A morphological mimic: An NTRK3-rearranged spindle cell neoplasm presenting as a groin mass.

Neurotrophic receptor tyrosine kinase (NTRK)-rearranged spindle cell neoplasms are a recently described group of soft tissue tumors. They commonly present as a painless mass on the extremities of children and young adults. They are characterized microscopically by a heterogeneous spectrum of infiltrative spindle cell proliferations, which can morphologically mimic several other spindle cell neoplasms. Their identification is vital, as they may be amenable to treatment with tyrosine kinase-targeted therapy. This case report describes a rare NTRK3-rearranged spindle cell neoplasm in the groin of a 29-year-old female and provides further clinical and morphological features of this entity.

Aggressive B-cell non-Hodgkin lymphomas: a report of the lymphoma workshop of the 20th meeting of the European Association for Haematopathology.

Aggressive B-cell non-Hodgkin lymphomas are a heterogeneous group of diseases and our concepts are evolving as we learn more about their clinical, pathologic, molecular genetic features. Session IV of the 2020 EAHP Workshop covered aggressive, predominantly high-grade B-cell lymphomas, many that were difficult to classify. In this manuscript, we summarize the features of the submitted cases and highlight differential diagnostic difficulties. We specifically review issues related to high-grade B-cell lymphomas (HGBCLs) with MYC and BCL2 and/or BCL6 rearrangements including TdT expression in these cases, HGBCL, not otherwise specified, large B-cell lymphomas with IRF4 rearrangement, high-grade/large B-cell lymphomas with 11q aberration, Burkitt lymphoma, and pleomorphic mantle cell lymphoma. Since the workshop, the 5th edition of the WHO Classification for Haematolymphoid Tumours (WHO-HAEM5) and International Consensus Classification (ICC) 2022 were published. We endeavor to use the updated terminology.

Lymphomas with plasmablastic features: a report of the lymphoma workshop of the 20th meeting of the European Association for Haematopathology.

Lymphomas with plasmablastic features are a heterogeneous group of aggressive and mostly uncommon neoplasms of varied aetiologies, presenting in immunocompetent individuals as well as in immunodeficiency, associated with EBV and Kaposi sarcoma virus infections, and some as progression from indolent B-cell lymphomas. They show overlapping diagnostic features and pose a differential diagnosis with other aggressive B-cell lymphomas that can downregulate the B-cell expression programme. The spectrum of rare reactive proliferations and all lymphomas defined by plasmablastic features, together with an expanding range of poorly characterised, uncommon conditions at the interface between reactive lymphoid proliferations and neoplasia submitted to the session V of the 20th European Association for Haematopathology/Society for Hematopathology lymphoma workshop are summarised and discussed in this paper.

The spectrum of nodular lymphocyte predominant Hodgkin lymphoma: a report of the lymphoma workshop of the 20th meeting of the European Association for Haematopathology.

Session 4 of the 2021 European Association of Haematopathology/Society for Hematopathology Workshop focused on nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). First, the spectrum of immunophenotypic variations in NLPHL and the defining criteria for classic Hodgkin Lymphoma (CHL) were discussed. The added value of further immunophenotypic characterization of both tumor cells and microenvironment to support the differential diagnosis was presented. Next, unusual cases with combined growth patterns and evolution of morphological features over time were presented to explore the clinicopathological impact of presumed high-risk patterns. Based on a large collection of cases, the defining morphological, immunophenotypical, and gene expression features of T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) and THRLBCL-like NLPHL (pattern E) were reviewed to explore this challenging differential diagnosis and critically evaluate whether aggressive behavior and transformation of NLPHL can be predicted in practice.

Mediastinal large B cell lymphoma and surrounding gray areas: a report of the lymphoma workshop of the 20th meeting of the European Association for Haematopathology.

