Emerging molecular subtypes and therapies in acute lymphoblastic leukemia.

Tremendous strides have been made in the molecular and cytogenetic classification of acute lymphoblastic leukemia based on gene expression profiling data, leading to an expansion of entities in the recent International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias and 2022 WHO Classification of Tumours: Haematolymphoid Tumors, 5th edition. This increased diagnostic and therapeutic complexity can be overwhelming, and this review compares nomenclature differences between the ICC and WHO 5th edition publications, compiles key features of each entity, and provides a diagnostic algorithmic approach. In covering B-lymphoblastic leukemia (B-ALL), we divided the entities into established (those present in the revised 4th edition WHO) and novel (those added to either the ICC or WHO 5th edition) groups. The established B-ALL entities include B-ALL with BCR::ABL1 fusion, BCR::ABL1-like features, KMT2A rearrangement, ETV6::RUNX1 rearrangement, high hyperdiploidy, hypodiploidy (focusing on near haploid and low hypodiploid), IGH::IL3 rearrangement, TCF3::PBX1 rearrangement, and iAMP21. The novel B-ALL entities include B-ALL with MYC rearrangement; DUX4 rearrangement; MEF2D rearrangement; ZNF384 or ZNF362 rearrangement, NUTM1 rearrangement; HLF rearrangement; UBTF::ATXN7L3/PAN3,CDX2; mutated IKZF1 N159Y; mutated PAX5 P80R; ETV6::RUNX1-like features; PAX5 alteration; mutated ZEB2 (p.H1038R)/IGH::CEBPE; ZNF384 rearranged-like; KMT2A-rearranged-like; and CRLF2 rearrangement (non-Ph-like). Classification of T-ALL is complex with some variability in how the subtypes are defined in recent literature. It was classified as early T-precursor lymphoblastic leukemia/lymphoma and T-ALL, NOS in the WHO revised 4th edition and WHO 5th edition. The ICC added an entity into early T-cell precursor ALL, BCL11B-activated, and also added provisional entities subclassified based on transcription factor families that are aberrantly activated.

Molecular Pathology of Mature Lymphoid Malignancies.

Lymphoid malignancies are a broad and heterogeneous group of neoplasms. In the past decade, the genetic landscape of these tumors has been explored and cataloged in fine detail offering a glimpse into the mechanisms of lymphomagenesis and new opportunities to translate these findings into patient management. A myriad of studies have demonstrated both distinctive and overlapping molecular and chromosomal abnormalities that have influenced the diagnosis and classification of lymphoma, disease prognosis, and treatment selection.

Comparison of Cervical Cancer Screen Results on Female-to-Male Transgender Patients With Female Patients.

OBJECTIVES: There are limited data on cervical screen results from female-to-male (FTM) transgender patients. Herein, we compiled demographic information and cervical screen testing on FTM transgender patients and compared with age-appropriate controls. METHODS: A search of our previous and current databases was performed for Papanicolaou (Pap) tests from patients taking testosterone and/or with a diagnosis of gender dysphoria, transsexualism, or transvestism. Patient data were reviewed. Relative risks of abnormal Pap smear and human papillomavirus (HPV) infection were calculated against age-matched controls. RESULTS: Eighty-nine Pap tests from FTM transgender individuals were identified, with a mean age of 31.3 years (range, 21-60 years). The Pap test diagnoses were distributed as follows: negative for intraepithelial lesion (n = 84, 94.4%), atypical squamous cells of undetermined significance (n = 0), low-grade intraepithelial lesion (n = 4, 4.5%), and high-grade squamous intraepithelial lesion (n = 1, 1.1%). Fifty (56.2%) patients had concurrent high-risk HPV testing with four (8%) positive results. Relative risk was 0.625 (95% confidence interval [CI], 0.25-1.59; P = .32) for an abnormal Pap test and 0.55 (95% CI, 0.19-1.52; P = .24) for HPV compared with 267 age-matched controls. Of note, 13.5% of patients older than 21 years had documentation of never having a prior Pap test in our medical record. CONCLUSIONS: In our study, FTM transgender individuals were not at a higher or lower risk of HPV infection or abnormal Pap test result compared with women. However, larger studies are needed to support our findings.

Risk Assessment of Human Papillomavirus-Positive Cytology-Negative Cervical Cancer Screening in Black and White Women.

