Recent World Health Organization Classification Research Articles

Surrogate immunohistochemistry markers in adult gliomas – Experience in a tertiary care hospital

Objectives: The recent World Health Organization classification has recommended the usage of surrogate immunohistochemical markers for molecular classification of gliomas. However, only a few studies have attempted to study the expression of the entire panel of markers. The current study was undertaken to study the association of recognized surrogate immunohistochemical markers (isocitrate dehydrogenase 1 [IDH-1], alpha-thalassemia mental retardation X-linked [ATRX] and p53) in different histological lineages and grades of adult gliomas. Materials and Methods: This study was conducted on 118 cases of adult gliomas diagnosed on histopathology over a 2-year duration in a tertiary care hospital. The expression of surrogate immunohistochemistry markers (IDH-1, ATRX, and p53) in these cases was studied. Statistical analysis: Descriptive statistical analysis with the Statistical Package for the Social Science system version 17.0. Results: The frequency of IDH-1 positivity was significantly higher in oligodendrogliomas (OG: 76.5%; oligoastrocytoma: 100%) versus astrocytoma (AS) (grades 2 and 3: 48.1%). It was also significantly higher in diffuse gliomas (grades 2 and 3) versus glioblastomas (64% vs. 16.9%). Among IDH-mutant diffuse gliomas, ATRX loss was significantly higher in AS versus OGs (84.6% vs. 7.7%). P53 overexpression correlated significantly with histological subtype (AS 2,3: 55.6% vs. OG: 5.9%). Conclusions: The surrogate immunohistochemical panel of IDH-1, ATRX, and p53 showed significant association with distinct histopathological subtypes and is helpful in molecular stratification. Cut-offs of ≥ 10% nuclear positivity for p53 and 50% loss of nuclear ATRX expression showed a good correlation.

Diagnosis of invasive encapsulated follicular variant papillary thyroid carcinoma by protein-based machine learning.

Although the criteria for follicular-pattern thyroid tumors are well-established, diagnosing these lesions remains challenging in some cases. In the recent World Health Organization Classification of Endocrine and Neuroendocrine Tumors (5th edition), the invasive encapsulated follicular variant of papillary thyroid carcinoma was reclassified as its own entity. It is crucial to differentiate this variant of papillary thyroid carcinoma from low-risk follicular pattern tumors due to their shared morphological characteristics. Proteomics holds significant promise for detecting and quantifying protein biomarkers. We investigated the potential value of a protein biomarker panel defined by machine learning for identifying the invasive encapsulated follicular variant of papillary thyroid carcinoma, initially using formalin- fixed paraffin-embedded samples. We developed a supervised machine-learning model and tested its performance using proteomics data from 46 thyroid tissue samples. We applied a random forest classifier utilizing five protein biomarkers (ZEB1, NUP98, C2C2L, NPAP1, and KCNJ3). This classifier achieved areas under the curve (AUCs) of 1.00 and accuracy rates of 1.00 in training samples for distinguishing the invasive encapsulated follicular variant of papillary thyroid carcinoma from non-malignant samples. Additionally, we analyzed the performance of single-protein/gene receiver operating characteristic in differentiating the invasive encapsulated follicular variant of papillary thyroid carcinoma from others within The Cancer Genome Atlas projects, which yielded an AUC > 0.5. We demonstrated that integration of high-throughput proteomics with machine learning can effectively differentiate the invasive encapsulated follicular variant of papillary thyroid carcinoma from other follicular pattern thyroid tumors.

LMNA::NTRK1 and PRDX1::NTRK1 Atypical Spitz Tumor: A Report of Two Additional Cases With Histological, Immunohistochemical, and Molecular Insights.

Over the past decade, advancements in molecular biology have contributed to changes in the diagnostic classification of Spitz neoplasms, including Spitz nevi, atypical Spitz tumors, and Spitz melanomas. The recent World Health Organization classification of skin tumors identifies fusion kinases, including NTRK1, NTRK2, and NTRK3, as critical drivers of these lesions. New fusion genes have continued to expand the spectrum of known molecular alterations, particularly within the category of Spitz NTRK-rearranged lesions. We present 2 new cases of NTRK-rearranged Spitz lesions: an atypical Spitz tumor with common LMNA::NTRK1 fusion and an atypical Spitz tumor with a rare PRDX1::NTRK1 fusion. Clinical, histopathological, immunohistochemical, and molecular analyses were performed to diagnose these patients. This report adds to the growing body of knowledge on NTRK-rearranged Spitz lesions and underscores the importance of integrating molecular findings with morphological and immunohistochemical data for the accurate classification and understanding of these neoplasms.