Session 3 of the 2021 European Association for Haematopathology/Society for Hematopathology Workshop focused on mediastinal large B cell lymphomas and surrounding gray areas. One half of the session was dedicated to primary mediastinal large B cell lymphoma (PMBL) and included cases with classic clinicopathologic features, as well as cases with either morphologic or immunophenotypic variation, and PMBL-like cases with primary extramediastinal disease. The role of additional immunophenotyping and/or molecular testing to aid in the diagnosis of PMBL was discussed. The second half of the session focused on mediastinal and non-mediastinal gray zone lymphomas (GZL) with features intermediate between diffuse large B cell lymphoma (DLBCL) and classic Hodgkin lymphoma (CHL). Several cases illustrating the current challenges in separating this entity from PMBL/DLBCL and CHL were presented. There was discussion regarding the clinical and genetic differences between mediastinal and non-mediastinal GZLs. Rare cases of PMBL and GZL associated with EBV or follicular lymphoma were reviewed. Finally, several cases included in the session highlighted composite or sequential CHL and PMBL/DLBCL and/or GZL, highlighting challenges in separating such cases from GZL.

How I Diagnose EBV-Positive B- and T-Cell Lymphoproliferative Disorders.

OBJECTIVES: Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) encompass a group of well-defined entities of B-, T-, and natural killer (NK)-cell derivation. The diagnosis of these disorders is challenging because of clinical and morphologic features that may overlap with other benign and malignant EBV+ lymphoproliferations. This review describes our approach to the diagnosis of EBV-associated LPDs. METHODS: Two cases are presented that illustrate how we diagnose EBV-associated LPDs. The first case represents a systemic EBV+ T-cell lymphoma of childhood and the second case an EBV+ mucocutaneous ulcer. The clinicopathologic features that help distinguish these entities from biological and morphologic mimickers are emphasized. RESULTS: The accurate diagnosis of EBV-associated LPDs requires the incorporation of histologic and immunophenotypic features, the assessment of the EBV latency program, and, most important, complete clinical findings. Clonality analysis is not helpful in distinguishing benign from malignant EBV+ LPDs. CONCLUSIONS: The better understanding of EBV-associated LPDs has resulted in the recognition of well-defined entities of B-, T-, and NK-cell derivation and consequently improvement of their treatment with curative intent. It is critical to distinguish benign from malignant EBV+ LPDs to avoid overtreatment.

Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease.

Fifty-five cases of t(14;18)- follicular lymphoma (FL) were genetically characterized by targeted sequencing and copy number (CN) arrays. t(14;18)- FL predominated in women (M/F 1:2); patients often presented during early clinical stages (71%), and had excellent prognoses. Overall, t(14;18)- FL displayed CN alterations (CNAs) and gene mutations carried by conventional t(14;18)+ FL (cFL), but with different frequencies. The most frequently mutated gene was STAT6 (57%) followed by CREBBP (49%), TNFRSF14 (39%), and KMT2D (27%). t(14;18)- FL showed significantly more STAT6 mutations and lacked MYD88, NOTCH2, MEF2B, and MAP2K1 mutations compared with cFL, nodal marginal zone lymphoma (NMZL), and pediatric-type FL (PTFL). We identified 2 molecular clusters. Cluster A was characterized by TNFRSF14 mutations/1p36 alterations (96%) and frequent mutations in epigenetic regulators, with recurrent loss of 6q21-24 sharing many features with cFL. Cluster B showed few genetic alterations; however, a subgroup with STAT6 mutations concurrent with CREBBP mutations/16p alterations without TNFRSF14 and EZH2 mutations was noted (65%). These 2 molecular clusters did not distinguish cases by inguinal localization, growth pattern, or presence of STAT6 mutations. BCL6 rearrangements were demonstrated in 10 of 45 (22%) cases and did not cluster together. Cases with predominantly inguinal presentation (20 of 50; 40%) had a higher frequency of diffuse growth pattern, STAT6 mutations, CD23 expression, and a lower number of CNAs, in comparison with noninguinal cases (5.1 vs 9.1 alterations per case; P < .05). STAT6 mutations showed a positive correlation with CD23 expression (P < .001). In summary, t(14;18)- FL is genetically a heterogeneous disorder with features that differ from cFL, NMZL, and PTFL.

Epstein-Barr Virus-Positive Mucocutaneous Ulcers Complicate Colitis Caused by Immune Checkpoint Regulator Therapy and Associate With Colon Perforation.

