in pathology laboratories (adapted from Reference [68])</caption><thead><tr><th>Method</th><th>Target</th><th>Advantages</th><th>Disadvantages</th></tr></thead><tbody><tr><td>Flow cytometry</td><td>Detection of CAR-protein on cell surface: Protein L; anti-idiotype antibody; anti-linker antibodies; antigen Fc.</td><td><ul><li>High throughput</li><li>Multiplexing</li><li>Phenotype assessment</li></ul></td><td><ul><li>Lack of spatial localization</li><li>Availability and specificity of antibodies</li><li>Variability of staining and gating protocols</li><li>Difficulty detecting low-frequency CAR T-cells</li></ul></td></tr><tr><td>Immunohistochemistry</td><td>Anti-linker antibodies against CD19 CAR; Anti-EGFR against truncated EGFR tag; antibodies against specific epitopes within CAR</td><td><ul><li>Spatial localization</li><li>Multiplexing</li></ul></td><td><ul><li>Availability and specificity of antibodies</li><li>Difficulty to be quantitative</li></ul></td></tr><tr><td>In situ hybridization</td><td>RNA sequences in CAR transcript (i.e. wood-chuck hepatitis posttranscriptional regulating element)</td><td><ul><li>Spatial localization</li><li>Multiplexing</li></ul></td><td><ul><li>Dependent on RNA stability</li></ul></td></tr></tbody></table>

CAR chimeric antigen receptors; EGFR: epidermal growth factor receptor

an early event in ibrutinib-treated patients [70, 71]. DLBCL is the most common type of Richter transformation and has a poor prognosis with an overall survival of 12 months [72]. Approximately 25% of the patients who discontinued BTKI therapy experienced rapid disease progression [73]. Besides dis-continuation of BTKI therapy, various side effects of this drug type including bleeding, various toxicities as well as drug-drug interactions may necessitate dose modifications or interruption of treatment. BTKI-treatment is also typically interrupted for 3–7 days before and after surgery to reduce bleeding risk as well as in case of serious infection. The few reports dealing with temporal interruption of BTKI treatment mostly due to drug unrelated causes described also a disease flare in 25% of the patients as reported after treatment discontinuation. This disease flare manifested as clinical symptoms, laboratory abnormalities, or radiographic findings of progressive disease [74]. Symptoms/ signs in these cases promptly resolved after drug reinitiation. There was no pathological assessment of these cases and the sole predictive factors were progressive disease at time of hold and more than 24 months of BTKI exposure.

In contrast to the aggressive presentation of Richter transformation, there is a condition known as “pseudo-Richter” transformation representing an incidental finding in SLL/ CLL patients with temporary interruption of BTKIs due to surgery/acute infection [75, 76]. Up to now, eight reported patients exhibited features of histologic transformation with DLBCL-like morphology with CLL-like and non-GCB (Hans) phenotype, were frequently IGHV mutated (5 tested), exhibited trisomy 12 (6/8), TP53 mutation/17p deletion (5/8), and no MYC rearrangement, whereas none showed latent EBV infection by EBER in situ hybridization. Testing for mutations in *BTK* or its immediate downstream target *PLCG2* was not performed in any of these cases. None of the cases exhibited progressive/transformed disease after resumption of BTKI treatment (3–32 months follow-up). In contrast, true Richter transformation is refractory to BTKI and requires aggressive chemotherapy.

The 6 cases submitted to this workshop section (LYWS-26 presented by P. Farinha, LYWS-90-1 and 90-2 submitted by B. Shah, LYWS-97 submitted by K. Kamarádowá, LYWS-218 submitted by G. Lukose and LYWS-211 submitted by L. Qiu) had in common that an incidental histological examination of lymph nodes for detected or clinically suspected concomitant malignancy was performed. In all cases with reported history, BTKI treatment was interrupted 5–7 days prior to surgery (Supplemental Table 6). The investigated lymph nodes did not exhibit infiltrates of the suspected malignancies but showed either a vaguely nodular or diffuse infiltrate composed of sheets of cells with centroblastoid or immunoblastic features occasionally admixed with some pro-lymphocytes and paraimmunoblasts. All cases retained the CLL/SLL immunophenotype with co-expression of CD20, CD23, and CD5 with variable intensities with the exception of one case (LYWS-90-1) where CD5 was almost absent (Figure 7). With the exception of case LYWS-90-1, all other cases showed an additional expression of IRF4/MUM1. In two of these cases (LYWS-90-1 and LYWS-221), the peripheral blood also exhibited circulating suspicious blastoid cells. FISH analysis for *MYC* or for additional *BCL2* and *BCL6* translocations was done in three cases (LYWS-90-1, 90-2, and LYWS-221) with negative results. Only in one case (LYWS-218), a comparative study with the CLL in peripheral blood was performed that showed a novel acquisition of *TP53* mutation in the “pseudo-Richter” sample. Unfortunately, the observation period of this patient is still too short to permit further conclusions.

**Fig. 7** Pseudo-Richter transformation. Morphology and immunophenotypic findings in pseudo-Richter transformation. The infiltrate is composed of sheets from cells with centroblastoid and immunoblastic features (A LYWS-26 courtesy of P. Farinha; B LYWS-221 courtesy of L. Qiu) usually co-expressing CD20 (C, LYWS-221), CD23 (D, LYWS-221), and CD5 (E, LYWS 90-2 courtesy of B. Shah) and show high Ki67 index (F, LYWS-90-2 courtesy of B. Shah)

<figure><img src="image_20.png" /></figure>
A

<figure><img src="image_21.png" /></figure>

B

<figure><img src="image_22.png" /></figure>

C

<figure><img src="image_23.png" /></figure>

D

<figure><img src="image_24.png" /></figure>

E

<figure><img src="image_25.png" /></figure>

F

<figure><img src="image_26.png" /></figure>
In all cases, there was no disease progression after reini-
tiation of BTKI treatment. Interestingly in case LYWS-90-1
BTKI hold lasted for 2.5 years due to postoperative com-
plications without any disease progression. Awareness of
pseudo-Richter transformation is thus critical to avoid not
only a premature cessation of effective BTKI therapy but
also an increased patient morbidity with aggressive chemo-
therapy intended for true Richter transformation.

One additional CLL case treated with BTK inhibitor ibrutinib for 3 years and 10 months (LYWS-17 submitted by A. Tzankov) developed a tumorous mass obstructing the left bronchus. This mass exhibited histologic and immunophenotypic features of an ALK-negative anaplastic large cell lymphoma. This is the second case of a T-cell lymphoma observed by the authors to occur in a CLL patient treated with ibrutinib. As there is evidence that ibrutinib interferes with T-cell functions [77–79], it may be hypothesized that this treatment might increase the risk of developing T-cell lymphoma.

