Navigating The 2022 International Consensus and World Health Organization Classifications of Hematopathology: A Call for Unified Diagnostic Language.

CONTEXT.­: In 2022, 2 distinct guidelines for the diagnosis of myeloid neoplasms became available: the 5th edition of the World Health Organization guideline (WHO2022) solely and the International Consensus Classification (ICC). Despite major overlap, there are important differences that can have important implications. OBJECTIVE.­: To explore the current opinions and diagnostic practices of hemato-oncologists and hematopathologists across the United States. DESIGN.­: An online anonymous survey was created using REDCap, and a secure link was shared via email to fellowship program leaderships and via posts on social media. RESULTS.­: A total of 310 responses were obtained. Only 33 of 309 respondents (10.7%) reported using solely the 2016 World Health Organization guideline to make diagnoses, whereas 167 of 309 (54%) supplemented it with other guidelines. The rest were either not sure (17; 5.5%), used WHO2022 solely (46; 14.9%), or used ICC solely (6; 1.9%). The choice of guideline was not related to region (P = .15), practice setting (P = .86), or hospital size (P = .22). More than 90% reported it is a source of confusion in clinical diagnosis, management, trial design, and other areas. CONCLUSIONS.­: Overall, our study found that having 2 distinct guidelines could be a source of confusion for physicians and calls for a unified diagnostic language.

Liquid biopsy-based circulating tumour (ct)DNA analysis of a spectrum of myeloid and lymphoid malignancies yields clinically actionable results.

AIMS: Liquid biopsy (LBx)-based next-generation sequencing (NGS) of circulating tumour DNA (ctDNA) can facilitate molecular profiling of haematopoietic neoplasms (HNs), particularly when tissue-based NGS is infeasible. METHODS AND RESULTS: We studied HN LBx samples tested with FoundationOne Liquid CDx, FoundationOne Liquid, or FoundationACT between July 2016 and March 2022. We identified 271 samples: 89 non-Hodgkin lymphoma (NHL), 43 plasma-cell neoplasm (PCN), 41 histiocytoses, 27 myelodysplastic syndrome (MDS), 25 diffuse large B-cell lymphoma (DLBCL), 22 myeloproliferative neoplasm (MPN), 14 Hodgkin lymphoma (HL), and 10 acute myeloid leukaemia (AML). Among 73.4% with detectable pathogenic alterations, median maximum somatic allele frequency (MSAF) was 16.6%, with AML (36.2%), MDS (19.7%), and MPN (44.5%) having higher MSAFs than DLBCL (3.9%), NHL (8.4%), HL (1.5%), PCN (2.8%), and histiocytoses (1.8%) (P = 0.001). LBx detected characteristic alterations across HNs, including in TP53, KRAS, MYD88, and BTK in NHLs; TP53, KRAS, NRAS, and BRAF in PCNs; IGH in DLBCL; TP53, ATM, and PDCD1LG2 in HL; BRAF and MAP2K1 in histiocytoses; TP53, SF3B1, DNMT3A, TET2, and ASXL1 in MDS; JAK2 in MPNs; and FLT3, IDH2, and NPM1 in AML. Among 24 samples, the positive percent agreement by LBx was 75.7% for variants present in paired buffy coat, marrow, or tissues. Also, 75.0% of pairs exhibited alterations only present on LBx. These were predominantly subclonal (clonal fraction of 3.8%), reflecting the analytical sensitivity of LBx. CONCLUSION: These data demonstrate that LBx can detect relevant genomic alterations across HNs, including at low clonal fractions, suggesting a potential clinical utility for identifying residual or emerging therapy-resistant clones that may be undetectable in site-specific tissue biopsies.

Phenotypic clues that predict underlying cytogenetic/genetic abnormalities in myeloid malignancies: A contemporary review.