BACKGROUND & AIMS: Cancer therapy with immune checkpoint inhibitors can cause colitis and colon perforation. We investigated whether infection with Epstein Barr virus (EBV) associates with development and severity of colitis in patients receiving immune checkpoint inhibitor therapies. METHODS: We performed a retrospective analysis of fixed colon tissues from 16 patients (12 men, 4 women, median age, 69.5 y) with colitis after immune checkpoint inhibitor therapy (9 patients treated with anti-CTLA4, 3 patients treated with anti-PD1, and 4 patients received a combination). Ten tissue samples were biopsies and 6 were collected during resection (4 surgeries for colon perforation). Patients were treated between 2010 and 2018 in the United Kingdom. The tissues were analyzed by pathology, in situ hybridization (to detect EBV-encoded small RNAs [EBERs]), and immunohistochemistry. Clinical data were also collected. RESULTS: Colon tissues from 4 of the 13 patients who received anti-CTLA4 (alone or in combination, 4 with colon perforation) had EBV-positive lymphoproliferations that manifested as florid ulcers associated with polymorphous infiltrates containing EBV-positive blasts (CD30+ or CD30-negative, CD20+, CD3-negative, and EBER+), plasma cells (CD138+, CD20-negative, and EBER+ or EBER-negative), and small B cells (CD20+, CD3-negative, and EBER+ or EBER-negative), consistent with EBV-positive mucocutaneous ulcers (EBVMCUs). In analyses of biopsies collected from 2 patients with EBVMCUs over multiple time points, we found that earlier biopsies had no or only a few EBV-positive cells, whereas 1 later biopsy had EBVMCU and co-infection with cytomegalovirus. EBVMCUs were associated with steroid-refractory colitis (100% of EBV-positive patients vs 12.5% of EBV-negative patients; P = .008) and colon perforation (100% of EBV-positive patients vs no EBV-negative patients; P = .001). CONCLUSIONS: We found that colon tissues from 4/13 patients with colitis after anti-CTLA4 therapy (4/6 patients who underwent resection and 4/4 patients with colon perforation) contained EBVMCUs. EBVMCUs seem to arise secondarily in areas of inflamed colon due to immunosuppressive treatment for colitis. EBVMCUs are associated with steroid-refractory colitis and colon perforation.

Trauma or tumour: giant cell tumour of distal biceps tendon sheath, an unusual cause of elbow pain.

We report the case of a middle-age lady who presented following minor trauma, with dominant-sided anterior elbow pain and swelling of 6 months in duration. She was assessed clinically, and underwent investigations, which confirmed features consistent with giant cell tumour (GCT) of distal biceps tendon sheath. She underwent uneventful en-bloc excisional surgery. She did not have radiotherapy. She is now 5 years postoperatively asymptomatic, with full function, and with no signs of recurrence.

Granulysin, a novel marker for extranodal NK/T cell lymphoma, nasal type.

Granulysin is a cytolytic protein expressed in cytotoxic T and natural killer (NK) cells. Abnormal serum levels of granulysin in lymphomas with NK and cytotoxic phenotype have been shown to correlate with tumour progression. In this study, we investigated the expression pattern of granulysin in routine sections of normal and reactive lymphoid tissues as well as in a large series of lymphomas. In normal tissues, granulysin labelled a small population of cells that double immunostaining revealed to belong to the pool of cytotoxic T/NK cells. Among lymphoid neoplasms, the highest expression of granulysin (71%) was found in extranodal NK/T cell lymphomas of nasal type (ENKTL). To note is that 29% of ENKTLs, which were negative for one or more of classical cytotoxic markers strongly expressed granulysin. Furthermore, expression of granulysin was observed in rare cases of T cell lymphomas with a cytotoxic phenotype (i.e. ALK-negative anaplastic large cell lymphoma (26%), enteropathy-associated T cell lymphoma (12%) and peripheral T cell lymphoma, NOS (4%)). None of the investigated non-Hodgkin B cell lymphomas, Hodgkin lymphoma and plasma cell myeloma were granulysin positive. The results suggest granulysin as a novel marker for a subset of cytotoxic NK cell derived malignancies and its usefulness is highlighted in those ENKTLs that lack expression of other cytotoxic markers but retain granulysin expression.