Dasatinib-associated lymphadenopathy

Dasatinib is a second-generation oral ABL tyrosine kinase inhibitor (TKI) that has been approved for treatment of chronic myeloid leukemia (CML) and Ph+ B-ALL. Besides ABL, it inhibits among many targets also PDGFR-β, C-KIT, and SRC tyrosine kinases and can suppress memory T-cell function. There is a spectrum of lymphoid proliferations reported to be associated with dasatinib treatment: (i) a transient peripheral lymphocytosis composed of T- and NK LGLS secondary to splenic contraction [80], (ii) pleural and pericardial effusions in about 30% of the patients [81] with the rare observation (6 cases reported) of HHV8- and EBV-negative primary effusion-based lymphoma (ICC)/fluid overload-associated large B-cell lymphoma, EBV-positive or EBV-negative, iatrogenic setting (5th edition WHO) showing a benign clinical course following discontinuation of dasatinib [82], and (iii) lymphadenopathy as described in the next paragraph.

Up to now, 18 cases of lymphadenopathy associated with dasatinib have been reported in the literature, all in the setting of CML [83–87]. All published cases displayed a predominant follicular hyperplasia, sometimes accompanied by interfollicular/paracortical hyperplasia. The usually florid follicular hyperplasia showed large germinal centers with irregular borders and occasionally broad invaginated mantle zones arranged as cuffs surrounding perforating capillaries and thus exhibited hybrid features of progressive transformation of germinal centers and Castleman-type changes. In two cases an EBV-reactivation could be identified with EBER-positive cells within germinal centers and in interfollicular areas [23, 84]. Dasatinib treatment was discontinued leading to a regression of lymphadenopathies in the patients with available follow up

(range 2–9 weeks). Dasatinib was replaced in most patients with another tyrosine kinase inhibitor with no reported recurrence of lymphadenopathy. The mechanism of dasatinib-associated lymphadenopathy is unknown. The risk of malignant transformation is currently also unknown with some reports in the literature of B-cell lymphoma development associated with dasatinib and bosutinib treatment.

Three cases of dasatinib-associated lymphadenopathy were submitted to this workshop session (LYWS-226 presented by I. Siddiqi, LYWS-291 submitted by M. Donzel and LYWS-188 submitted by L. B. Smith (Supplemental Table 7). All were adults (45–66 years old) with localized cervical (2) and axillary (1) lymphadenopathy. Case LYWS-226 showed a florid follicular hyperplasia as already described in the literature. There was also an accompanying EBV+ polymorphic LPD with detection of a clonal TR (Figure 8). The other case, LYWS-291, displayed a paracortical hyperplasia. The third case, LYWS-188, had an interesting clinical history with development of cervical lymphadenopathy under dasatinib that showed follicular hyperplasia in a biopsy (not submitted). Dasatinib was discontinued and the lymphadenopathy regressed after 1 month. TKI therapy was reinitiated using bosutinib that led to the development of neck lymphadenopathy. The lymph node exhibited serpiginous and irregular follicles arranged back to back with incomplete mantle zones. As flow cytometry detected a lambda-restricted CD10+ B-cell population and array CGH a loss of 3.47 Mb at 1p36.32p36.31, the review panel felt that these data were sufficient for diagnosing pediatric-type follicular lymphoma. Discontinuation of bosutinib led to disappearance of lymphadenopathy similar to a single reported case of a follicular lymphoma that disappeared after discontinuation of therapy [88].

COVID-19 vaccination associated
lymphadenopathy

Mass vaccination against coronavirus disease 2019 (COVID-19) has been a global health strategy to control the COVID-19 pandemic. mRNA-based vaccinations (Pfizer/BioNTech, New York, NY, USA, BNT162b2 and Moderna, Cambridge, MA USA, mRNA-1273) and viral recombinant vaccine (AstraZeneca, Cambridge, UK, ChAdOx1) have been proven to be successful in this respect. With the wide use of vaccines some adverse events post COVID-19 vaccinations have been reported.

Vaccine-associated lymphadenopathy (VAL) due to reac-
tive lymph node changes is well described and reported
in association with BCG, hepatitis B, HPV, and tetanus
vaccines among others. This is however the first time that
mRNA vaccines have been approved for clinical applica-
tion. The COVID-19 vaccines act primarily through deliv-
ery of an mRNA into cells, where the mRNA is translated
into a target protein against which the immune system will
mount an immune response. Such vaccines will cause both

<figure><img src="image_27.png" /></figure>
<figure><img src="image_28.png" /><figcaption>**Fig. 8** Dasatinib associated lymphadenopathy. Case LYWS-226 (images courtesy of M. Movassaghi) showed in large areas the typical picture of a florid follicular hyperplasia with irregular shaped follicles and focal progressive transformation of germinal centers (A overview and B detail of an irregular shaped follicle). There was also a demarcated area (C) with a polymorphic infiltrate composed of small lymphocytes, scattered B-immunoblasts, and plasma cells (D)</figcaption></figure>

cell-mediated (T cell) and humoral (B cell) responses resulting in increased likelihood of patients developing a lymphadenopathy. The histologic features of COVID-19-VAL are not

with polytypic expression of the immunoglobulin light chains (not shown). Some immunoblasts were latently infected by the Epstein-Barr-virus (EBV) as demonstrated in EBER in-situ hybridization (E). In addition, there were single cells expressing the BZLF1-Protein of EBV indicative of a transition of the latent into the lytic viral infection phase (F)

well established as the vast majority of these lymphadenopathies are not biopsied. The patterns described include the following: atypical follicular hyperplasia with monotonous
population of centroblasts, increased lymphoplasmacytic and plasmacytic cells, occasional weak BCL2 expression as well as a light chain restriction that varied between the different germinal centers [89]; extrafollicular activation of B blasts [90, 91]; necrotizing histiocytic lymphadenitis/Kikuchi-Fujimoto disease [92, 93]; Langerhans cell hyperplasia and hemophagocytosis [94]; idiopathic multicentric Castleman disease [95].

For this workshop session, four cases of this type of lymphadenopathy (Supplemental Table 8) have been submitted (LYWS-18 submitted by A.Tzankov, LYWS-85 submitted by M. Hanna, LYWS-149 submitted by I.N. Sah-Bandar and LYWS-384 submitted by J.L. Solórzano-Rendón). In contrast to the reported more frequent occurrence in females, most patients (3/4) were males. According to the available clinical data, the lymphadenopathy occurred 7 days up to 1 month after vaccination and in one case was apparently persistent for 6 months prior to biopsy. In two patients, there was a cervical and in the other two a generalized lymphadenopathy accompanied by splenomegaly. Only one patient exhibited a complicated clinical picture (LWS-149). This patient had a history of long-term medication with allopurinol and presented with altered mental status, fever, rash, fatigue, anemia, thrombocytopenia, and cervical lymphadenopathy. He had received a COVID-19 vaccine 7 days prior admission. In conjunction with the findings of a skin biopsy, a DRESS syndrome was diagnosed. The most frequent histological finding was a paracortical hyperplasia in three cases. These showed a hyperplasia of extrafollicular B-blasts which in one case coexisted with hyperplastic follicles exhibiting light chain restriction. One case also exhibited a population of immature myeloid cells and a marginal zone hyperplasia. The case with DRESS was characterized by features of an EBV reactivation with necrotic foci, few EBER-positive blastoid cells, single cells expressing the BZLF1 protein of EBV, and a mixture of polytypic plasma cells and eosinophils. As DRESS has been occasionally reported following COVID-19 vaccination [96–98], the review panel felt that rather the vaccination and not the long-term administration of allopurinol was responsible for DRESS in this case.

