A Brief Overview of the Molecular Landscape of Myelodysplastic Neoplasms.

Myelodysplastic neoplasm (MDS) is a heterogeneous group of clonal hematological disorders that originate from the hematopoietic and progenitor cells and present with cytopenias and morphologic dysplasia with a propensity to progress to bone marrow failure or acute myeloid leukemia (AML). Genetic evolution plays a critical role in the pathogenesis, progression, and clinical outcomes of MDS. This process involves the acquisition of genetic mutations in stem cells that confer a selective growth advantage, leading to clonal expansion and the eventual development of MDS. With the advent of next-generation sequencing (NGS) assays, an increasing number of molecular aberrations have been discovered in recent years. The knowledge of molecular events in MDS has led to an improved understanding of the disease process, including the evolution of the disease and prognosis, and has paved the way for targeted therapy. The 2022 World Health Organization (WHO) Classification and the International Consensus Classification (ICC) have incorporated the molecular signature into the classification system for MDS. In addition, specific germline mutations are associated with MDS development, especially in pediatrics and young adults. This article reviews the genetic abnormalities of MDS in adults with a brief review of germline predisposition syndromes.

Radiologic Features of Well-circumscribed Orbital Tumors With Histopathologic Correlation: A Multi-center Study.

PURPOSE: To delineate specific imaging characteristics of solitary fibrous tumors, schwannomas, cavernous venous malformations, and well-circumscribed orbital lymphoma. METHODS: Patients undergoing excisional biopsy of solitary fibrous tumor, schwannomas, cavernous venous malformations, or well-circumscribed orbital lymphoma with preoperative MRIs available for review were identified at 3 academic centers in the United States and Australia. An exploratory statistical analysis was performed to identify important radiologic features, which were subsequently included in a random forest model. Histopathologic correlates were evaluated in representative cases. RESULTS: A total of 91 cases were included with a mean age of 52.9 ± 17.2 years. Nearly all solitary fibrous tumors were located in the anterior or mid orbit (87.5%) and they more commonly demonstrated intralesional heterogeneity on T2-weighted imaging (45.5%) (p < 0.01). Compared with the other tumors, schwannomas tended to be intraconal (66.7%) and were often in the mid or posterior orbit (83.4%) (p < 0.01). Cavernous venous malformations characteristically demonstrated progressive contrast enhancement (93.9%; p < 0.01). Most lesions in all 4 groups were hypointense on T1-weighted imaging (80%-100%; p = 0.14) and only well-circumscribed orbital lymphoma tended to also be hypointense on T2 (81.8%) (p < 0.01). Finally, cases of lymphoma had significantly lower apparent diffusion coefficient ratios (0.9 ± 0.2) (p < 0.001), while the other 3 groups were not significantly different from one another (cavernous venous malformations: 1.8 ± 0.4; schwannomas: 1.8 ± 0.5; and solitary fibrous tumor: 1.6 ± 0.6) (p = 0.739). CONCLUSIONS: Key features that aid in the differentiation of these 4 tumors from one another include T2 intensity and homogeneity, early contrast-enhancement pattern, and ADC ratio.

This is Jeopardy! A flexible coverage-based schedule model to address wellness for pathology training programs.

Scheduling rotations for a pathology training program involves balancing educational requirements, service coverage, and paid time off (PTO). Absences can affect training as residents cross-cover, managing multiple services at once. Other specialties utilize a "Jeopardy" based system for covering absences. In this system, residents on outpatient services are "jeopardized" to cover inpatient services for trainee absences. Borrowing this concept, we created a schedule model with a "Jeopardy-Elective" (JE) rotation to support resident absences. Prior to 2018-19, our residency program consisted of a 12 month-long rotation schedule. We adopted a 13 four-week block rotation model system, adding four JE rotations per resident over the course of training. The JE resident covered services during trainee absences and spent the remaining rotation on elective. We then conducted a pre- and post-intervention survey of all residents who trained in both systems. Following the change in schedule model, our results showed a statistically significant increase in resident satisfaction with taking PTO (p = 0.0014), finding coverage (p = 0.0006), and taking a sick day (p = 0.03). The mean number of days covered by the JE resident was 8.5 ± 2.7 workdays (out of 20). PTO usage increased from 16 to 20 days/resident while mean number of sick days decreased from 1.7 to 1.3 days per resident. There was overwhelming support with 82% of residents wanting to retain the new system going forward. Through use of the JE rotation, our program improved service coverage issues and resident satisfaction, with the long-term goal of enhanced resident well-being and enriched resident learning experiences.