OBJECTIVES: As we move toward human papillomavirus (HPV) only as the preferred cervical cancer screening method, we performed a retrospective analysis of Black and White women with negative cytology (Papanicolaou negative [PAPneg]) and positive high-risk HPV (hrHPV) (HPVpos) results and determined follow-up. METHODS: We searched our pathology data system for patients with PAPneg/HPVpos results (2017-2019). Follow-up data were reviewed (39 months), and a comparison among race was performed. RESULTS: In total, 1,728 patients were identified (Black, 53%; White, 47%). Twenty-nine percent of the patients had no follow-up with no difference among the races. HPV 16 was more common among Whites (P < .01), while non-16/18 hrHPV was more common among Black patients (P = .01). A total of 30 (3.3%) Black and 26 (3.2%) White patients were diagnosed with cervical intraepithelial neoplasia grade 2/3 (CIN 2/3). More White women were diagnosed on biopsy alone (negative endocervical curettage) compared with Black women (20 vs 9, P < .01). Meanwhile, there were 21 Black and 6 White women with CIN 2/3 on endocervical curettage (P = .01). CONCLUSIONS: Follow-up of women with PAPneg/HPVpos remains a challenge. There was no disparity in follow-up when cohorts were compared. However, Black women had higher numbers of high-grade intraepithelial lesions on endocervical curettage.

Ancillary studies on cell blocks from fine needle aspiration specimens of salivary gland lesions: A multi-institutional study.

BACKGROUND: Ancillary studies are commonly performed on cell blocks prepared from fine-needle aspiration (FNA) specimens. There are limited studies in application of ancillary studies on cell blocks from salivary gland (SG) FNAs. This multi-institutional study evaluates the role of ancillary studies performed on cell blocks in the diagnosis of SG lesions, and their impact on clinical management. METHOD: The electronic pathology archives of three large academic institutions were searched for SG FNAs with ancillary studies performed on cell blocks. The patient demographics, FNA site, cytologic diagnosis, ancillary studies, and surgical follow-up were recorded. If needed, the cytologic diagnoses were reclassified as per the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC). RESULTS: 117 SG FNA cases were identified including 3, 10, 11, 6, 23, 4, and 60 cases in MSRSGC categories I, II, III, IVa, IVb, V, VI, respectively with surgical follow-up available ranging from 27% to 100% within each category. Ancillary studies including histochemistry, immunocytochemistry (IHC), and in situ hybridization (ISH) were beneficial in 60%-100% of cases in each category. Risk of malignancy was 100% in both the suspicious for malignancy (V) and malignant (VI) categories. Ancillary studies improved diagnosis in 60% of non-neoplastic cases (II, 6/10), 100% of benign neoplasm cases (IVa, 6/6), and 98.3% of malignant cases (VI, 59/60). CONCLUSION: Judicious and case-based ancillary studies performed on SG FNA cell blocks with sufficient material can improve the diagnostic yield by further characterization of the atypical/neoplastic cells, particularly in MSRSGC categories IVa-VI.

COVID-19 pandemic impact on cytopathology practice in the post-lockdown period: An international, multicenter study.

BACKGROUND: In a previous worldwide survey, the authors showed a drastic reduction in the number of cytological specimens processed during the coronavirus disease 2019 "lockdown" period along with an increase in malignancy rates. To assess the continued impact of the pandemic on cytological practices around the world, they undertook a second follow-up worldwide survey collecting data from the post-lockdown period (2020). METHODS: Participants were asked to provide data regarding their cytopathology activity during the first 12 weeks of their respective national post-lockdown period (2020), which ranged from April 4 to October 31. Differences between the post-lockdown period and the corresponding 2019 period were evaluated, and the authors specifically focused on rates of malignant diagnoses. RESULTS: A total of 29 respondents from 17 countries worldwide joined the survey. Overall, a lower number of cytological specimens (n = 236,352) were processed in comparison with the same period in 2019 (n = 321,466) for a relative reduction of 26.5%. The overall malignancy rate showed a statistically significant increase (12,442 [5.26%] vs 12,882 [4.01%]; P < .001) during the same time period. Similar results were obtained if both malignancy and suspicious for malignancy rates were considered together (15,759 [6.58%] vs 16,011 [4.98%]; P < .001). CONCLUSIONS: The data showed a persistent reduction in the cytological specimen volume during the post-lockdown period (2020). However, the relative increase in the cytological workload in the late part of the post-lockdown is a promising finding of a slow return to normality.

Molecular Pathology of Mature Lymphoid Malignancies.

Lymphoid malignancies are a broad and heterogeneous group of neoplasms. In the past decade, the genetic landscape of these tumors has been explored and cataloged in fine detail offering a glimpse into the mechanisms of lymphomagenesis and new opportunities to translate these findings into patient management. A myriad of studies have demonstrated both distinctive and overlapping molecular and chromosomal abnormalities that have influenced the diagnosis and classification of lymphoma, disease prognosis, and treatment selection.