## Miscellaneous

Case LYWS-72 submitted by S-B Ng was a 46-year-old female with an intrauterine device inserted 2 years earlier. Endometrial biopsy showed an ulceration and a superficial dense B-cell predominant infiltrate without evidence of clonality that was classified as a reactive lymphoid hyperplasia. Case LYWS-138 submitted by T. Lakic was a 35-year-old male with a history of HIV infection on retroviral therapy who developed an EBV-positive lymphoma that could not further be classified by the review panel.

## Conclusions

The cases in session 3 highlighted the importance of having sufficient clinical information including drug history and distribution of disease, which are essential for reliable diagnosis. Besides sufficient clinical information extensive molecular testing may be necessary for diagnosis. Small biopsy samples may hamper precise diagnosis in such cases (see box).

Box 1

* Immunosuppressive/immunomodulatory therapy may lead to a broad spectrum of B or T/NK cell lineage LPDs

* B-lineage LPDs are usually EBV positive

* Polymorphic B lineage LPDs in this cohort were frequently associated with steroids, while monomorphic B lineage LPDs are associated with a broad variety of drugs (MTX, azathioprine, mycophenolate, IL23 inhibitors)

* LPDs of T or NK/T lineage range from non-clonal to clonal, are usually EBV-negative and associated with a broad variety of drugs (MTX, TNF-inhibitors, anti-Integrin antibody). Their diagnosis is challenging, molecular tests are necessary.

* LPDs associated with therapeutic interventions for solid tumors were extremely variable without clear-cut pathogenesis in most instances.

* Diagnosis of DRESS is problematic as the criteria in the literature remain conflicting and controversial

* DRESS-associated histologic patterns observed in lymph nodes are variable. The most difficult differential diagnosis is with T-cell lymphoma (especially TFH lymphomas) where clonality analysis is essential for diagnosis as these cases do not harbor clonal T-cell expansions.

* LPDs observed after CAR T-cell therapy for B-cell neoplasms exhibited unexpected phenotypes resulting either from lineage switching/transdifferentiation, or from harvested T cells already harboring cancer-associated variants.

* Unusual morphological/immunophenotypical findings in infiltrates post CAR T-cell therapies should prompt extensive additional studies including in-depth molecular analysis to verify their pathogenesis

* In situ detection of CAR T cells is possible, but still fraught with problems

* Pseudo-Richter transformation can only be diagnosed in conjunction of clinical data on temporal interruption of BTKI treatment in SLL/CLL patients. It resembles Richter transformation by morphology, exhibits a retained SLL/CLL immunophenotype and disappears after reintroduction of therapy

* Dasatinib-associated lymphadenopathy is a rare condition in CML patients with a characteristic morphology of florid follicular hyperplasia with large, irregular germinal centers. Clonality analysis is advisable in difficult cases. Discontinuation of treatment leads to spontaneous regression.

* COVID-19 associated lymphadenopathy has been thoroughly analysed only in a limited number of cases. Paracortical hyperplasia was the most frequent finding in the submitted cases. DRESS may occur in association with this type of vaccination.

**Supplementary Information** The online version contains supplementary material available at https://doi.org/10.1007/s00428-025-04197-0.

**Acknowledgements** The authors thank Dr. Irene Gonzalez-Menendez from the Institute of Pathology, University of Tübingen, Germany for
scanning all the cases and helping in organizing the workshop. We want to thank the immunohistochemistry lab of the Institute of Pathology University of Würzburg, Germany for performing additional immunostainings and Stefania Pittaluga from the Department of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA for performing the immunostains for HHV6 detection. The authors also thank the workshop participants for their case submissions and for allowing us to use the case images in this review.

**Author contribution** I.A, T.L., and J.R.C. reviewed all the cases, designed the analysis of the cases, and wrote the manuscript. G.G., S.D., M.P., O.B. M.vdB., B.S., L-Q. M., and C.L. participated in discussion of the cases and helped to write the manuscript. All authors read and agree with the content of this manuscript.

**Funding** Open Access funding enabled and organized by Projekt DEAL.

**Data availability** Not applicable

## Declarations

**Conflict of interest** The authors declare no competing interests

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## References

1. Lian J, Yue Y, Yu W, Zhang Y (2020) Immunosenescence: a key player in cancer development. J Hematol Oncol 13:151. https://doi.org/10.1186/s13045-020-00986-z

2. Natkunam Y, Goodlad JR, Chadburn A, de Jong D, Gratzinger D, Chan JK, Said J, Jaffe ES (2017) EBV-positive B-cell prolifera- tions of varied malignant potential: 2015 SH/EAHP workshop report-part 1. Am J Clin Pathol 147:129–152. https://doi.org/10. 1093/ajcp/aqw214

3. Pina-Oviedo S, Miranda RN, Medeiros LJ (2018) Cancer therapy- associated lymphoproliferative disorders: an under-recognized type of immunodeficiency-associated lymphoproliferative disor- der. Am J Surg Pathol 42:116–129. https://doi.org/10.1097/PAS. 0000000000000954

4. Krishnan B, Morgan GJ (2007) Non-Hodgkin lymphoma second- ary to cancer chemotherapy. Cancer Epidemiol Biomarkers Prev 16:377–380. https://doi.org/10.1158/1055-9965.EPI-06-1069

5. Anand K, Ensor J, Pingali SR, Hwu P, Duvic M, Chiang S, Miranda R, Zu Y, Iyer S (2020) T-cell lymphoma secondary to checkpoint inhibitor therapy J Immunother Cancer 8 https://doi. org/10.1136/jitc-2019-000104

6. Duke TC, Nair R, Torres-Cabala C, Amaria RN, Keiser E, Miranda R, Iyer SP, Heberton M (2020) Angioimmunoblastic

T-cell lymphoma associated with immune checkpoint inhibi- tor treatment. JAAD Case Rep 6:1264–1267. https://doi.org/10. 1016/j.jdcr.2020.09.020

7. Matsumura T, Tsuchihashi K, Yamamoto T, Jinnouchi F, Kusano W, Kusumoto Y, Arimizu K, Ohmura H, Kuma Y, Moriyama S, Yamaguchi K, Ito M, Isobe T, Ariyama H, Oda Y, Akashi K, Baba E (2024) Lymphoproliferative disorder in an esophageal cancer patient treated with pembrolizumab. Intern Med. https://doi.org/ 10.2169/internalmedicine.3743-24

8. Rejeski K, Perez A, Iacoboni G, Blumenberg V, Bucklein VL, Volkl S, Penack O, Albanyan O, Stock S, Muller F, Karschnia P, Petrera A, Reid K, Faramand R, Davila ML, Modi K, Dean EA, Bachmeier C, von Bergwelt-Baildon M, Locke FL, Bethge W, Bullinger L, Mackensen A, Barba P, Jain MD, Subklewe M (2023) Severe hematotoxicity after CD19 CAR-T therapy is associated with suppressive immune dysregulation and limited CAR-T expan- sion Sci Adv 9:eadg3919. https://doi.org/10.1126/sciadv.adg3919