Profiling endogenous, environmental, and infectious disease mutational signatures in blastic plasmacytoid dendritic cell neoplasms.

BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematopoietic disease derived from plasmacytoid dendritic lineage cells. The disease typically shows skin as well as frequent bone marrow and peripheral blood involvement. However, the pathogenesis of this disease is still not well understood. While somatic point mutations and genetic rearrangements have been described in BPDCN, the types and origins of these mutations and relationships to other cancer types is not well understood. MATERIALS AND METHODS: To probe the origins of BPDCN, we analyzed the exome sequence data of 9 tumor-normal pair cases of BPDCN. We utilized SignatureAnalyzer, SigProfiler and a custom microbial analysis pipeline to understand the relevance of endogenous and environmental mutagenic processes. RESULTS: Our results identified a significant tobacco exposure and aging genetic signature as well as signatures related to nucleotide excision repair deficiency, ultra violet (UV) exposure, and endogenous deamination in BPDCN. We also assessed the samples for microbial infectious disease organisms but did not find a link to a microbial etiology. CONCLUSION: The identification of a tobacco exposure and aging genetic signature in patients with BPDCN suggests that environmental and endogenous genetic changes may be central to the oncogenesis of BPDCN.

Isolated Asymptomatic Colonic Plasmacytoma Presenting as a Polyp at Screening Colonoscopy.

Isolated extramedullary plasmacytomas (IEMPs) are rare. Extramedullary plasmacytomas (EMPs) are uncommon and mostly occur in the nasopharynx or upper respiratory tract. EMP involvement of the gastrointestinal tract occurs in approximately 10% of cases, more often in the small bowel than the colon. Less than 40 cases of colonic IEMP have been reported. Asymptomatic colonic IEMPs are extremely rare with few reported cases. We present a 57-year-old asymptomatic man with a colonic IEMP found during screening colonoscopy. A sigmoid colon polyp was removed and diagnosed as a plasmacytoma. Further investigation revealed it to be an isolated lesion.

Orbital Involvement in Acute Adult Leukemias: Case Series and Review of Literature.

Orbital involvement in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) is well-described in children but is uncommon in adults. This series reports 2 adult patients with orbital leukemic involvement and summarizes the existing literature. A 37-year-old male with recently diagnosed AML underwent induction therapy and subsequently developed a tan-pink colored sub-conjunctival lesion in the left eye. Incisional biopsy confirmed AML. A 35-year-old male with history of ALL presented with left-sided orbital mass. Fine needle aspiration biopsy confirmed ALL. Literature review of adult-onset orbital leukemia yielded 29 cases of AML and 3 cases of ALL. Orbital involvement of acute adult-onset leukemia tends to be unilateral, presents in the extraconal space and can occur at any point during systemic leukemic disease. Chemotherapy is the mainstay of treatment, often in combination with radiation and/or hematopoietic stem cell transplant.

An Analysis of the Pathologic Features of Blastic Plasmacytoid Dendritic Cell Neoplasm Based on a Comprehensive Literature Database of Cases.

CONTEXT.­: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcome. BPDCN diagnostically overlaps with entities such as acute myeloid leukemia, histiocytic/dendritic cell neoplasms, and natural killer/T-cell lymphomas. Unfortunately, large, patient-centered studies that comprehensively analyze clinical, pathologic, and other diagnostic features are lacking. As such, there is an incomplete understanding of this disease. OBJECTIVE.­: To better characterize BPDCN, a multicenter working group consisting of hematopathologists and dermatopathologists gathered in person and remotely to review the current understanding of BPDCN, discuss specific issues regarding the diagnosis and differential diagnosis, and perform a retrospective analysis of the literature. DATA SOURCES.­: The working group curated a database of published BPDCN patient cases (BPDCN Network literature database), and following careful discussion and review, 361 articles were identified, comprising a total of 1513 individually annotated patients. CONCLUSIONS.­: By conducting an in-depth analysis, not only did we confirm known findings such as frequent skin involvement (84% of patients; 861 of 1028) and a male predominance among older patients (>60 years old; male to female ratio of 3.5:1; 617:177), but we also identified a number of underrecognized features, such as significant central nervous system involvement (38% of cases; 24 of 64), and a more equal male to female prevalence among patients younger than 40 years (male to female ratio of 1.25:1; 167:134). Furthermore, we were able to accurately summarize the immunophenotypic, cytogenetic, and molecular features of this disease. BPDCN is a complex disease with distinct morphologic, immunophenotypic, and molecular findings. Continual updates of the literature database generated here and further analysis can allow for prospective refinement of our understanding of this orphan disease.