EBV-Positive Lymphoproliferations of B- T- and NK-Cell Derivation in Non-Immunocompromised Hosts.

The contribution of Epstein-Barr virus (EBV) to the development of specific types of benign lymphoproliferations and malignant lymphomas has been extensively studied since the discovery of the virus over the last 50 years. The importance and better understanding of the EBV-associated lymphoproliferative disorders (LPD) of B, T or natural killer (NK) cell type has resulted in the recognition of new entities like EBV+ mucocutaneous ulcer or the addition of chronic active EBV (CAEBV) infection in the revised 2016 World Health Organization (WHO) lymphoma classification. In this article, we review the definitions, morphology, pathogenesis, and evolving concepts of the various EBV-associated disorders including EBV+ diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), EBV+ mucocutaneous ulcer, DLBCL associated with chronic inflammation, fibrin-associated DLBCL, lymphomatoid granulomatosis, the EBV+ T and NK-cell LPD of childhood, aggressive NK leukaemia, extranodal NK/T-cell lymphoma, nasal type, and the new provisional entity of primary EBV+ nodal T- or NK-cell lymphoma. The current knowledge regarding the pathogenesis of B-cell lymphomas that can be EBV-associated including Burkitt lymphoma, plasmablastic lymphoma and classic Hodgkin lymphoma will be also explored.

Mutations of MAP2K1 are frequent in pediatric-type follicular lymphoma and result in ERK pathway activation.

Pediatric-type follicular lymphoma (PTFL) is a B-cell lymphoma with distinctive clinicopathological features. Recently, recurrent genetic alterations of potential importance for its pathogenesis that disrupt pathways associated with the germinal center reaction (TNFRSF14, IRF8), immune escape (TNFRSF14), and anti-apoptosis (MAP2K1) have been described. In an attempt to shed more light onto the pathogenesis of PTFL, an integrative analysis of these mutations was undertaken in a large cohort of 43 cases previously characterized by targeted next-generation sequencing and copy number array. Mutations in MAP2K1 were found in 49% (20/41) of the cases, second in frequency to TNFRSF14 alterations (22/41; 54%), and all together were present in 81% of the cases. Immunohistochemical analysis of the MAP2K1 downstream target extracellular signal-regulated kinase demonstrated its phosphorylation in the evaluable cases and revealed a good correlation with the allelic frequency of the MAP2K1 mutation. The IRF8 p.K66R mutation was present in 15% (6/39) of the cases and was concomitant with TNFRSF14 mutations in 4 cases. This hot spot seems to be highly characteristic for PTFL. In conclusion, TNFRSF14 and MAP2K1 mutations are the most frequent genetic alterations found in PTFL and occur independently in most cases, suggesting that both mutations might play an important role in PTFL lymphomagenesis.

Genome-wide analysis of pediatric-type follicular lymphoma reveals low genetic complexity and recurrent alterations of TNFRSF14 gene.

Pediatric-type follicular lymphoma (PTFL) is a variant of follicular lymphoma (FL) with distinctive clinicopathological features. Patients are predominantly young males presenting with localized lymphadenopathy; the tumor shows high-grade cytology and lacks both BCL2 expression and t(14;18) translocation. The genetic alterations involved in the pathogenesis of PTFL are unknown. Therefore, 42 PTFL (40 males and 2 females; mean age, 16 years; range, 5-31) were genetically characterized. For comparison, 11 cases of conventional t(14:18)(-) FL in adults were investigated. Morphologically, PTFL cases had follicular growth pattern without diffuse areas and characteristic immunophenotype. All cases showed monoclonal immunoglobulin (IG) rearrangement. PTFL displays low genomic complexity when compared with t(14;18)(-) FL (mean, 0.77 vs 9 copy number alterations per case; P <001). Both groups presented 1p36 alterations including TNFRSF14, but copy-number neutral loss of heterozygosity (CNN-LOH) of this locus was more frequently observed in PTFL (40% vs 9%; P =075). TNFRSF14 was the most frequently affected gene in PTFL (21 mutations and 2 deletions), identified in 54% of cases, followed by KMT2D mutations in 16%. Other histone-modifying genes were rarely affected. In contrast, t(14;18)(-) FL displayed a mutational profile similar to t(14;18)(+) FL. In 8 PTFL cases (19%), no genetic alterations were identified beyond IG monoclonal rearrangement. The genetic landscape of PTFL suggests that TNFRSF14 mutations accompanied by CNN-LOH of the 1p36 locus in over 70% of mutated cases, as additional selection mechanism, might play a key role in the pathogenesis of this disease. The genetic profiles of PTFL and t(14;18)(-) FL in adults indicate that these are two different disorders.