9. Herman KE, Tuttle KL (2024) Overview of secondary immuno- deficiency. Allergy Asthma Proc 45:347–354. https://doi.org/10. 2500/aap.2024.45.240063

10. Labrosse R, Haddad E (2023) Immunodeficiency secondary to biologics. J Allergy Clin Immunol 151:686–690. https://doi.org/ 10.1016/j.jaci.2023.01.012

11. Tokuhira M, Tamaru JI, Kizaki M (2019) Clinical management for other iatrogenic immunodeficiency-associated lymphoproliferative disorders. J Clin Exp Hematop 59:72–92. https://doi.org/10.3960/ jslt.19007

12. Ohmoto A, Fuji S (2021) Clinical features and treatment strategies for post-transplant and iatrogenic immunodeficiency-associated lymphoproliferative disorders. Blood Rev 49:100807. https://doi. org/10.1016/j.blre.2021.100807

13. Satou A, Tsuzuki T, Nakamura S (2019) Other iatrogenic immu- nodeficiency-associated lymphoproliferative disorders with a T- or NK-cell phenotype. J Clin Exp Hematop 59:56–63. https://doi.org/ 10.3960/jslt.19013

14. Momose S, Tamaru JI (2019) Iatrogenic immunodeficiency-asso- ciated lymphoproliferative disorders of B-cell type that develop in patients receiving immunosuppressive drugs other than in the post-transplant setting. J Clin Exp Hematop 59:48–55. https://doi. org/10.3960/jslt.19014

15. Tanaka K, Ichikawa A, Umezawa N, Yamamoto K, Yoshifuji K, Okada K, Nogami A, Umezawa Y, Nagao T, Sakashita C, Mori T, Tohda S, Koike R, Yasuda S, Yamamoto M (2023) Lymphoprolifera- tive disorder risk after methotrexate treatment for rheumatoid arthri- tis. Cancer Sci 114:3719–3727. https://doi.org/10.1111/cas.15894

16. Kurita D, Miyoshi H, Ichikawa A, Kato K, Imaizumi Y, Seki R, Sato K, Sasaki Y, Kawamoto K, Shimono J, Yamada K, Muto R, Kizaki M, Nagafuji K, Tamaru JI, Tokuhira M, Ohshima K (2019) Methotrexate-associated lymphoproliferative disorders in patients with rheumatoid arthritis: clinicopathologic features and prognostic factors. Am J Surg Pathol 43:869–884. https://doi.org/ 10.1097/PAS.00000000000001271

17. Crane GM, Powell H, Kostadinov R, Rocafort PT, Rifkin DE, Burger PC, Ambinder RF, Swinnen LJ, Borowitz MJ, Duffield AS (2015) Primary CNS lymphoproliferative disease, mycopheno- late and calcineurin inhibitor usage. Oncotarget 6:33849–33866. https://doi.org/10.18632/oncotarget.5292

18. De Jong D, Roemer MG, Chan JK, Goodlad J, Gratzinger D, Chadburn A, Jaffe ES, Said J, Natkunam Y (2017) B-cell and classical Hodgkin lymphomas associated with immunodefi- ciency: 2015 SH/EAHP workshop report-part 2 Am J Clin Pathol 147:153-170. https://doi.org/10.1093/ajcp/aqw216

19. Kotlyar DS, Osterman MT, Diamond RH, Porter D, Blonski WC, Wasik M, Sampat S, Mendizabal M, Lin MV, Lichtenstein GR (2011) A systematic review of factors that contribute to hepato- splenic T-cell lymphoma in patients with inflammatory bowel
disease. Clin Gastroenterol Hepatol 9(36-41):e31. https://doi.org/10.1016/j.cgh.2010.09.016

20. Carvao J, Magno Pereira V, Jacinto F, Sousa Andrade C, Jasmins L (2019) Hepatosplenic T-cell lymphoma: a rare complication of monotherapy with thiopurines in Crohn's disease. GE Port J Gastroenterol 26:279-284. https://doi.org/10.1159/000493350

21. Arber DAB MJ, Cook JR, de Leval L, Goodlad JR, Hasserjian RP, King RL, Kvasnicka MB, Orazi, A. (2025) The international consensus classification of myeloid and lymphoid neoplasms. Wolters Kluwer

22. Board WCoTE (2024) Haematolymphoid tumours. International Agency for Research on Cancer, Lyon (France)

23. Natkunam Y, Gratzinger D, de Jong D, Chadburn A, Goodlad JR, Chan JK, Said J, Jaffe ES (2017) Immunodeficiency and dysregulation: report of the 2015 workshop of the Society for Hematopathology/European Association for Haematopathology. Am J Clin Pathol 147:124-128. https://doi.org/10.1093/ajcp/aqw200

24. Rafiq M, Hayward A, Warren-Gash C, Denaxas S, Gonzalez-Izquierdo A, Lyratzopoulos G, Thomas S (2020) Allergic disease, corticosteroid use, and risk of Hodgkin lymphoma: a United Kingdom nationwide case-control study. J Allergy Clin Immunol 145:868-876. https://doi.org/10.1016/j.jaci.2019.10.033

25. Bernatsky S, Ramsey-Goldman R, Joseph L, Boivin JF, Costenbader KH, Urowitz MB, Gladman DD, Fortin PR, Nived O, Petri MA, Jacobsen S, Manzi S, Ginzler EM, Isenberg D, Rahman A, Gordon C, Ruiz-Irastorza G, Yelin E, Bae SC, Wallace DJ, Peschken CA, Dooley MA, Edworthy SM, Aranow C, Kamen DL, Romero-Diaz J, Askanase A, Witte T, Barr SG, Criswell LA, Sturfelt GK, Blanco I, Feldman CH, Dreyer L, Patel NM, St Pierre Y, Clarke AE (2014) Lymphoma risk in systemic lupus: effects of disease activity versus treatment. Ann Rheum Dis 73:138-142. https://doi.org/10.1136/annrheumdis-2012-202099

26. Blauvelt A, Lebwohl M, Langley RG, Rowland K, Yang YW, Chan D, Miller M, You Y, Yu J, Thaçi D, Foley P, Papp KA (2023) Malignancy rates through 5 years of follow-up in patients with moderate-to-severe psoriasis treated with guselkumab: pooled results from the VOYAGE 1 and VOYAGE 2 trials. J Am Acad Dermatol 89:274-282. https://doi.org/10.1016/j.jaad.2023.03.035

27. Bellinato F, Gisondi P, Girolomoni G (2022) Risk of lymphohematologic malignancies in patients with chronic plaque psoriasis: a systematic review with meta-analysis. J Am Acad Dermatol 86:86-96. https://doi.org/10.1016/j.jaad.2021.07.050

28. Gibson SE, Swerdlow SH, Craig FE, Surti U, Cook JR, Nalesnik MA, Lowe C, Wood KM, Bacon CM (2011) EBV-positive extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue in the posttransplant setting: a distinct type of posttransplant lymphoproliferative disorder? Am J Surg Pathol 35:807-815. https://doi.org/10.1097/PAS.0b013c3182190999