Precise subclassification of myeloid malignancies per the World Health Organization (WHO) classification system and the International Consensus Classification of Myeloid Neoplasms and Acute Leukaemias (ICC) requires investigation and documentation of the presence of cytogenetic and/or molecular genetic changes. These ancillary studies not only help in diagnosis, but also the prognosis of disease; however, they take time to be completed. In contrast, morphological evaluation of material from the blood and bone marrow specimens of cases where myeloid malignancies are suspected is usually completed quickly. Cytomorphological assessment may predict genetic changes and can be helpful in triaging acuity. This is especially true in haematological emergencies such as acute promyelocytic leukaemia (APL), where prompt APL-specific therapy can be life changing. Similarly, some morphological clues may help identify core binding factor leukaemias where a diagnosis of acute myeloid leukaemia (AML) could be rendered without reaching the 20% blast cutoff with immediate treatment-decision implications, or even a subset of cases of AML with FLT3 ITD/NPM1 mutation(s) which show characteristic features. Even though FISH/cytogenetics and/or PCR are still required for establishing the final diagnosis, evaluation for the presence of specific cytomorphological features that help predict genetic changes can be a useful tool to help guide early therapy.

Polyamine catabolism is concentrated in tumor-associated histiocytes in diffuse large B-cell lymphoma and classic Hodgkin lymphoma.

Polyamines are cationic molecules necessary for cell survival, growth, and replication [1-5]. Polyamines come in a variety of structural forms and are principally regulated by two enzymes, spermine/spermidine acetyltransferase-1 (SAT1) and ornithine decarboxylase-1 (ODC1). SAT1 targets the polyamines spermidine and spermine for degradation via acetylation, while ODC1 is involved in converting the polyamine precursor molecule to more complex polyamines [6-8]. Polyamines and their regulatory enzymes have been implicated in tumor metastasis [9,10] and in crosstalk between oncogenes [11-13] in numerous types of cancer, but their role has never been evaluated in B-cell malignancies. In this study, we examine the expression of SAT1 in diffuse large B-cell lymphoma (DLBCL) and classic Hodgkin lymphoma (HL). We found that SAT1 is expressed in all examined cases of DLBCL (n = 15) and HL (n = 5), though the levels of expression across cases vary. We also note that SAT1 expression appears to be concentrated in tumor-associated histiocytes, rather than tumor cells in both DLBCL and HL. We propose that these findings indicate that the polyamine catabolic enzyme, SAT1, plays an unappreciated role in the pathogenesis of B-cell neoplasms.

Indolent T-Cell Lymphoproliferative Disease: A Rare Case of a Benign Lymphoma of the Gastrointestinal Tract With Extra-Gastrointestinal Involvement.

Indolent T-cell lymphoproliferative disease of the gastrointestinal (GI) tract is an exceedingly rare benign proliferation of clonal and mature-appearing lymphoid cells originating from the GI tract. We discuss the case of a 52-year-old woman with indolent T-cell lymphoproliferative disease of the GI tract manifesting as chronic diarrhea and profound weight loss. Interestingly, the patient also had extra-GI involvement of her disease process, which has not been previously reported. Our patient was managed with steroids with improvement in symptoms and weight gain. We provide a review of the literature to highlight the importance of early recognition and intervention of this disease entity.

Isolated leukemia cutis as extramedullary relapse of acute myeloid leukemia.

Acute myeloid leukemia (AML) arises from clonal expansion of malignant hematopoietic precursor cells in the bone marrow. In rare instances, AML can recur with prominent extramedullary manifestations (i.e., leukemia cutis or myeloid sarcoma), either simultaneously or preceding marrow involvement, or as a sole site of primary disease relapse.

The utility of a gross dissection anatomical model for simulation-based learning in pathology.

INTRODUCTION: The examination of morphological alterations in tissues is fundamental in Pathology. Traditional training in gross dissection has several limitations, including the risk of transmissible diseases, formaldehyde exposure and limited specimen availability. We describe a teaching method using anatomical simulators. METHODS: Liquid silicone-based artisan neoplastic anatomical models were used in conjunction with clinical scenarios. Eighty-five medical students participated in a gross dissection experience and were asked to complete a feedback questionnaire. Additionally, a workshop was organized for students to compare three different teaching methods. The first one used still images (Group1-G1), the second a video explanation (Group2-G2), and the third directly observed a pathologist while grossing (Group3-G3). RESULTS: The knowledge acquisition questionnaire showed an average value of 4.4 out of 5 (1-5) (range 3.4-4.7, σ0.89). The categories 'knowledge of resection margins' and 'macroscopic diagnosis' received the highest values (4.8, σ0.11 and 4.7, σ0.32, respectively), followed by 'understanding of handling and gross examination of the surgical specimen' (4.5, σ0.49), 'prognosis' (4.3, σ0.67) and 'understanding of a tumor resection' (3.9, σ0.96) (p<0.05). Regarding teaching methods, G3 spent less time than G2 and G1 with mean times of 15'39″ (σ2'12″), 16'50″ (σ3'45″), and 17'52″ (σ2'12″), respectively (p<0.05). Gross dissection marks (0-5) showed statistically significant differences (p<0.05). G2 obtained better results (3.7;σ0.54) than G3 (3.4;σ0.94) or G1 (3.1;σ0.8). CONCLUSIONS: This preliminary study demonstrates that it is possible to implement a gross dissection simulation module at medical school and thus enable the acquisition of skills in a secure environment.