Molecular Classification of Large B-Cell Lymphoma and High-Grade B-Cell Lymphoma Cases and Association with Outcomes in Morocco

Background: High-grade B-cell lymphoma with c-MYC and BCL2 and/or BCL6 rearrangements (HGBL-DHL/THL) is a recently identified category in the most recent World Health Organization (WHO) classification. For all tumors displaying the appearance of diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL), it is necessary to perform fluorescence in situ hybridization (FISH) in order to achieve an accurate diagnosis. The findings of FISH and immunohistochemistry (IHC) examinations from 50 DLBCL/HGBL samples obtained from Hassan II University Hospital in Fez/Morocco are reported. Methods: This retrospective study included 50 patients diagnosed with DLBCL/HGBL over a period of nine years (2013–2022) and treated with RCHOP chemotherapy protocol. All patients underwent a histological study followed by an immunohistochemical study to confirm the diagnosis and to classify patients according to cell of origin into non-GCB and GCB subtypes; then, a cytogenetic study using FISH was performed to classify patients according to the presence or absence of rearrangements in the c-MYC, BCL2 and BCL6 genes. A comparison was made between the molecular subtypes of DLBCL/HGBL in relation to clinicopathological features and outcomes. Results: Among the 50 cases studied in our population, we found 5 cases of HGBL with DLBCL morphology and 45 cases of DLBCL, which consisted of 13 cases (28.89%) of GCB subtype and 32 cases (71.11%) of non-GCB subtype based on the immunohistochemistry Hans algorithm. After FISH testing of all cases, we found three cases of double-hit lymphoma (DHL) and one case of triple-hit lymphoma (THL). Thus, HGBL-DHL/THL accounted for 8% of the cases. Furthermore, two cases were detected with only one rearrangement in the BCL2 gene and one case harboring a rearrangement in the BCL6 gene. DHL and THL patients and patients with a single rearrangement (BCL2 or BCL6) have a worse prognosis than patients with no rearrangement. Conclusions: DHL and THL are an aggressive entity of HGBL with poorer outcomes in comparison to DLBCL/HGBL NOS. First-line treatment with the RCHOP chemotherapy protocol may not be effective for all aggressive DLBCL cases. More targeted treatment is crucial for better patient outcomes.

Diagnostic issues in neuroendocrine neoplasms ofthe lung.

Bronchopulmonary neuroendocrine neoplasms (BP-NENs) account for approximately 30% of all NENs. Although BP-NENs and NENs of the gastroenteropancreatic organs (GEP-NENs) share morphological and molecular features, they differ in terms of their terminology and classification. Bronchopulmonary neuroendocrine tumors (BP-NETs) have classically been termed as carcinoid and grouped into typical (TC) and atypical carcinoid (AC) based on the presence or absence of necrosis and mitotic count. In the most recent World Health Organization (WHO) classification for NENs of endocrine organs (WHO 2022), BP-NETs-NET G1 and G2-are introduced as synonyms of TC and AC, respectively. However, the Ki-67 index, which defines the grade of NETs in digestive organs, is only discussed in the descriptive text and not included into the criteria for classification of BP-NENs. In addition, well-differentiated NENs with high mitotic counts which correspond toNET G3 in the GEP organ system are not defined. This review discusses the role of Ki-67 for aproper classification of BP-NETs/carcinoids.

Modelling and drug targeting of a myeloid neoplasm with atypical 3q26/MECOM rearrangement using patient-specific iPSCs.

Structural variations involving enhancer hijacking induce aberrant oncogene expression and cause tumorigenesis. A rare translocation, t(3;8)(q26.2;q24), is associated with MECOM and MYC rearrangement, causing myeloid neoplasms with a dismal prognosis. The most recent World Health Organization classification recognises myeloid neoplasms with MECOM rearrangement as acute myeloid leukaemia (AML) with defining genetic abnormalities. Recently, the increasing use of induced pluripotent stem cell (iPSC) technology has helped elucidate the pathogenic processes of haematological malignancies. However, its utility for investigating enhancer hijacking in myeloid neoplasms remains unclear. In this study, we generated iPSC lines from patients with myelodysplastic syndromes (MDS) harbouring t(3;8)(q26.2;q24) and differentiated them into haematopoietic progenitor cells to model the pathophysiology of MDS with t(3;8)(q26.2;q24). Our iPSC model reproduced the primary patient's MECOM expression changes and histone H3 lysine 27 acetylation (H3K27ac) patterns in the MECOM promoter and MYC blood enhancer cluster (BENC). Furthermore, we revealed the apoptotic effects of the bromodomain and extra-terminal motif (BET) inhibitor on iPSC-derived MDS cells by suppressing activated MECOM. Our study demonstrates the usefulness of iPSC models for uncovering the precise mechanism of enhancer hijacking due to chromosomal structural changes and discovering potential therapeutic drug candidates for cancer treatment.