29. Cassidy DP, Vega F, Chapman JR (2017) Epstein-Barr virus-positive extranodal marginal zone lymphoma of bronchial-associated lymphoid tissue in the posttransplant setting: an immunodeficiency-related (posttransplant) lymphoproliferative disorder? Am J Clin Pathol 149:42-49. https://doi.org/10.1093/ajcp/aqx134

30. Jiang Y, Li Y, Zhu B (2015) T-cell exhaustion in the tumor microenvironment. Cell Death Dis 6:e1792. https://doi.org/10.1038/cddis.2015.162

31. Kurachi M (2019) CD8(+) T cell exhaustion. Semin Immunopathol 41:327-337. https://doi.org/10.1007/s00281-019-00744-5

32. Dolina JS, Van Braeckel-Budimir N, Thomas GD, Salek-Ardakani S (2021) CD8(+) T cell exhaustion in cancer. Front Immunol 12:715234. https://doi.org/10.3389/fimmu.2021.715234

33. Yin Q, Wu L, Han L, Zheng X, Tong R, Li L, Bai L, Bian Y (2023) Immune-related adverse events of immune checkpoint inhibitors: a review. Front Immunol 14:1167975. https://doi.org/10.3389/fimmu.2023.1167975

34. Wang SJ, Dougan SK, Dougan M (2023) Immune mechanisms of toxicity from checkpoint inhibitors trends. Cancer 9:543-553. https://doi.org/10.1016/j.trecan.2023.04.002

35. Tetzlaff MT, Jazaeri AA, Torres-Cabala CA, Korivi BR, Landon GA, Nagarajan P, Choksi A, Chen L, Uemura M, Aung PP, Diab A, Sharma P, Davies MA, Amaria R, Prieto VG, Curry JL (2017) Erythema nodosum-like panniculitis mimicking disease recurrence: a novel toxicity from immune checkpoint blockade therapy-Report of 2 patients J Cutan Pathol 44:1080-1086. https://doi.org/10.1111/cup.13044

36. Ellis SR, Vierra AT, Millsop JW, Lacouture ME, Kiuru M (2020) Dermatologic toxicities to immune checkpoint inhibitor therapy: a review of histopathologic features. J Am Acad Dermatol 83:1130-1143. https://doi.org/10.1016/j.jaad.2020.04.105

37. Richtig G, Cerroni L, Schmidt H, Beham-Schmid C, Deinlein T, Vallant C, Richtig E (2021) Talimogene laherparepvec can initiate plasma cell invasion into infiltrated melanoma lesions-a case series. J Eur Acad Dermatol Venereol 35:e209-e211. https://doi.org/10.1111/jdv.16922

38. Cardones AR (2020) Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. Clin Dermatol 38:702-711. https://doi.org/10.1016/j.clindermatol.2020.06.008

39. Kroshinsky D, Cardones ARG, Blumenthal KG (2024) Drug reaction with eosinophilia and systemic symptoms. N Engl J Med 391:2242-2254. https://doi.org/10.1056/NEJMra2204547

40. Bocquet H, Bagot M, Roujeau JC (1996) Drug-induced pseudolymphoma and drug hypersensitivity syndrome (drug rash with eosinophilia and systemic symptoms: dress). Semin Cutan Med Surg 15:250-257. https://doi.org/10.1016/s1085-5629(96)80038-1

41. Kardaun SH, Sekula P, Valeyrie-Allanore L, Liss Y, Chu CY, Creamer D, Sidoroff A, Naldi L, Mockenhaupt M, Roujeau JC, RegiSCAR study group (2013) Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol 169:1071-1080. https://doi.org/10.1111/bjd.12501

42. Shiohara T, Inaoka M, Kano Y (2006) Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpesviruses and antiviral and antidrug immune responses. Allergol Int 55:1-8. https://doi.org/10.2332/allergolint.55.1

43. Zhu H, Ren V (2023) Immunopathogenic insights on preferential human herpesvirus-6 reactivation in drug rash with eosinophilia and systemic symptoms: a scoping review. J Cutan Med Surg 27:388-398. https://doi.org/10.1177/12034754231177590

44. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Machinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA (2018) Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 378:439-448. https://doi.org/10.1056/NEJMoa1709866

45. Wang M, Munoz J, Goy A, Locke FL, Jacobson CA, Hill BT, Timmerman JM, Holmes H, Jaglowski S, Flinn IW, McSweeney PA, Miklos DB, Pagel JM, Kersten MJ, Milpied N, Fung H, Topp MS, Houot R, Beitinjaneh A, Peng W, Zheng L, Rossi JM, Jain RK, Rao AV, Reagan PM (2020) KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med 382:1331-1342. https://doi.org/10.1056/NEJMoa1914347

46. Munshi NC, Anderson LD Jr, Shah N, Madduri D, Berdeja J, Lonial S, Raje N, Lin Y, Siegel D, Oriol A, Moreau P, Yakoub-Agha I, Delforge M, Cavo M, Einsele H, Goldschmidt H, Weisel
K, Rambaldi A, Reece D, Petrocca F, Massaro M, Connarn JN, Kaiser S, Patel P, Huang L, Campbell TB, Hege K, San-Miguel J (2021) Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med 384:705–716. https://doi.org/10.1056/NEJMoa2024850

47. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, Timmerman JM, Stiff PJ, Friedberg JW, Flinn IW, Goy A, Hill BT, Smith MR, Deol A, Farooq U, McSweeney P, Munoz J, Avivi I, Castro JE, Westin JR, Chavez JC, Ghobadi A, Komanduri KV, Levy R, Jacobsen ED, Witzig TE, Reagan P, Bot A, Rossi J, Navale L, Jiang Y, Aycock J, Elias M, Chang D, Wiezorek J, Go WY (2017) Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 377:2531–2544. https://doi.org/10.1056/NEJMoa1707447

48. Singh N, Orlando E, Xu J, Xu J, Binder Z, Collins MA, O'Rourke DM, Melenhorst JJ (2020) Mechanisms of resistance to CAR T cell therapies. Semin Cancer Biol 65:91–98. https://doi.org/10.1016/j.semcancer.2019.12.002

49. Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, Lin Y, Braunschweig I, Hill BT, Timmerman JM, Deol A, Reagan PM, Stiff P, Flinn IW, Farooq U, Goy A, McSweeney PA, Munoz J, Siddiqi T, Chavez JC, Herrera AF, Bartlett NL, Wiezorek JS, Navale L, Xue A, Jiang Y, Bot A, Rossi JM, Kim JJ, Go WY, Neelapu SS (2019) Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre phase 1-2 trial. Lancet Oncol 20:31–42. https://doi.org/10.1016/S1470-2045(18)30864-7

50. Majzner RG, Mackall CL (2018) Tumor antigen escape from CAR T-cell therapy. Cancer Discov 8:1219–1226. https://doi.org/10.1158/2159-8290.CD-18-0442

51. Zhou X, Rasche L, Kortum KM, Mersi J, Einsele H (2023) BCMA loss in the epoch of novel immunotherapy for multiple myeloma: from biology to clinical practice. Haematologica 108:958–968. https://doi.org/10.3324/haematol.2020.266841