Heterotopic Mesenteric Ossification With Trilineage Hematopoiesis.

Heterotopic ossification (HO) histologically refers to extraskeletal bone formation in non-ossifying tissues, most commonly noted in the extremities, buttocks, abdominal wall, and hip joints. HO developing in the mesentery (heterotopic mesenteric ossification, HMO) is very rare, with fewer than 100 cases reported in the literature. It usually occurs in adult male patients with a history of repeated abdominal trauma. So far, only two cases of HMO have been reported with the development of hematopoietic bone marrow. Here, we report the third case of HMO with true trilineage hematopoiesis in a 66-year-old female with suspicious mesenteric-retained foreign material from prior surgical procedures, including hysterectomy for endometrial adenocarcinoma and multiple repairs for incisional hernia.

Nodular Histiocytic/Mesothelial Hyperplasia Mimicking Mesenteric Metastasis.

Nodular histiocytic/mesothelial hyperplasia (NHMH) is a rare histologic entity, characterized by localized benign reactive proliferation of histiocytes and mesothelial cells. The presence of this rare entity poses a challenge in differential diagnosis, both in radiological findings and pathological interpretations under certain circumstances, and consequently has been misdiagnosed as malignancy. Here, we report a case of mesenteric NHMH in a patient with colonic mucinous adenocarcinoma. Histology shows numerous large calretinin (+) mesothelial cells mixed with CD68 (+) histiocytes by immunohistochemistry. In contrast to almost all previously reported cases with typical features of histiocytic predominance, the current case of NHMH mainly consists of mesothelial cells with intermixed histiocytes. The findings expand the histologic spectrum of NHMH and contribute to awareness of this entity in the differential diagnosis.

Hemophagocytic Lymphohistiocytosis.

CONTEXT.­: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder of immune regulation that can eventually result in end-organ damage and death. HLH is characterized by uncontrolled activation of cytotoxic T lymphocytes, natural killer cells, and macrophages that can lead to a cytokine storm. The diagnosis of HLH is often challenging due to the diverse clinical manifestations and the presence of several diagnostic mimics. The prognosis is generally poor, warranting rapid diagnosis and aggressive management. OBJECTIVE.­: To provide a comprehensive review of the pathogenesis, clinical features, diagnosis, and management of HLH. DATA SOURCES.­: Peer-reviewed literature. CONCLUSIONS.­: HLH is a condition where a complete understanding of the pathogenesis, early diagnosis, and proper management has an important role in determining patient outcome. Genetic mutations causing impairment in the function of cytotoxic T lymphocytes and natural killer cells have been identified as the root cause of familial HLH; however, the specific pathogenesis of acquired HLH is unclear. The HLH-2004 protocol used in the diagnosis of HLH was originally developed for the pediatric population. The HLH-2004 protocol still forms the basis of the diagnosis of HLH in adults, although its use in adults has not been formally validated yet. Treatment of HLH is primarily based on the HLH-94 protocol, which involves suppressing the inflammatory response, but the treatment needs to be modified in adults depending on the underlying cause and comorbidities.

A Case of Primary Myelofibrosis With Transformation to Leukemia Cutis.