Cribriform morular thyroid carcinoma: Clinicopathological and molecular basis for both a preventive and therapeutic approach for a rare tumor (Review).

Cribriform morular thyroid carcinoma (CMTC) has been included within the group of thyroid tumors of uncertain histogenesis in the recent World Health Organization classification of endocrine tumors. Most CMTCs occur in young euthyroid women with multiple (and bilateral) thyroid nodules in cases associated with familial adenomatous polyposis (FAP) or as single nodules in sporadic cases. CMTC generally behaves indolently, while aggressiveness and mortality are associated with high‑grade CMTC. This tumor histologically displays a distinctive combination of growth patterns with morular structures. Strong diffuse nuclear and cytoplasmic immunostaining for β‑catenin is the hallmark of CMTC. Tumor cells are also positive for thyroid transcription factor‑1 and for estrogen and progesterone receptors, but negative for thyroglobulin and calcitonin. It is possible that the CMTC phenotype could result from blockage in the terminal/follicular differentiation of follicular cells (or their precursor cells) secondary to the permanent activation of the Wnt/β‑catenin pathway. In CMTC, the activation of the Wnt/β‑catenin pathway is the central pathogenetic event, which in FAP‑associated cases results from germline mutations of the APC regulator of WNT signaling pathway (APC) gene, and in sporadic cases from somatic inactivating mutations in the APC, AXIN1 and CTNNB1 genes. Estrogens appear to play a tumor‑promoting role by stimulating both the PI3K/AKT/mTOR and the RAS/RAF/MAPK signaling pathways. Additional somatic mutations (i.e. RET rearrangements, or KRAS, phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit α, telomerase reverse transcriptase or tumor protein 53 mutations) may further potentiate the development and progression of CMTC. While hemithyroidectomy would be the treatment of choice for sporadic cases without high‑risk data, total thyroidectomy would be indicated in FAP‑associated cases. There is insufficient clinical data to propose therapies targeting the Wnt/β‑catenin pathway, but multikinase or selective inhibitors could be used in a manner analogous to that of conventional thyroid tumors. It is also unknown whether adjuvant antiestrogenic therapy could be useful in the subgroup of women undergoing surgery with high‑risk CMTC, as well as when there is tumor recurrence and/or metastasis.

The evolving molecular characterisation, histological criteria and nomenclature of adenoid ameloblastoma as a World Health Organisation tumour type.

Adenoid ameloblastoma (AA) was recently recognised as a separate tumour type in the most recent World Health Organisation (WHO) classification of head and neck tumours. This decision has been considered controversial by several groups, who have described AA as a subtype of ameloblastoma, a hybrid odontogenic tumour or to fall within the spectrum of other recognised odontogenic tumours, including dentinogenic ghost cell tumour and adenomatoid odontogenic tumour. Here we review the reasons for the WHO decision to classify AA as a separate tumour type. We also critique molecular and histological findings from recent reports published since the WHO classification. While acknowledging that the classification of tumours is constantly evolving, the balance of current evidence suggests that AA should remain a distinct tumour type, and not a subtype of ameloblastoma, pending further molecular characterisation.

A Novel EPC1 :: KDM2B Fusion in High-grade Endometrial Stromal Sarcoma.

The spectrum of endometrial stromal sarcoma (ESS) has expanded substantially since the publication of the most recent World Health Organisation (WHO) Classification of Female Genital Tumours and the advent of widely available genomic testing. We describe a uterine mesenchymal tumor harboring a novel EPC1 :: KDM2B fusion, best classified within the umbrella of high-grade endometrial stromal sarcoma (HGESS). This tumor was composed of a uniform population of spindled cells with some myxoid stroma, a mitotic rate of up to 21/10 high-power fields, and a largely pushing margin with focal vascular invasion. Immunohistochemistry showed strong and diffuse cyclin D1 positivity while CD10, WT1, DOG1, CD117, CD34, CD99, S100, MelanA, SMA, desmin, and h-caldesmon were negative. The tumor was confined to the uterus and no recurrence has been detected thus far, albeit with a short follow-up interval of 9mo.