52. Orlando EJ, Han X, Tribouley C, Wood PA, Leary RJ, Riester M, Levine JE, Qayed M, Grupp SA, Boyer M, De Moerloose B, Nemecek ER, Bittencourt H, Hiramatsu H, Buechner J, Davies SM, Verneris MR, Nguyen K, Brogdon JL, Bitter H, Morrissey M, Pierog P, Pantano S, Engelman JA, Winckler W (2018) Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat Med 24:1504–1506. https://doi.org/10.1038/s41591-018-0146-z

53. Asnani M, Hayer KE, Naqvi AS, Zheng S, Yang SY, Oldridge D, Ibrahim F, Maragkakis M, Gazzara MR, Black KL, Bagashev A, Taylor D, Mourelatos Z, Grupp SA, Barrett D, Maris JM, Sotillo E, Barash Y, Thomas-Tikhonenko A (2020) Retention of CD19 intron 2 contributes to CART-19 resistance in leukemias with subclonal frameshift mutations in CD19. Leukemia 34:1202–1207. https://doi.org/10.1038/s41375-019-0580-z

54. Jacoby E, Nguyen SM, Fountaine TJ, Welp K, Gryder B, Qin H, Yang Y, Chien CD, Seif AE, Lei H, Song YK, Khan J, Lee DW, Mackall CL, Gardner RA, Jensen MC, Shern JF, Fry TJ (2016) CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nat Commun 7:12320. https://doi.org/10.1038/ncomm s12320

55. Sworder BJ, Kurtz DM, Alig SK, Frank MJ, Shukla N, Garofalo A, Macaulay CW, Shahrokh Esfahani M, Olsen MN, Hamilton J, Hosoya H, Hamilton M, Spiegel JY, Baird JH, Sugio T, Carleton M, Craig AFM, Younes SF, Sahaf B, Sheybani ND, Schroers-Martin JG, Liu CL, Oak JS, Jin MC, Beygi S, Huttmann A, Hanoun C, Duhrsen U, Westin JR, Khodadoust MS, Natkunam Y, Majzner RG, Mackall CL, Diehn M, Miklos DB, Alizadeh AA (2023) Determinants of resistance to engineered T cell therapies

targeting CD19 in large B cell lymphomas Cancer Cell 41:210-225 e215. https://doi.org/10.1016/j.ccell.2022.12.005

56. Laurent C, Syrykh C, Hamon M, Adelaide J, Guille A, Escudie F, Jalowicki G, Fina F, Bardet A, Mescam L, Molina TJ, Dartigues P, Parrens M, Sujobert P, Besson C, Birnbaum D, Xerri L (2022) Resistance of B-cell lymphomas to CAR T-cell therapy is associated with genomic tumor changes which can result in transdifferentiation. Am J Surg Pathol 46:742–753. https://doi.org/10.1097/PAS.00000000000001834

57. Zhang Q, Orlando EJ, Wang HY, Bogusz AM, Liu X, Lacey SF, Strauser HT, Nunez-Cruz S, Nejati R, Zhang P, Brooks S, Watt C, Melenhorst JJ, June CH, Schuster SJ, Wasik MA (2020) Transdifferentiation of lymphoma into sarcoma associated with profound reprogramming of the epigenome. Blood 136:1980–1983. https://doi.org/10.1182/blood.2020005123

58. Padmanabha N, Weinstock MJ, Xu S, Lepe M, Garrett LA, Kappes UP, Michaels PD (2024) Transdifferentiation of diffuse large B-cell lymphoma to a poorly differentiated neoplasm following. CAR T-cell therapy. J Hematop 17:149–153. https://doi.org/10.1007/s12308-024-00592-9

59. Samur MK, Fulciniti M, Aktas Samur A, Bazarbachi AH, Tai YT, Prabhala R, Alonso A, Sperling AS, Campbell T, Petrocca F, Hege K, Kaiser S, Loiseau HA, Anderson KC, Munshi NC (2021) Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma. Nat Commun 12:868. https://doi.org/10.1038/s41467-021-21177-5

60. Da Vià MC, Dietrich O, Truger M, Arampatzi P, Duell J, Heidemeier A, Zhou X, Danhof S, Kraus S, Chatterjee M, Meggendorfer M, Twardziok S, Goebeler ME, Topp MS, Hudecek M, Prommersberger S, Hege K, Kaiser S, Fuhr V, Weinhold N, Rosenwald A, Erhard F, Haferlach C, Einsele H, Körtüm KM, Saliba AE, Rasche L (2021) Homozygous gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma Nature Medicine 27. https://doi.org/10.1038/s41591-021-01245-5

61. Levine BL, Pasquini MC, Connolly JE, Porter DL, Gustafson MP, Boelens JJ, Horwitz EM, Grupp SA, Maus MV, Locke FL, Ciceri F, Ruggeri A, Snowden J, Heslop HE, Mackall CL, June CH, Sureda AM, Perales MA (2024) Unanswered questions following reports of secondary malignancies after CAR-T cell therapy. Nat Med 30:338–341. https://doi.org/10.1038/s41591-023-02767-w

62. Cappell KM, Kochenderfer JN (2023) Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol 20:359–371. https://doi.org/10.1038/s41571-023-00754-1

63. Ghilardi G, Fraietta JA, Gerson JN, Van Deerlin VM, Morrissette JJD, Caponetti GC, Paruzzo L, Harris JC, Chong EA, Susanibar Adaniya SP, Svoboda J, Nasta SD, Ugwuanyi OH, Landsburg DJ, Fardella E, Waxman AJ, Chong ER, Patel V, Pajarillo R, Kulikovskaya I, Lieberman DB, Cohen AD, Levine BL, Stadtmauer EA, Frey NV, Vogl DT, Hexner EO, Barta SK, Porter DL, Garfall AL, Schuster SJ, June CH, Ruella M (2024) T cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy. Nat Med 30:984–989. https://doi.org/10.1038/s41591-024-02826-w

64. Ozdemirli M, Loughney TM, Deniz E, Chahine JJ, Albitar M, Pittaluga S, Sadigh S, Armand P, Uren A, Anderson KC (2024) Indolent CD4+ CAR T-cell lymphoma after Cilta-cel CAR T-cell therapy. N Engl J Med 390:2074–2082. https://doi.org/10.1056/NEJMoa2401530

65. Bishop DC, Clancy LE, Simms R, Burgess J, Mathew G, Moezzi L, Street JA, Sutrave G, Atkins E, McGuire HM, Gloss BS, Lee K, Jiang W, Maddock K, McCaughan G, Avdic S, Antonenas V, O’Brien TA, Shaw PJ, Irving DO, Gottlieb DJ, Blyth E, Micklethwaite KP (2021) Development of CAR T-cell lymphoma in 2 of 10 patients effectively treated with piggyBac-modified CD19 CAR T cells Blood 138:1504-1509. https://doi.org/10.1182/blood.2021010813
66. Hamilton MP, Sugio T, Noordenbos T, Shi S, Bulterys PL, Liu CL, Kang X, Olsen MN, Good Z, Dahiya S, Frank MJ, Sahaf B, Mackall CL, Gratzinger D, Diehn M, Alizadeh AA, Miklos DB (2024) Risk of second tumors and T-cell lymphoma after CAR T-cell therapy. N Engl J Med 390:2047–2060. https://doi.org/10.1056/NEJMoa2401361