ABSTRACT: We report an extraordinary case of primary myelofibrosis with transformation to leukemia cutis. A 64-year-old Caucasian man with a history of JAK2-positive primary myelofibrosis presented with erythematous papulonodules on his right lower extremity. A punch biopsy revealed a normal epidermis with an underlying diffuse dermal infiltrate composed of medium-to-large-sized myeloid cells and leukocytes. Neoplastic cells were immunoreactive for LCA, CD34, CD61, CD117, and CD68 and negative for lysozyme, CD20, CD3, myeloperoxidase, and TdT. These findings were consistent with a diagnosis of leukemia cutis. A concurrent bone marrow biopsy demonstrated a markedly fibrotic, hypercellular marrow without a significant increase in blasts. With no morphologic evidence of bone marrow involvement by acute myeloid leukemia, our case suggests that the patient's primary myelofibrosis transformed to leukemia cutis. Our patient died 2 months after the onset of his skin nodules. Our case demonstrates that leukemia cutis should be included in the differential diagnosis for cutaneous nodular lesions in patients with a history of an advanced-stage hematological malignancy.

Elevating Twitter-Based Journal Club Discussions by Leveraging a Voice-Based Platform: #HemepathJC Meets Clubhouse.

PURPOSE OF REVIEW: Social media-based scientific journal clubs provide an opportunity to promote published literature to a broader audience and allow robust multi-disciplinary and inter-professional discussion. Hematopathology Journal Club (#HemepathJC) on Twitter has successfully conducted monthly sessions since November 2019, covering topics related to lymphoma and leukemia. RECENT FINDINGS: To enhance connectivity, multitasking, and productivity, we present our experience of leveraging the voice-based platform Clubhouse concurrent with Twitter. The Twitter and Clubhouse partnership for #hemepathJC holds the potential to increase dissemination of scientific knowledge and further promote journal club format discussion.

Social Media for Hematopathologists: Medical Practice Reinvented-#Hemepath.

PURPOSE OF REVIEW: Social media engagement by medical professionals with varied background subspecialties has steadily gained popularity in recent years. As a heavily visual discipline, pathology has been able to leverage social media platforms for trainee education, curbside and official consultations, interdisciplinary communication, and interactions among medical professionals and patient education. The pathology community has been at the forefront of using social media as an educational forum, and the hematopathology community has emerged as one of the strongest and most influential presences on these online platforms. In this review, we perform an in-depth analysis of various Twitter metrics to demonstrate key trends in the usage of social media as it pertains to hematopathology using the hashtag #Hemepath and we describe specific details on how hematopathologists have managed to take advantage of Twitter in furthering our mission of advancing medical education and disseminating knowledge using these innovative virtual educational experiences. RECENT FINDINGS: The hematopathology community has a great degree of enthusiasm among residents, fellows, and faculty in sharing educational material using case-based examples, participating in group-based online activities, introducing new publications by article authors or readership, and disseminating educational "pearls" from medical conferences, using hashtags and digital images that otherwise would not be readily available to many around the globe. This practice is helping reshape the structure of our field and is providing opportunities to optimize the educational experience by enhancing the instant exposure to cutting-edge information and expert opinions, among other valuable features. The hematopathology community has leveraged social media platforms for disseminating educational material and strengthening interdisciplinary interactions and is a "poster child" for a medical subspecialty that has thrived and flourished by more broadly adopting virtual educational platforms. We hope that this review will provide details on how social media platforms can be used by others in the medical field to achieve similar goals.

The Stem Cell-associated Transcription Factor SOX2 as a Diagnostic Marker of High-grade Squamous Intraepithelial Lesion of the Uterine Cervix in Comparison With p16 and Ki-67.

The transcription factor SOX2 has been identified as an oncogene involved in the pathogenesis of squamous cell carcinoma (SCC) of multiple sites, including the uterine cervix. The relationship between SOX2 overexpression and the continuum of precancerous lesions of the cervix has not been previously elucidated. We evaluated SOX2 immunohistochemical expression in normal cervix, low-grade squamous intraepithelial lesion (LSIL) (mild squamous dysplasia), high-grade squamous intraepithelial lesion (HSIL) (moderate and severe dysplasia) and SCC of the cervix in comparison with p16 and Ki-67. Staining patterns were scored as negative, basal one third of the epithelium, lower two third, or full thickness. The results showed that SOX2 expression was limited to the basal one third in 84% of LSIL cases, whereas 95% of HSIL showed SOX2 expression up to two third or full thickness (P<0.0001). p16 and Ki-67 displayed similar results. The difference in SOX2 expression between moderate and severe dysplasia was not statistically significant (P=0.53). Invasive SCC positivity was as follows: SOX2 94%; p16 89%; and Ki-67 100%. Our findings support a role for SOX2 in the progression of squamous dysplasia to SCC. The Lower Anogenital Standardization Terminology Project's recent assertion of a lack of a biological correlate to cervical intraepithelial neoplasia II is also upheld by SOX2. For equivocal situations in which a diagnosis of cervical intraepithelial neoplasia II would have been made, Lower Anogenital Standardization Terminology recommends p16, or other biomarkers such as Ki-67 to clarify the diagnosis. SOX2, with a clean nuclear staining pattern, may also be suitable for this role.