Comparison of laboratory methods for the detection of neoplastic plasma cells in plasma cell dyscrasias.

AIMS: To compare the ability of immunohistochemistry (IHC), multiparameter flow cytometry (MFC) and fluorescence in situ hybridisation (FISH) to detect clonal plasma cells. We also attempted to outline a testing strategy for monitoring multiple myeloma patients. METHODS: A retrospective review was performed on 278 CD138+sorted FISH studies from November 2019 to December 2020 along with their concurrent IHC and MFC results. A p value was computed using McNemar's test for paired data. Association was calculated using the non-parametric Spearman correlation coefficient. RESULTS: Using the Mc Nemar's test for paired data, CD138+sorted FISH studies achieved the highest proportion of positive results and was significantly greater than MFC (63% vs 53%, p=0.01). FISH had more positive results than IHC, although this did not reach statistical significance (60% vs 57%, p=0.34). IHC and MFC had high correlation and high agreement (90.3% agreement, kappa=0.805, p<0.0001). CD138+sorted FISH studies achieved the highest proportion of positive results relative to IHC and MFC, indicating that it may be a reliable marker for clonal plasma cell detection. CONCLUSIONS: While CD138+sorted FISH is primarily used for prognostication, it may be employed as a single test for detection and monitoring clonality in certain scenarios. Further studies are needed to monitor the outcomes of patients with positive FISH and negative IHC and MFC. Additionally, there was high agreement between IHC and MFC, suggesting that performing both tests may not be necessary.

Concordance of Peripheral Blood and Bone Marrow Next-Generation Sequencing in Hematologic Neoplasms.

Objective: Mutational analysis by next-generation sequencing (NGS) obtained by peripheral blood NGS has been of clinical interest to use as a minimally invasive screening tool. Our study evaluates the correlation between NGS results on peripheral blood and bone marrow in hematolymphoid disease. Method: We evaluated patients who had NGS for presumed hematologic malignancy performed on peripheral blood and bone marrow within a 1-year interval of each other. We excluded cases in which chemotherapy or bone marrow transplant occurred in the interval between the two tests. The concordance across peripheral blood and bone marrow NGS results was assessed by kappa coefficient analysis. Results: A total of 163 patients were studied. Concordance of peripheral blood and bone marrow NGS found in 150 patients (92.0%) with a kappa coefficient of 0.794 (kappa standard error 0.054) and P value for testing kappa <0.0001. Myeloid neoplasms showed concordant results in 77/78 cases (98.7%) with a kappa coefficient of 0.916. Lymphoid neoplasms showed concordant results in 26/31 cases (83.9%) with a kappa coefficient of 0.599. Nonneoplastic cases showed concordant results in 47/54 cases (87.0%) with a kappa coefficient of 0.743. Conclusion: Peripheral blood NGS is a reliable tool for mutational analysis and provides a less invasive method for screening and monitoring of the molecular profile.

NCCN Guidelines® Insights: Hodgkin Lymphoma, Version 2.2022.

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte-predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

Ocular Toxoplasmosis: No Stranger to the Masquerade Ball.

Purpose: This article illustrates multiple atypical manifestations of ocular toxoplasmosis masquerading as acute retinal necrosis and vitreoretinal lymphoma. Methods: Two case presentations are discussed, and the body of pertinent literature is reviewed and discussed. Results: In these cases, an extensive workup and attention to history lead to the correct diagnosis and management. Conclusions: Aggressive cases of ocular toxoplasmosis may present in a variety of phenotypes that may mimic other vision- and potentially life-threatening conditions, particularly in a milieu of inadequate endogenous and exogenous antimicrobial defenses.

Solitary Extramedullary Plasmacytoma of the Lacrimal Sac With Associated Crystal-Storing Histiocytosis.

PURPOSE: To report a rare case of crystal-storing histiocytosis associated with solitary extramedullary plasmacytoma of the lacrimal sac and to review literature on the 2 entities to summarize important diagnostic, management, and prognostic considerations. METHODS: A case report of the ophthalmologic presentation, pathology workup, and oncologic management is presented. Literature search with focus on lesions occurring in ophthalmic sites and management guidelines from expert panels and working groups. RESULTS: Crystal-storing histiocytosis associated with solitary extramedullary plasmacytoma arose within the lacrimal sac of a previously healthy middle-aged woman and presented as a painless nodule with epiphora. The biopsy tissue showed sheets of crystal-filled histiocytes, interspersed with monoclonal plasma cells and rarely demonstrated plasma cell phagocytosis. Imaging and laboratory studies confirmed the localized nature. CONCLUSIONS: Crystal-storing histiocytosis is an uncommon entity in which crystals, most commonly arising from altered immunoglobulins, aggregate within histiocytes and form symptomatic mass lesions. It has been reported in ophthalmic regions in patients with a concurrent lymphoproliferative or plasma cell disorder and can rarely predate a malignancy. The current case is notable because crystal-storing histiocytosis occurs with a localized process, solitary extramedullary plasmacytoma, and presents in an unusual site, the lacrimal sac. Tissue biopsy with multimodal pathological evaluation is necessary to make the diagnosis. Ophthalmologists should recognize that crystal-storing histiocytosis is commonly associated with a hematologic malignancy and, when appropriate, refer the patient for oncologic management. Surveillance may be indicated in cases with no established etiology. Solitary extramedullary plasmacytoma should also be monitored, as a proportion of cases progress to multiple myeloma.

Educational cost-effective intervention to reduce pathologist's peripheral blood smears reviews with non-contributory findings: an academic institution experience.

Peripheral blood smear (PBS) review by a pathologist is a necessary and invaluable diagnostic tool. However, innovative highly sophisticated haematology analysers that flag peripheral blood abnormalities have decreased the need for a PBS review. Ordering practices including PBS reviews lumped as part of an 'order set' or with complete blood count (CBC) constituted most PBS requests at our institution. A retrospective review of all PBS review orders from 1 April 2016 to 31 January 2017 was performed to investigate the ordering practices at our institution. A total of 2864 PBS were ordered during the above study period. In many cases, the PBS report did not add any significant clinical information beyond that acquired by the CBC and differential count. These findings inspired policy changes within our institution for pathologist PBS reviews. Within the electronic order system, all PBS orders for inpatients were linked to a pop-up window with criteria for peripheral smear review and instructions on the approval policy. Outpatient orders required clinicians to request pathology approval. This implementation reduced total number of PBS orders by 42.5% with no adverse effect on patient management. Empowering pathologists and clinicians with guidelines on PBS review orders is a beneficial educational exercise of resource utilisation. Discussion with physicians regarding clinical indications reduces non-contributory PBS reviews, provides guidance to appropriate testing, and aptly allocates pathologist and laboratory staff time and resources.

Systemic Mastocytosis: Advances in Diagnosis and Current Management.

Mastocytosis is a rare hematologic disorder characterized by abnormal proliferation and accumulation of neoplastic mast cells in various body sites. Isolated skin involvement is termed cutaneous mastocytosis (CM) and the term systemic mastocytosis (SM) refers to multi-organ involvement, most commonly of the bone marrow, skin, liver, and spleen. A subset of patients with SM have an associated clonal hematologic neoplasm which is most commonly myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myelogenous leukemia and this entity is termed SM with associated hematological neoplasm (AHN). Bone marrow involvement is present in all patients regardless of the subtype of SM. The genetic hallmark of SM is a somatic gain-of-function point mutation within the KIT gene. Other molecular aberrations that have been reported include somatic mutations in TET2, SRSF2, ASXL1, CBL, RUNX1, and RAS and these are common in SM-AHN. The clinical presentation of SM can range from indolent to advanced depending on extent of mast cell burden and genetic profile. In the case of indolent SM, the goal of treatment is to control mediator release-related effects as well as to reduce mast cell burden. In the case of SM-AHN, therapy is primarily that of the AHN and allogeneic hematopoietic stem cell transplantation is the preferred therapy in suitable candidates.

Secondary cytogenetic abnormalities in core-binding factor AML harboring inv(16) vs t(8;21).

Patients with core-binding factor (CBF) acute myeloid leukemia (AML), caused by either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), have higher complete remission rates and longer survival than patients with other subtypes of AML. However, ∼40% of patients relapse, and the literature suggests that patients with inv(16) fare differently from those with t(8;21). We retrospectively analyzed 537 patients with CBF-AML, focusing on additional cytogenetic aberrations to examine their impact on clinical outcomes. Trisomies of chromosomes 8, 21, or 22 were significantly more common in patients with inv(16)/t(16;16): 16% vs 7%, 6% vs 0%, and 17% vs 0%, respectively. In contrast, del(9q) and loss of a sex chromosome were more frequent in patients with t(8;21): 15% vs 0.4% for del(9q), 37% vs 0% for loss of X in females, and 44% vs 5% for loss of Y in males. Hyperdiploidy was more frequent in patients with inv(16) (25% vs 9%, whereas hypodiploidy was more frequent in patients with t(8;21) (37% vs 3%. In multivariable analyses (adjusted for age, white blood counts at diagnosis, and KIT mutation status), trisomy 8 was associated with improved overall survival (OS) in inv(16), whereas the presence of other chromosomal abnormalities (not trisomy 8) was associated with decreased OS. In patients with t(8;21), hypodiploidy was associated with improved disease-free survival; hyperdiploidy and del(9q) were associated with improved OS. KIT mutation (either positive or not tested, compared with negative) conferred poor prognoses in univariate analysis only in patients with t(8;21).

Core-binding factor acute myeloid leukemia with t(8;21): Risk factors and a novel scoring system (I-CBFit).

BACKGROUND: Although the prognosis of core-binding factor (CBF) acute myeloid leukemia (AML) is better than other subtypes of AML, 30% of patients still relapse and may require allogeneic hematopoietic cell transplantation (alloHCT). However, there is no validated widely accepted scoring system to predict patient subsets with higher risk of relapse. METHODS: Eleven centers in the US and Europe evaluated 247 patients with t(8;21)(q22;q22). RESULTS: Complete remission (CR) rate was high (92.7%), yet relapse occurred in 27.1% of patients. A total of 24.7% of patients received alloHCT. The median disease-free (DFS) and overall (OS) survival were 20.8 and 31.2 months, respectively. Age, KIT D816V mutated (11.3%) or nontested (36.4%) compared with KIT D816V wild type (52.5%), high white blood cell counts (WBC), and pseudodiploidy compared with hyper- or hypodiploidy were included in a scoring system (named I-CBFit). DFS rate at 2 years was 76% for patients with a low-risk I-CBFit score compared with 36% for those with a high-risk I-CBFit score (P < 0.0001). Low- vs high-risk OS at 2 years was 89% vs 51% (P < 0.0001). CONCLUSIONS: I-CBFit composed of readily available risk factors can be useful to tailor the therapy of patients, especially for whom alloHCT is not need in CR1 (ie, patients with a low-risk I-CBFit score).

Use of CD42b immunohistochemical stain for the detection of Histoplasma.

In pathologic specimen, Histoplasma capsulatum can frequently be identified by morphology and special stains such as GMS and PAS. Incidentally, we noted unusual staining of the platelet associated marker CD42b/GP1b expressed on the surface of fungal organisms. Evaluation of additional cases demonstrated that a majority of histoplasmosis cases (15/18 cases; 83%) showed positive staining with CD42b/GP1b, comparable to GMS stain results. Other platelet associated markers such as Factor VIII and CD61 showed no or rare expression (1/18 cases with Factor VIII). Studies have shown that 14-3-3 proteins bind directly to cytoplasmic domain of CD42b/GP1b. Significant homology is seen between fungal and human 14-3-3 proteins which may represent a molecular basis for our observation. Our study demonstrated that CD42b/GP1b staining by immunohistochemistry can aid in detection of Histoplasma organisms. Further studies with organisms with similar morphologic features such as Blastomyces and Leishmania may demonstrate a diagnostic utility in speciating organisms.