NPM1-Mutated Myeloid Neoplasms: Updated Outcomes with High-Intensive Chemotherapy Regardless of the Blast Percentage

Background: The most recent World Health Organization (WHO) classification has stablished NPM1-mutated myeloid neoplasms (MNs) to be acute myeloid leukemia (AML) regardless of bone marrow (BM) blast percentage. In contrast, the new International Consensus Classification (ICC) considers NPM1-mutant MNs as AML only in the presence of ≥10% BM blasts. Previous studies from our group and others have reported favorable outcomes of NPM1-mutant MNs with <20% blasts when treated with intensive chemotherapy. Here we seek to further evaluate clinical outcomes of this group of pts. Methods: We retrospectively re-evaluated the patient's characteristics, disease features and outcomes in patients with NPM1-mutated oligoblastic AML (<20% blasts) (oligo-AML). In addition, we also evaluated the clinicopathological characteristics in a cohort of patients with secondary NPM1-mutated AML (sAML), the majority of which had received treatment before progressing to AML. The Kaplan-Meier method was used to estimate the overall survival (OS), event-free survival (EFS) and relapse-free survival (RFS). Results: We identified 54 patients with NPM1-mutated oligo-AML. Median age was 62 years (range, 19-87) and most of them were female (59%). Median bone marrow (BM) blasts was 10%. Most patients could have been classified as CMML-2 (7/54, 13%), MDS-EB1 (7/54, 13%) and MDS-EB2 (24/54, 44%), based on the 2016 WHO classification. Median NPM1 variant allele frequency (VAF) was 0.38 (range, 0.05-0.52) and 38 patients (70%) had normal karyotype. These patients harbored a median of 1 co-mutation (range, 0-5), predominantly DNA methylation pathway, such as DNMT3A (31%) or TET2 (23.5%), or RAS pathway, mainly NRAS (25.5%), but rarely exhibited mutations in other functional pathways (Figure 1). Twenty-three patients (43%) progressed to AML with >20% BM blasts within a median of 10.7 months. Of 54 patients, 46 patients (82%) received chemotherapy-based regimens [61% low-intensity chemotherapy (LI-Chemo) based on hypomethylating agents or low-dose cytarabine and 21% high-intensity chemotherapy (HI-Chemo)] and 21 patients (39%) received a stem cell transplant (SCT). With a median follow up of 67.6 months (LI-Chemo of 48.3 months; HI-Chemo of 71.4 months), the median OS, EFS and RFS was 30.4 months, 30.4 months and 14.7 months for the LI-Chemo group, respectively, but median OS, EFS and RFS were not reached (NR) for HI-Chemo group. However, when compared by age, patients with <60 years had trends to have better OS with LI-Chemo or HI-Chemo than patients aged ≥60 years (Figure 2). In addition, 5 patients received chemotherapy-based regimens with venetoclax, however improved OS was only seen when combined with HI-Chemo and SCT (n=2, with a median OS NR without deaths, likely related to younger people). In parallel, we identified 31 patients with NPM1-mutated sAML progressed from oligo-AML. Median age was 67 years (range, 31-83) and female were 58%. Median BM blasts was 40%. Median NPM1 VAF was 0.38 (range, 0.02-0.56). Most patients did not exhibit clonal cytogenetic evolution and remained with a diploid karyotype (65%). Seventy-four percent of patients (17 out of 23 tested) had known prior NPM1-mutated oligo-AML, and in 6 patients NPM1 mutation was acquired at progression. Median number of co-mutations were 3 (range, 0-7). DNTM3A (65%) or TET2 (33.3%) mainly co-occurred with RAS pathway mutations, and in particular FLT3-ITD (26.7%) or FLT3-TKD (13.3%) (Figure 1). Eleven of 31 patients (36%) received LI-Chemo regimens, whereas 15 of 31 patients (48%) had HI-Chemo regimens. Nine patients (29%) underwent SCT. With a median follow up of 39.6 months (LI-Chemo of 55.5 months; HI-Chemo of 39.4 months), the median OS, EFS and RFS was 11.4 months, 12.4 months and NR for LI-Chemo, respectively; and 13.2 months, 6.5 months and NR for HI-Chemo, respectively. No significant differences were seen depending on the number of therapies received for previous oligo-AML. Previously untreated patients who received a venetoclax-based regimen with SCT had prolonged survival (n=4, median OS NR, with median follow up of 41 months). Conclusions: NPM1-mutated acute myeloid leukemia can be treated as such irrespective of blasts burden. For these cases, especially young patients, should be treated with intensive chemotherapy and subsequent allogeneic stem cell transplant as a clear curative approach.

Updates in pathobiological aspects of anaplastic large cell lymphoma.