67. Fortuna GG, Banerjee R, Savid-Frontera C, Song J, Moran-Segura CM, Nguyen JV, Lekakis L, Fernandez-Pol S, Samraj AN, Naresh KN, Vazquez-Martinez M, Baz RC, Spiegel JY, Mikkilineni L, Gubatan JM, Sidana S, de Menezes Silva Corraes A, Kalariya NM, Patel KK, Shim KG, Fonseca R, Ferreri C, Voorhees PM, Richard S, Valdes CR, Sireesha A, Wolf JL, Cowan AJ, Sborov DW, Locke FL, Lin Y, Wang Y, Hansen DK (2024) Immune effec- tor cell-associated enterocolitis following chimeric antigen recep- tor T-cell therapy in multiple myeloma Blood Cancer J 14:180. https://doi.org/10.1038/s41408-024-01167-8

68. Chen PH, Raghunandan R, Morrow JS, Katz SG (2024) Finding your CAR: the road ahead for engineered T cells. Am J Pathol 194:1409–1423. https://doi.org/10.1016/j.ajpath.2024.04.002

69. Parikh SA, Kay NE, Shanafelt TD (2014) How we treat Rich- ter syndrome. Blood 123:1647–1657. https://doi.org/10.1182/ blood-2013-11-516229

70. Jain P, Thompson PA, Keating M, Estrov Z, Ferrajoli A, Jain N, Kantarjian H, Burger JA, O’Brien S, Wierda WG (2017) Long- term outcomes for patients with chronic lymphocytic leukemia who discontinue ibrutinib. Cancer 123:2268–2273. https://doi.org/ 10.1002/cncr.30596

71. Maddocks KJ, Ruppert AS, Lozanski G, Heerema NA, Zhao W, Abruzzo L, Lozanski A, Davis M, Gordon A, Smith LL, Mantel R, Jones JA, Flynn JM, Jaglowski SM, Andritsos LA, Awan F, Blum KA, Grever MR, Johnson AJ, Byrd JC, Woyach JA (2015) Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol 1:80– 87. https://doi.org/10.1001/jamaoncol.2014.218

72. Wang Y, Tschautscher MA, Rabe KG, Call TG, Leis JF, Kenderian SS, Kay NE, Muchtar E, Van Dyke DL, Koehler AB, Schwager SM, Slager SL, Parikh SA, Ding W (2020) Clinical characteris- tics and outcomes of Richter transformation: experience of 204 patients from a single center. Haematologica 105:765–773. https:// doi.org/10.3324/haematol.2019.224121

73. Hampel PJ, Ding W, Call TG, Rabe KG, Kenderian SS, Witzig TE, Muchtar E, Leis JF, Chanan-Khan AA, Koehler AB, Fonder AL, Schwager SM, Slager SL, Shanafelt TD, Kay NE, Parikh SA (2019) Rapid disease progression following discontinuation of ibrutinib in patients with chronic lymphocytic leukemia treated in routine clinical practice. Leuk Lymphoma 60:2712–2719. https:// doi.org/10.1080/10428194.2019.1602268

74. Hampel PJ, Call TG, Rabe KG, Ding W, Muchtar E, Kenderian SS, Wang Y, Leis JF, Witzig TE, Koehler AB, Fonder AL, Schwa- ger SM, Van Dyke DL, Braggio E, Slager SL, Kay NE, Parikh SA (2020) Disease flare during temporary interruption of ibrutinib therapy in patients with chronic lymphocytic leukemia. Oncologist 25:974–980. https://doi.org/10.1634/theoncologist.2020-0388

75. Barnea Slonim L, Ma S, Behdad A, Chen Q (2020) Pseudo-richter transformation of chronic lymphocytic leukaemia/small lympho- cytic lymphoma following ibrutinib interruption: a diagnostic pitfall. Br J Haematol 191:e22–e25. https://doi.org/10.1111/bjh. 16948

76. Hampel PJ, Cherng HJ, Call TG, Ding W, Khanlari M, McPhail ED, Miranda RN, Lin P, Tawbi HA, Ferrajoli A, Wierda WG, Jain N, Parikh SA (2020) Incidental Richter transformation in chronic lymphocytic leukemia patients during temporary interruption of ibrutinib. Blood Adv 4:4508–4511. https://doi.org/10.1182/blood advances.2020002454

77. Long M, Beckwith K, Do P, Mundy BL, Gordon A, Lehman AM, Maddocks KJ, Cheney C, Jones JA, Flynn JM, Andritsos LA,

Awan F, Fraietta JA, June CH, Maus MV, Woyach JA, Caligiuri MA, Johnson AJ, Muthusamy N, Byrd JC (2017) Ibrutinib treat- ment improves T cell number and function in CLL patients. J Clin Invest 127:3052–3064. https://doi.org/10.1172/JCI89756

78. Flinsenberg TWH, Tromedjo CC, Hu N, Liu Y, Guo Y, Thia KYT, Noori T, Song X, Aw Yeang HX, Tantalo DG, Handun- netti S, Seymour JF, Roberts AW, Ritchie D, Koldej R, Neeson PJ, Wang L, Trapani JA, Tam CS, Voskoboinik I (2020) Dif- ferential effects of BTK inhibitors ibrutinib and zanubrutinib on NK-cell effector function in patients with mantle cell lymphoma. Haematologica 105:e76–e79. https://doi.org/10.3324/haematol. 2019.220590

79. Mhibik M, Wiestner A, Sun C (2019) Harnessing the effects of BTKi on T cells for effective immunotherapy against CLL. Int J Mol Sci. https://doi.org/10.3390/ijms21010068

80. Marcos-Jimenez A, Carvoeiro DC, Ruef N, Cuesta-Mateos C, Roy-Vallejo E (2023) Gomez-Garcia de Soria V, Lagana C, Del Campo L, Zubiaur P Villapalos-Garcia G, Abad-Santos F Stein JV Munoz-Calleja C Dasatinib-induced spleen contraction leads to transient lymphocytosis. Blood Adv 7:2418–2430. https://doi. org/10.1182/bloodadvances.2022009279

81. Fox LC, Cummins KD, Costello B, Yeung D, Cleary R, Forsyth C, Tatarczuch M, Burbury K, Motorna O, Shortt J, Fleming S, McQuillan A, Schwarer A, Harrup R, Holmes A, Ratnasingam S, Chan KL, Hsu WH, Ashraf A, Putt F, Grigg A (2017) The incidence and natural history of dasatinib complications in the treatment of chronic myeloid leukemia. Blood Adv 1:802–811. https://doi.org/10.1182/bloodadvances.2016003889

82. Christe L, Veloza L, Gros L, Bisig B, Blum S, Hewer E, de Leval L (2022) HHV8-negative primary effusion-based large B-cell lymphoma in a patient with chronic myeloid leukemia, BCR::ABL1-positive under dasatinib treatment: report of a new case and literature review. Diagn Cytopathol 50:E351–E356. https://doi.org/10.1002/dc.25027