Routine C4d immunohistochemistry in cardiac allografts: Long-term outcomes.

BACKGROUND: In the past decade, C4d has emerged as a potential marker for antibody-mediated rejection (AMR); however, evidence on its use as a prognostic tool has been controversial. Although the International Society for Heart and Lung Transplantation guideline recommends early routine surveillance of C4d in heart transplantation, there is no consensus on its value in the pathologic assessment of AMR. Herein we present a correlation analysis of C4d immunoreactivity in endomyocardial biopsies with clinical cardiac dysfunction, cellular rejection, human leukocyte antigen (HLA) status, cardiac allograft vasculopathy (CAV) and death. METHODS: A total of 5,840 endomyocardial biopsies from 296 heart transplant recipients (January 2004 to December 2014) were stained prospectively for C4d. Strong, diffuse endothelial staining was considered positive. All patients had at least 1 year of follow-up. Positive C4d staining was present in 53 biopsies from 28 patients. Sixteen of 28 patients had clinically significant cardiac dysfunction at the time of positive biopsy. In C4d-positive patients, the mean panel-reactive antibody (PRA) level was 33%. Ten patients demonstrated a first C4d positivity within the first year post-transplant, whereas 18 patients had C4d positivity after 1 year post-transplant. At autopsy, all 11 C4d-positive patients examined demonstrated cardiac allograft vasculopathy (CAV) as the underlying cause of death. In contrast, only 2 of 8 (25%) C4d-negative patients had CAV at autopsy. In the surviving cohort, there was an angiographic diagnosis of higher-than-moderate CAV in 10 patients (3.8%). RESULTS: C4d-positive patients contributed to 67% of the overall institutional mortality in heart transplant recipients. Late C4d positivity (>1 year post-transplant) demonstrated an even higher risk for developing CAV and poor prognosis than early C4d positivity (within 1 year). In the C4d-negative group with postmortem examination, 75% (6 of 8) deaths were due to non-cardiac causes. CONCLUSIONS: Our findings show a positive association of C4d with CAV and death. We identified a prognostic role for C4d in heart transplantation warranting routine long-term detection of this marker in the pathologic evaluation of cardiac AMR.

Radical Nephrectomy for Renal Cell Carcinoma: Its Contemporary Role Related to Histologic Type, Tumor Size, and Nodal Status: A Retrospective Study.

OBJECTIVES: Staging for renal cell carcinoma (RCC) depends on tumor size and the status of the regional lymph nodes. Although lymph node involvement by tumor yields the most accurate staging and prognostic information in patients with carcinomas of various genitourinary organs, the role of lymph node sampling (LNS) in patients with RCC to definitively establish nodal metastases remains unsettled. METHODS: In this retrospective study of 399 patients with RCC treated by total nephrectomy, 115 cases were subjected to lymph node dissection. RESULTS: The corresponding primary tumors averaged larger than 8 cm. Twenty-nine showed positive lymph nodes (25%). The present review confirms that primary tumor size is a key indicator of nodal involvement. Clear cell and papillary tumors larger than 4 cm involve lymph nodes more commonly than other types of RCC. Sarcomatoid differentiation occurred in all major cell types and existed in numbers too few to predict the likelihood of nodal metastases. CONCLUSIONS: LNS in RCC for staging purposes may be warranted based on tumor size (>4 cm) as determined by imaging as well as histologic cell type, the latter suggesting a selective role for preoperative fine needle aspiration or core biopsy.