Continuing Undergraduate Pathology Medical Education in the Coronavirus Disease 2019 (COVID-19) Global Pandemic: The Johns Hopkins Virtual Surgical Pathology Clinical Elective.

CONTEXT.­: In the early months of the response to the coronavirus disease 2019 (COVID-19) pandemic, the Johns Hopkins University School of Medicine (JHUSOM) (Baltimore, Maryland) leadership reached out to faculty to develop and implement virtual clinical clerkships after all in-person medical student clinical experiences were suspended. OBJECTIVE.­: To develop and implement a digital slide-based virtual surgical pathology (VSP) clinical elective to meet the demand for meaningful and robust virtual clinical electives in response to the temporary suspension of in-person clinical rotations at JHUSOM. DESIGN.­: The VSP elective was modeled after the in-person surgical pathology elective to include virtual previewing and sign-out with standardized cases supplemented by synchronous and asynchronous pathology educational content. RESULTS.­: Validation of existing Web communications technology and slide-scanning systems was performed by feasibility testing. Curriculum development included drafting of course objectives and syllabus, Blackboard course site design, electronic-lecture creation, communications with JHUSOM leadership, scheduling, and slide curation. Subjectively, the weekly schedule averaged 35 to 40 hours of asynchronous, synchronous, and independent content, approximately 10 to 11 hours of which were synchronous. As of February 2021, VSP has hosted 35 JHUSOM and 8 non-JHUSOM students, who have provided positive subjective and objective course feedback. CONCLUSIONS.­: The Johns Hopkins VSP elective provided meaningful clinical experience to 43 students in a time of immense online education need. Added benefits of implementing VSP included increased medical student exposure to pathology as a medical specialty and demonstration of how digital slides have the potential to improve standardization of the pathology clerkship curriculum.

Nicotinamide phosphoribosyltransferase expression and clinical outcome of resected stage I/II pancreatic ductal adenocarcinoma.

BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT) plays a key role in the biosynthesis of nicotinamide adenine dinucleotide (NAD+), which is a vital cofactor in redox reactions and a substrate for NAD+ consuming enzymes including CD38, PARPs and sirtuins. NAMPT over-expression has been shown in various cancers and its inhibition decreases cancer cell growth, making it an attractive therapeutic target. Here we examine the NAMPT expression in a large cohort of resected stage I/II pancreatic ductal adenocarcinomas (PDAs) and correlate its expression with clinical outcomes and pathologic features. METHODS: A retrospective review of patients with PDAs was conducted at a single institution. Tissue microarrays (TMAs) containing primary PDAs and their metastatic lymph nodes (mLNs) were constructed and stained for NAMPT expression. Each TMA core was evaluated for staining intensity of cancer cells (0 = no staining, 1+ = weak, 2+ = moderate, 3+ = strong) and a mean score was calculated for each case with at least two evaluable cores. NAMPT expression was correlated with clinicopathological variables using chi-squared or Fisher's exact test, and t-tests for categorical and continuous variables, respectively. Survival probabilities were estimated and plotted using the Kaplan-Meier method. Cox proportional hazards regression was used to assess the effects of NAMPT staining values on recurrence-free survival (RFS) and overall survival (OS). This study was conducted under an approved IRB protocol. RESULTS: 173 primary PDAs had at least 2 TMA cores with identifiable cancer cells. The mean IHC score was 0.55 (range: 0 to 2.33). The mean IHC score of mLNs was 0.39 (range: 0-2), which was not significantly different from their primary tumors (mean IHC score = 0.47, P = 0.38). Sixty-four percent (111/173) of PDAs were positive for NAMPT staining. Stage II tumors were more likely to be positive (68% of 151 vs 41% of 22; P = 0.01). Non-obese non-diabetic patients were more likely to have NAMPT+ tumors (43.7% vs. 27.9%, P = 0.04). While RFS and OS were not statistically different between NAMPT+ vs. NAMPT- PDAs, patients with NAMPT- tumors tended to have a longer median OS (26.0 vs. 20.4 months, P = 0.34). CONCLUSION: NAMPT expression was detected in 64% of stage I/II PDAs and up to 72% in non-obese non-diabetic patients. Frequency of NAMPT expression correlated with pathological stage, consistent with published literature regarding its role in cancer progression. While RFS and OS were not statistically significantly different, patients with NAMPT+ PDAs tended to have a shorter survival. Thus, NAMPT inhibition may prove beneficial in clinical trials.