Anaplastic large cell lymphomas (ALCL) encompass several distinct subtypes of mature T-cell neoplasms that are unified by the expression of CD30 and anaplastic cytomorphology. Identification of the cytogenetic abnormality t(2;5)(p23;q35) led to the subclassification of ALCLs into ALK+ ALCL and ALK- ALCL. According to the most recent World Health Organization (WHO) Classification of Haematolymphoid Tumours as well as the International Consensus Classification (ICC) of Mature Lymphoid Neoplasms, ALCLs encompass ALK+ ALCL, ALK- ALCL, and breast implant-associated ALCL (BI-ALCL). Approximately 80% of systemic ALCLs harbor rearrangement of ALK, with NPM1 being the most common partner gene, although many other fusion partner genes have been identified to date. ALK- ALCLs represent a heterogeneous group of lymphomas with distinct clinical, immunophenotypic, and genetic features. A subset harbor recurrent rearrangement of genes, including TYK2, DUSP22, and TP63, with a proportion for which genetic aberrations have yet to be characterized. Although primary cutaneous ALCL (pc-ALCL) is currently classified as a subtype of primary cutaneous T-cell lymphoma, due to the large anaplastic and pleomorphic morphology together with CD30 expression in the malignant cells, this review also discusses the pathobiological features of this disease entity. Genomic and proteomic studies have contributed significant knowledge elucidating novel signaling pathways that are implicated in ALCL pathogenesis and represent candidate targets of therapeutic interventions. This review aims to offer perspectives on recent insights regarding the pathobiological and genetic features of ALCL.

Urothelial carcinoma; an overview of histology, molecular subtypes, and clinical implications based on the latest WHO classification

The incidence of urothelial carcinoma is increasing worldwide (including in Iran). Bladder cancer can be classified in various manners according to the standardized histomorphology set by the World Health Organization (WHO). Various genetic modifications occurring at the DNA level and the resulting variations in RNA expression give rise to different subcategories that have important implications for diagnosis, prognosis, and treatment. The molecular basis of these morphologic variances is now better understood because of recent developments in molecular biology. With updates on the genetic and clinical characteristics, we highlight the histologic traits of the divergent differentiation and subtypes recognized by the most recent WHO classification (5th edition). Molecular subtypes of lower and upper tract cancer can be used to characterize their clinical behaviors and determine therapeutic responses to neoadjuvant chemotherapy. In this overview article, we also present a preliminary analysis of our ongoing data collection on molecular features of urothelial carcinoma.

Epstein–Barr virus-associated B-cell lymphoproliferative disorder meeting the definition of CAEBV B cell disease: a case report

BackgroundChronic active Epstein-Barr virus infection (CAEBV) is a systemic EBV-positive lymphoproliferative disorder (EBV-LPD) considered to be associated with a genetic immunological abnormality, although its cause is still unclear. EBV is usually detected in T cells or NK cells in CAEBV patients with only a few cases involving B cells described in East Asia, which may be due to differences in genetic and environmental factors.Case descriptionA 16-year-old boy who seemed to be diagnosed as CAEBV of B cell type was studied. The patient had IM-like symptoms persisting for more than 3 months, high levels of EBV DNA in the PB, and positive EBER in situ hybridization in B cells. In addition, to exclude underlying genetic disorders, we performed next-generation sequencing (NGS) and whole-exome sequencing (WES), which identified the missense mutation in PIK3CD (E1021K), ADA (S85L) and CD3D (Q140K) in the patient while no same genetic mutation was detected in his parents and sister. However, there is no diagnosis of CAEBV of B cell type in the most recent World Health Organization classification of tumors of hematopoietic and lymphoid tissues, therefore we finally diagnosed this patient as EBV-B-LPD.ConclusionsThis study shows a rare case of a patient meeting the definition of CAEBV B-cell disease in East Asia. Meanwhile, the case indicates that the missense mutation and the disease are related.

A sneak peek into the diagnostic conundrum of neuroendocrine neoplasms of the breast: An updated review with a brief illustrative case series

Abstract Neuroendocrine neoplasms (NENs) of the breast are uncommon tumours that have been a hitherto poorly and variably defined entity. In the recent fifth Edition World Health Organisation (WHO) classification of breast tumour, NENs are dichotomously classified into neuroendocrine tumours (NETs) and neuroendocrine carcinomas (NECs), mirroring the classification of NENs in other organ systems. Both NETs and NECs are invasive tumours in the breast. However, the clinical significance of neuroendocrine differentiation (NED) in breast cancers, especially in NETs of the breast, is not yet fully understood, and a large overlap appears to exist between breast cancers showing NED and invasive breast carcinoma of no special type (IBC-NST). Although breast NECs show distinct clinical and morphological features and show overlapping molecular features with their counterpart in other organs, especially the high-grade component. Diagnosis of NETs based on the morphological characteristics alone can be challenging; one reason is that breast NETs do not necessarily have the same morphological characteristics as those of NENs arising in other organs and are genetically heterogeneous and harbour molecular alterations that differ from IBC, NST. The keynote changes in the current WHO are the exclusion of other histological subtypes that is, solid papillary carcinoma and a hypercellular variant of mucinous carcinoma which are strong immunohistochemical mimickers of NED and the inclusion of large cell neuroendocrine carcinoma (LCNEC). Thus, the heterogeneity of breast tumours with NED and the changes in their classifications over the years have left many open issues that still need to be resolved. Data regarding the prognostic significance of NED is conflicting and histologic grade and tumour stage remain the main prognostic parameters. Current management of NENs is similar to that of IBC of NST. In this review article, we will summarise the journey of NENs of the breast with an update on the recent WHO classification and discuss their differences from NENs arising in other organs by highlighting an interesting case series depicting their clinical, radiological, histological and molecular features.

P15 Progressive papulonodular eruption following COVID-19 infection: a rare diagnosis and review of the literature

Abstract We report a rare case of primary cutaneous CD8+ aggressive epidermotrophic cytotoxic T-cell lymphoma with striking clinical and histopathological features. A 51-year-old man, originally from Cameroon, presented to the department with a 6-week history of a progressive, itchy papulosquamous eruption that started on the lower abdomen shortly following infection with COVID-19. It became widespread over a short number of weeks, with blistering and ulceration in some areas. The patient reported fatigue with an intermittent low-grade pyrexia, but no systemic symptoms otherwise, and he was previously fit and well. Physical examination revealed an extensive, infiltrated papulonodular eruption with thick scale that was more marked in the skinfolds and involving the acral surfaces. Histology from three morphologically different sites showed marked epidermal hyperplasia and a prominent epidermotrophic infiltrate of medium-sized atypical lymphoid cells. There were frequent mitotic figures and evidence of apoptosis. Immunohistochemistry revealed that the atypical lymphoid cells in the epidermis were T cells expressing CD3, CD7 and CD8, together with cytotoxic markers and a high Ki67 proliferation fraction. These features were consistent with a diagnosis of CD8+ aggressive epidermotrophic cytotoxic T-cell lymphoma. Initial bloods and imaging were fairly unremarkable. Since the diagnosis, the patient has been treated with multiple types and courses of chemotherapy, with relapses in between. Most recently, the patient has been referred for total skin electron beam therapy with investigations for allogenic stem cell transplant ongoing. Owing to its rarity, primary cutaneous CD8+ aggressive epidermotrophic cytotoxic T-cell lymphoma is categorized only as a provisional entity in the most recent World Health Organization classification (Gilson D, Whittaker SJ, Child FJ et al. British Association of Dermatologists and U.K. Cutaneous Lymphoma Group Guidelines for the management of primary cutaneous lymphomas 2018. Br J Dermatol 2018; 180:496–526). Despite a variable and polymorphic presentation, the histology is distinctive in showing monomorphous, medium-sized atypical lymphocytes in the epidermis. We discuss the epidemiology of the disease and the paucity of therapeutic guidelines. In addition, our patient’s disease developed soon after COVID-19 infection; hence, we review the growing literature on the association between COVID-19 infection and vaccination and diagnosis, and relapse and remission of cutaneous T-cell lymphoma.

RUNX1 mutation has no prognostic significance in paediatric AML: a retrospective study of the AML-BFM study group

In acute myeloid leukaemia (AML) RUNX1 mutation is characterised by certain clinicopathological features with poor prognosis and adverse risk by the European LeukemiaNet recommendation. Though initially considered as provisional category, the recent World Health Organisation (WHO) classification of 2022 removed RUNX1-mutated AML from the unique entity. However, the significance of RUNX1 mutation in paediatric AML remains unclear. We retrospectively analysed a German cohort of 488 paediatric patients with de novo AML, enroled in the AMLR12 or AMLR17 registry of the AML-BFM Study Group (Essen, Germany). A total of 23 paediatric AML patients (4.7%) harboured RUNX1 mutations, 18 of which (78%) had RUNX1 mutation at initial diagnosis. RUNX1 mutations were associated with older age, male gender, number of coexisting alterations and presence of FLT3-ITD but mutually exclusive of KRAS, KIT and NPM1 mutation. RUNX1 mutations did not prognostically impact overall or event-free survival. Response rates did not differ between patients with and without RUNX1 mutations. This comprehensive study, comprising the largest analysis of RUNX1 mutation in a paediatric cohort to date, reveals distinct but not unique clinicopathologic features, with no prognostic significance of RUNX1-mutated paediatric AML. These results broaden the perspective on the relevance of RUNX1 alterations in leukaemogenesis in AML.

Clinicopathological features of five cases of CIC::DUX4 positive sarcomas, including literature review

According to the recent World Health Organization (WHO) classification, CIC-rearranged sarcomas, including CIC::DUX4-positive sarcomas constitute an aggressive subtype of undifferentiated round cell sarcomas. There is a single study on these tumors from our subcontinent. We present clinicopathological features of 5 additional cases of this tumor entity, including literature review.Thirty-nine undifferentiated round cell sarcomas, excluding Ewing sarcomas (ES), were tested for CIC::DUX4 fusion, including Type I (165 base pair size) and II (230 bp) by reverse transcription-polymerase chain reaction. Twenty-five of those tumors were tested for EWSR1 gene rearrangement, 5 for SS18 and 4 for SS18::SSX fusion, and were negative for those tests. Five tumors (12.8 %) were positive for CIC::DUX4(Type II) fusion.Five CIC:: DUX4-positive sarcomas occurred in 4 males and one female; of 25–43 years of age, in soft tissues, including thigh (n = 2), chest wall (n = 1), iliac region (n = 1) and foot (n = 1). Tumor size varied from 2.2 to 19 cm. Microscopically, the tumors were predominantly composed of nodules and sheets of malignant round to epithelioid cells, including “rhabdoid-like” (n = 2) and spindle-shaped (n = 2) with eosinophilic to vacuolated cytoplasm (4/5), distinct nucleoli (4/5), brisk mitoses, focal myxoid to hyalinised stroma (4/5) and necrosis (5/5). Immunohistochemically, tumor cells were positive for WT1 (5/5), calretinin (3/4), pan-keratin (1/4), CD99/MIC2 (“dot-like” to cytoplasmic membranous) (4/4), while negative for desmin (0/4), S100P (0/4), and NKX2.2 (0/5). INI1/SMARCB1 was retained (3/3). All patients underwent excision with adjuvant radiotherapy and chemotherapy (Ewing sarcoma regimen). A single patient developed recurrence, and 2 developed pulmonary metastasis, including one with brain metastasis.CIC:: DUX4-positive sarcomas are ultra-rare tumors, that mainly occur in the soft tissues and in young adult patients. Histopathologically, these tumors display a wide spectrum, including round to epithelioid cells, variable amount of cytoplasmic vacuolization and myxoid stroma with necrosis.Immunohistochemically, these tumors express WT1 and calretinin. Despite adjuvant therapies, these tumors have dismal outcomes, especially in large-sized tumors. CIC::DUX4-positive sarcomas need to be differentiated from their histopathological mimics, including ES, in view of significant treatment-related implications.

Role of Morphology in the Diagnosis of Acute Leukemias: Systematic Review

AbstractThe role of hematopathologists in the diagnosis of acute leukemia (AL) starts with the morphological examination of either peripheral blood smear or bone marrow. The morphological hallmark for the myeloblast includes “Auer rods” and “Phi bodies.” The addition of cytochemical stains such as myeloperoxidase, Sudan Black B, periodic acid-Schiff stain, nonspecific esterase, and Perls' stain acts as an important adjunct to the morphological classification in the resource-constrained settings. The recent World Health Organization classification still endorses the utility of morphology which requires the presence of either ≥ 20% lymphoblasts or myeloblasts/or its equivalents (monoblasts, promonocytes, or megakaryoblasts) and integrates it with the clinical features, immunophenotyping (IP), and molecular genetics for making the diagnosis of AL. Morphology can give clue to the specific diagnosis of acute myeloid leukemia (AML) with t(8:21), t(15:17), t(16:16), or inv(16) and this diagnosis can be made irrespective of blasts count if such translocations are demonstrated by molecular tests. There are some interesting findings such as blasts with “hand-mirror” morphology, nuclear cleavage, prominent cytoplasmic vacuoles, pseudo-Chediak-Higashi granules, cup-like nucleus, and other dysplastic features helping in differentiating lymphoid and myeloid leukemias. Transient abnormal myelopoiesis in Down syndrome and hypoplastic AL can be picked up on morphological examination. Bone marrow biopsy would be greatly beneficial and complementary to aspirate smears and is required for diagnosing exact cellularity, topography of cells, dyspoiesis, myelonecrosis, gelatinous marrow transformation, myelofibrosis, and IP can be performed using immunohistochemistry. Morphological examination in AL is not only helpful for diagnosis but also useful for predicting the prognosis in posttherapy cases, AML with myelodysplasia-related changes, therapy-related myeloid neoplasms, and mixed phenotype AL. Hematogones, blastoid mantle cell lymphoma, high grade B cell lymphoid with blastoid morphology, Burkitt leukemia, prolymphocytes in prolymphocytic leukemia, hairy cell leukemia variant, plasmablasts especially in plasmablastic leukemia, or plasma cell leukemia can mimic AL and IP is useful in these situations. Hence, morphology should be considered as a kind of “gold-standard” starting point for the analysis of AL cases. Morphological examination cannot be replaced and advanced tests cannot be used as surrogate for morphology.

Update in Pathology of Practically Encountered Lesions and Diseases in the Liver

This issue of the American Journal of Surgical Pathology, Reviews and Reports is devoted to recent advances and update in the pathology of the liver. The articles provide insights into the current nomenclature, classification, diagnosis, differential diagnoses, clinical and prognostic aspects of various liver diseases, and lesions that are informative to pathologists in their daily practice. Hepatocellular adenomas (HCAs) is generally a benign liver neoplasm that typically arises in the noncirrhotic liver; however, malignant transformation does occur, and hence, subtyping is critical. Drs Jung and Liu present a case of HCA that was initially diagnosed as inflammatory HCA on a biopsy and subsequently was confirmed to be β-catenin–activated inflammatory HCA on the resection specimen. They then comprehensively review recent updates on molecular classification and the key histologic features of each subtype and discuss common diagnostic pitfalls. Over the past decades, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) have been recognized to be heterogeneous in morphology, molecular features, and biological behavior. Recent World Health Organization classification describes various histomorphological subtypes of HCC and iCCA, some with characteristic molecular profiles, clinical correlates, and prognostic implications. In their review, Drs Hwang and Kim nicely discuss recently described subtypes of HCC and iCCA: macrotrabecular HCC, steatohepatitic HCC, scirrhous HCC, and small duct iCCA. Congestive hepatopathy shows a unique pattern of fibrosis, that is, pericentral fibrosis at early stage, which may progress to bridging fibrosis and cirrhosis. Making a diagnosis of congestive hepatopathy and staging its fibrosis are important tasks for pathologists, as patients may undergo liver biopsies before cardiac transplantation to assess the degree of liver fibrosis, which may impact clinical decision-making. Besides patients' own cardiac dysfunction, congestive hepatopathy can also be seen after a Fontan procedure. Drs Gosse and Bosch describe a case of congestive hepatopathy due to altered circulation with a Fontan procedure. They then discuss the fibrosis scoring systems recently described for Fontan-associated liver disease and congestive heart disease–associated hepatopathy. Combined hepatocellular-cholangiocarcinoma is a rare primary liver tumor with neoplastic components of both hepatocytic and cholangiocytic differentiation within the same tumor. There is recent consensus paper and World Health Organization classification of this unique tumor. Drs Kondo, Akiba, and Yano herein report a case of this tumor and thoughtfully review the terminology, classification, and clinical and pathological characteristics of combined hepatocellular-cholangiocarcinoma and its differential diagnosis. Hemophagocytic lymphohistiocytosis is a rare disease with a high mortality. Liver involvement is common, with most patients demonstrating acute hepatitis. Therefore, liver biopsies are frequently performed when this entity is suspected. Dr Xiong and colleagues summarize the clinical features of hemophagocytic lymphohistiocytosis, emphasizing its hepatic manifestations. They describe the highly variable histologic patterns and address difficulties encountered by pathologists. We are extremely grateful to all the contributors for sharing their expertise and knowledge in forming this issue. We hope that the information provides highlights and elucidates the practically encountered lesions in the liver. Guest Editors

Histomorphological Subtypes of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: Review and Update

AbstractPrimary liver cancers comprise a heterogeneous group of neoplasms, with the 2 main entities being hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Over the past decades, HCC and iCCA have been recognized to be heterogeneous in morphology, molecular features, and biological behavior, and the most recent World Health Organization classification of digestive system tumors describes various histomorphological subtypes of HCC and iCCA, some of which also have characteristic molecular features, clinical correlates, and prognostic implications. In this review, we discuss 4 recently described subtypes of HCC and iCCA—macrotrabecular HCC, steatohepatitic HCC, scirrhous HCC, and small duct iCCA—based on a series of cases.