Giant pseudoangiomatous stromal hyperplasia presenting in the breast of a prepubertal child.

Large benign lesions of the breasts are rare in children. We present a case of a 35 cm mass, weighing 2.7 kg in a 13-year-old girl with small developing breasts. Despite the enormity of the lesion, the patient managed to keep it concealed from her parents for 8 months. While initially suspicious of sarcoma a diagnosis of pseudoangiomatous stromal hyperplasia was suggested radiologically and confirmed histologically. Excision with reduction mammoplasty was performed, care taken not to disrupt the remaining breast tissue to facilitate future breast development. 18 months on, the cosmetic appearance of the breasts is good, with healthy underlying breast tissue developing. To the best of our knowledge this case is the largest documented breast tumour of this type in a patient of this age and illustrates the challenge of treating such tumours in the developing breast.

Prognostic significance of hypoxia inducible factor-1α and vascular endothelial growth factor expression in patients with diffuse large B-cell lymphoma treated with rituximab.

We evaluated hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression and their prognostic significance in diffuse large B-cell lymphoma (DLBCL). Expression of HIF-1α and VEGF was studied in 78 patients and results correlated with clinicopathological and prognostic data. HIF-1α and VEGF were expressed in 67% and 84% of patients, respectively, and a significant correlation was demonstrated between them (p < 0.001). Outcome was analyzed according to treatment. HIF-1α positive patients given rituximab demonstrated improved outcome, with 5-year overall survival of 72% for those receiving rituximab versus 65% for those not receiving rituximab, and 5-year progression-free survival (PFS) 76% versus 57%. No correlation was demonstrated between HIF-1α and other prognostic biomarkers including BCL6, CD10 and MUM-1. We demonstrated significantly improved PFS (p = 0.003) in patients receiving rituximab and showing BCL6 overexpression. The results confirm the significant association between HIF-1α and VEGF expression and suggest that HIF-1α expression is a favorable prognostic factor in patients with DLBCL treated with rituximab.

Neonatal hyperimmune T-cell reaction mimicking T-cell non-Hodgkin's lymphoma following BCG and hepatitis B co-vaccination.

We describe a case of a 2-week-old male infant who presented with a rapidly enlarging inguinal mass after having received both the bacille Calmette-Guérin (BCG) and hepatitis B vaccines at birth. The clinical picture raised suspicion of a neoplasm, and an excision biopsy was performed. It showed complete effacement of the lymph node architecture by a diffuse proliferation of monomorphic, mitotically active, and medium-sized T-cell blasts with strong expression of CD99. Coalescent necrotizing granulomas were also seen. The lymph node culture was negative for BCG. Upon expert review and additional molecular diagnostics, the initial pathological diagnosis of lymphoblastic T-cell lymphoma was changed to ectopic BCG lymphadenitis and hyperimmune post-vaccinal reaction. The atypical T-cell proliferation was most likely a result of the adjuvant effects of the co-administered vaccines. Post-vaccinal reactions usually involve the injection site or result in localized lymph node enlargements in the areas draining the inoculation site. This case highlights the importance of the clinical context for accurate interpretation of the pathological findings. In the setting of post-vaccinal lymphadenopathy, a biopsy is rarely needed but, when performed, should be interpreted with great caution.