83. Iurlo A, Bucelli C, Cattaneo D, Orofino N, Giannotta JA, Zappa M, Gianelli U, Cortelezzi A (2017) Reactive follicular hyperplasia on dasatinib treatment for chronic myeloid leukemia. Ann Hema- tol 96:1953–1954. https://doi.org/10.1007/s00277-017-3105-8

84. Ozawa MG, Ewalt MD, Gratzinger D (2015) Dasatinib-related fol- licular hyperplasia: an underrecognized entity with characteristic morphology. Am J Surg Pathol 39:1363–1369. https://doi.org/10. 1097/PAS.0000000000000488

85. Pilalas D, Koletsa T, Arsos G, Panselinas G, Exadaktylou P, Poly- chronopoulos G, Savopoulos C, Kaiafa GD (2020) Dasatinib asso- ciated lymphadenopathy in a chronic myeloid leukemia patient: a case report. Medicine (Baltimore) 99:e22791. https://doi.org/10. 1097/MD.000000000000022791

86. Roux C, Nicolini FE, Rea D, Niault M, Mollica L, Berger F, Chassagne-Clement C, Tigaud I, Tulliez M, Giraudier S, Turhan A, Rousselot P, Legros L (2013) Reversible lymph node follicular hyperplasia associated with dasatinib treatment of chronic mye- loid leukemia in chronic phase. Blood 122:3082–3084. https://doi. org/10.1182/blood-2013-07-513879

87. Bouquet E, Jourdain A, Machet MC, Beau-Salinas F, Jonville- Bera AP (2017) Dasatinib-associated follicular lymphoid hyper- plasia: first pediatric case report and literature review Pediatr Blood Cancer 64. https://doi.org/10.1002/pbc.26597

88. Zhou KI, Lin C, Neff JL, Galal A (2023) Dasatinib-associated fol- licular lymphoma in a patient with B-cell acute lymphoblastic leu- kaemia. BMJ Case Rep. https://doi.org/10.1136/bcr-2022-252739

89. Patil A, Swerdlow SH, Lossos IS, Chapman JR (2023) Atypical follicular hyperplasia with light chain-restricted germinal cent- ers after COVID-19 booster: a diagnostic pitfall. Virchows Arch 482:905–910. https://doi.org/10.1007/s00428-022-03400-w

90. Tzankov A, Rossle M (2022) Extrafollicular prolifera- tion of B-blasts: morphologic correlate to Spikevax-induced

<figure><img src="image_29.png" /></figure>
lymphadenopathy. Clin Case Rep 10:e05398. https://doi.org/10.1002/ccr3.5398

91. Menter T, Zinner CP, Berger CT, Went P, Tzankov A (2023) Case report: gene expression profiling of COVID-19 vaccination-related lymphadenopathies reveals evidence of a dominantly extrafollicular immune response. Front Immunol 14:1285168. https://doi.org/10.3389/fimmu.2023.1285168

92. Caocci G, Fanni D, Porru M, Greco M, Nemolato S, Firinu D, Faa G, Scuteri A, La Nasa G (2022) Kikuchi-Fujimoto disease associated with hemophagocytic lymphohistiocytosis following the BNT162b2 mRNA COVID-19 vaccination Haematologica 107:1222-1225. https://doi.org/10.3324/haematol.2021.280239

93. Tan HM, Hue SS, Wee A, See KC (2021) Kikuchi-fujimoto disease post COVID-19 vaccination: case report and review of literature. Vaccines. https://doi.org/10.3390/vaccines9111251

94. Tintle S, Chen M (2021) Lymphadenopathy with florid lymphoid and Langerhans cell hyperplasia and hemophagocytosis mimicking lymphoma after COVID-19 mRNA vaccination. EJHaem 2:845–847. https://doi.org/10.1002/jha2.265

95. Hoffmann C, Wechselberger T, Drexel H, Dertinger S, Dirnhofer S, Pierson SK, Fajgenbaum DC, Kessler A (2022) Idiopathic

multicentric Castleman disease occurring shortly after mRNA SARS-CoV-2 vaccine. Vaccines. https://doi.org/10.3390/vaccines10101725

96. Gamonal SBL, Marques NCV, Pereira HMB, Gamonal ACC (2023) Drug reaction with eosinophilia and systemic symptoms syndrome (DRESS) associated with pancreatitis and hepatitis following Pfizer-BioNTech mRNA COVID-19 vaccination. J Eur Acad Dermatol Venereol 37:e291–e293. https://doi.org/10.1111/jdv.18777

97. Schroeder JW, Gamba C, Toniato A, Group C-S, Rongioletti F (2022) A definite case of drug reaction with eosinophilia and systemic symptoms (DRESS) induced by administration of the Pfizer/BioNTech BNT162b2 vaccine for SARS-CoV2. Clin Dermatol 40:591–594. https://doi.org/10.1016/j.clindermatol.2022.02.018

98. Korekawa A, Nakajima K, Fukushi K, Nakano H, Sawamura D (2022) Three cases of drug-induced hypersensitivity syndrome associated with mRNA-based coronavirus disease 2019 vaccines. J Dermatol 49:652–655. https://doi.org/10.1111/1346-8138.16347

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## Authors and Affiliations

Ioannis Anagnostopoulos¹ Ⓓ · Tanja Lakic² Ⓓ · Olga Balague³ Ⓓ · Michiel Van den Brand⁴,⁵ Ⓓ · Stefan Dirnhofer⁶ Ⓓ · Gorana Gasljevic⁷,⁸ Ⓓ · Camille Laurent⁹ Ⓓ · Maurilio Ponzoni¹⁰ Ⓓ · Leticia Quintanilla-Martinez¹¹,¹² Ⓓ · Birgitta Sander¹³ Ⓓ · James R. Cook¹⁴ Ⓓ

<figure><img src="image_30.png" /></figure>

Ioannis Anagnostopoulos
ioannis.anagnostopoulos@uni-wuerzburg.de

¹ Institut für Pathologie, Julius-Maximilians Universität, Josef-Schneider-Straße 2, 97080 Würzburg, Germany

² Faculty of Medicine Novi Sad, University of Novi Sad and University Clinical Center of Vojvodina, Novi Sad, Serbia

³ Pathology Department, Hospital Clinic, Barcelona, Spain

⁴ Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands

⁵ Pathology-DNA location Rijnstate Hospital, Arnhem, the Netherlands

⁶ Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland

⁷ Department of Pathology, Institute of Oncology, Ljubljana, Slovenia

⁸ Medical Faculty, University of Maribor, Maribor, Slovenia

⁹ Department of Pathology, Cancer Institute, Toulouse University Hospital Center, University of Toulouse-Oncopole, Toulouse, France

¹⁰ Ateneo Vita-Salute San Raffaele University, Hematopathology Diagnostic Area, San Raffaele Scientific Institute, Pathology Unit, Milan, Italy

¹¹ Institut für Pathologie und Neuropathologie, Eberhard-Karls-Universität Tübingen and Comprehensive Cancer Center, University Hospital Tübingen, Tübingen, Germany

¹² Cluster of Excellence iFIT (EXC2180), Image-guided and functionally Instructed Tumor therapies” Eberhard-Karls-University, Tübingen, Germany

¹³ Department of Laboratory Medicine, Division of Pathology, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden

¹⁴ Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA