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Microscopic review of tissue sections is of foundational importance in pathology, yet the traditional chemistry-based histology laboratory methods are labour intensive, tissue destructive, poorly scalable to the evolving needs of precision medicine and cause delays in patient diagnosis and treatment. Recent AI-based techniques offer promise in upending histology workflow; one such method developed by PictorLabs can generate near-instantaneous diagnostic images via a machine learning algorithm. Here, we demonstrate the utility of virtual staining in a blinded, wash-out controlled study of 16 cases of lymph node excisional biopsies, including a spectrum of diagnoses from reactive to lymphoma and compare the diagnostic performance of virtual and chemical H&Es across a range of stain quality, image quality, morphometric assessment and diagnostic interpretation parameters as well as proposed follow-up immunostains. Our results show non-inferior performance of virtual H&E stains across all parameters, including an improved stain quality pass rate (92% vs 79% for virtual vs chemical stains, respectively) and an equivalent rate of binary diagnostic concordance (90% vs 92%). More detailed adjudicated reviews of differential diagnoses and proposed IHC panels showed no major discordances. Virtual H&Es appear fit for purpose and non-inferior to chemical H&Es in diagnostic assessment of clinical lymph node samples, in a limited pilot study., Competing Interests: Competing interests: SA, RK and YR are employees of PictorLabs. The authors have no other conflicts of interest or disclosures to report., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background:  Circulating tumor cells and clusters (CTC) from soft-tissue sarcoma (STS) that become entrapped in the lung can form micro-metastases and lead to pulmonary metastatic disease. Many patients with localized high-risk STS later develop metastases. Radiation is effective at reducing local recurrence by eradicating microscopic infiltration and satellites in the reactive zone surrounding the primary tumor. Prophylactic lung irradiation for patients with high-risk STS is a novel concept to potentially reduce the appearance of macroscopic metastases and improve survival. A proof-of-principle study was performed based on a novel approach: prophylactic lung radiation after resection of the primary tumor to address microscopic pulmonary deposits from CTC., Methods:  Immunocompromised mice and luciferase-expressing human fibrosarcoma (HT-1080-Luc) cell lines were used. In phase 1, HT-1080-Luc cells were injected into the tail vein to simulate CTC for the development of pulmonary metastases. Whole-lung irradiation (WLI) was then performed in the treated mice prior to the appearance of macroscopic metastases. In phase 2, a flank tumor was established to simulate a primary STS, followed by a tail-vein injection of HT-1080-Luc cells. Treatment groups included surgical removal of the primary STS and hemithoracic irradiation (HTI). Body weight and bioluminescence data were obtained and the mice were euthanized on Day 31 (phase 1) and Day 15 (phase 2) or when they reached 20% weight loss., Results:  In phase 1, prophylactic WLI increased survival and decreased pulmonary metastases. In phase 2, prophylactic HTI (left lung) decreased pulmonary metastases compared to controls. Lung histology showed dramatically decreased growth and number of established metastases with HTI. Resection of the primary tumor did not affect the growth of metastases., Conclusion:  Prophylactic WLI after resection of the primary tumor to inhibit the growth of pulmonary metastases from previously entrapped CTCs may be a promising approach to improve survival for patients with localized high-risk STS., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Animal subjects: University of Maryland, Baltimore, Institutional Animal Care and Use Committee (IACUC) Issued protocol number 1021001. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Ruditsky et al.)

Competing Interests: Declarations. Ethical approval: For this type of study formal consent is not required. The Institutional Review Board (IRB) has approved this study. Informed consent: For this type of study, informed consent is not required. Consent for publication: For this type of study, consent for publication is not required. Conflict of interest: The authors declare that they have no conflict of interest.

Background The current management of large, high-grade soft tissue sarcoma (STS) of the trunk and extremities includes radiation and surgical resection. The initial use of chemotherapy and targeted therapy are controversial and although most patients present with localized disease, many eventually develop incurable metastases. The results and analysis of the safety and antitumor activity of combined checkpoint inhibitor immunotherapy with neoadjuvant radiation for high-risk primary STS are presented here. Methods This was an integrated phase I/II prospective single-arm trial (Nutrition and Exercise in Critical Illness Trial (NEXIS) trial). Eligible patients were age ≥18 years with histologically confirmed intermediate or high-grade STS of the trunk or extremity ≥5 cm diameter and were Eastern Cooperative Oncology Group performance status 0-1. The treatment algorithm included neoadjuvant anti-PD-L1 (Durvalumab) and anti-CTLA-4 (Tremelimumab) for three cycles of four weeks/cycle along with external beam radiation for five weeks, followed by wide surgical resection, and adjuvant Durvalumab monotherapy for four cycles. High-grade toxicity was continually assessed for the first 12 patients in phase I and the primary endpoint for phase II was an excellent histological response (grade 0 or 1 score on a semi-quantitative assessment for tumor regression). This study was registered with ClinicalTrials.gov, number NCT03116529. Findings Between October 2017 and November 2021, 23 patients were enrolled. Five patients had progression of distant disease during neoadjuvant treatment and withdrew from the study before surgery. A total of 18 patients who completed at least the neoadjuvant immunotherapy, radiation and surgery were included for analysis. The most common tumor was undifferentiated pleomorphic sarcoma (n=9, 50%). The occurrence of any adverse event (AE) was recorded in 16 (88.9%) patients, and 3 (16.7%) patients had a serious AE. Eight out of 18 patients (44.4%) had disease-free survival at a median of 39.7 months. Four out of 18 patients (22.2%) were alive-with-disease at a median of 37.1 months from diagnosis of distant metastasis, and six out of 18 (33.3%) died of disease at a median of 20.8 months from diagnosis of distant metastasis. Local recurrence occurred in two patients (11.1%) and was concomitant with distant disease in each case. Based on Response Evaluation Criteria in Solid Tumors v1.1, a partial response was noted in five (27.8%) cases, stable disease in 10 (55.6%) cases, and progressive disease in three (16.7%) cases. Histological semiquantitative analysis revealed a "good" response in eight (44.4%) patients, a "moderate" response in four (22.2%) patients, and a "poor" response in six (33.3%) patients. The mean patient-reported outcome measures regarding fatigue, physical function, or physical interference demonstrated no significant differences between various timepoints before, during, or after treatment. Conclusion Neoadjuvant combined immunotherapy and radiation for high-risk STS was relatively well-tolerated. The histological, radiologic, and clinical outcome data in this novel trial were relatively similar to historical literature for non-immunotherapy treatment regimens., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. University of Maryland issued approval #HM-HP-00073356-25. ClinicalTrials.gov #: NCT03116529 Eligible patients will be approached for their consent to participate. All subjects must first read, understand, and sign the IRB/REB/IEC-approved ICF before any study-specific screening procedures are performed. The subject’s clinician will be involved in the consent conversation. Patients will be informed of the study goals and data to be collected. Additionally, patients and their families will be provided with written information describing the study, the risks and benefits of participation and what will be expected of them if they choose to participate. The consent form will describe the purpose of the study, the procedures to be followed, and the risks and benefits of participation. Copies of the signed consent forms will be given to the patient, and this fact will be documented in the patient’s record. Due to the high-risk nature of this study, no proxy (LAR) consent will be obtained. Prior to initiating the consent process, the participant’s treating physician will confirm that the participant has the ability to understand the relevant study information and communicate and maintain a choice. If the physician determines that the patient lacks the capacity to consent, the patient will be declared ineligible. Recognizing that consent is an ongoing process, the study team will encourage the participants to ask additional questions that may arise during the course of their participation in the study. The research staff will endeavor to answer all questions posed by the patient and his/her family to ensure their understanding of the protocol at all times. A limited number of questions will be asked of all patients after they are introduced to the study and have reviewed the consent form. These questions assess the person’s understanding of the study and what it means to participate, their appreciation of the consequences of participation, and their ability to consider alternatives to participation. A formal comprehension test may be utilized, or comprehension will be assessed by the person(s) obtaining the consent. The patient’s physician will ask the questions and determine the appropriateness of the responses. The study will not include children or prisoners. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: This study was supported by funds through the Maryland Department of Health’s Cigarette Restitution Fund Program (CH-649-CRF) and the National Cancer Institute Cancer Center Support Grant (CCSG) P30CA134274. The immunotherapy drugs were provided by the manufacturer, AstraZeneca. . Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Ng et al.)

Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Although immune checkpoint blockade (ICB) is currently approved for the treatment of extensive-stage small-cell lung cancer (SCLC) in combination with chemotherapy, relatively few patients have demonstrated durable clinical benefit (DCB) to these therapies. Biomarkers predicting responses are needed. Biopsies from 35 SCLC patients treated with ICB were subjected to transcriptomic analysis; gene signatures were assessed for associations with responses. Twenty-one patients were treated with ICB in the first-line setting in combination with platinum-based chemotherapy; fourteen patients were treated in the second-line setting with ICB alone. DCB after ICB in SCLC in the second-line setting (3 of 14 patients) was associated with statistically higher transcriptomic levels of genes associated with inflammation ( p = 0.003), antigen presentation machinery ( p = 0.03), interferon responses ( p < 0.05), and increased CD8 T cells ( p = 0.02). In contrast, these gene signatures were not significantly different in the first-line setting. Our data suggest that responses to ICB in SCLC in the second-line setting can be predicted by the baseline inflammatory state of the tumor; however, this strong association with inflammation was not seen in the first-line setting. We postulate that chemotherapy alters the immune milieu allowing a response to ICB. Other biomarkers will be needed to predict responses in first-line therapy patients.

Background: Aggressive B cell lymphoma with secondary central nervous system (CNS) involvement (SCNSL) carries a dismal prognosis. Chimeric antigen receptor (CAR) T cells (CAR-T) targeting CD19 have revolutionized the treatment for B cell lymphomas; however, only single cases with CNS manifestations successfully treated with CD19 CAR-T have been reported., Methods: We prospectively enrolled 4 patients with SCNSL into our study to assess clinical responses and monitor T cell immunity., Results: Two of four SNCSL patients responded to the CD19-targeted CAR-T. Only one patient showed a substantial expansion of peripheral (PB) CAR-T cells with an almost 100-fold increase within the first week after CAR-T. The same patient also showed marked neurotoxicity and progression of the SNCSL despite continuous surface expression of CD19 on the lymphoma cells and an accumulation of CD4 + central memory-type CAR-T cells in the CNS. Our studies indicate that the local production of chemokine IP-10, possibly through its receptor CXCR3 expressed on our patient's CAR-T, could potentially have mediated the local accumulation of functionally suboptimal anti-tumor T cells., Conclusions: Our results demonstrate expansion and homing of CAR-T cells into the CNS in SNCSL patients. Local production of chemokines such as IP-10 may support CNS infiltration by CAR-T cells but also carry the potential of amplifying local toxicity. Future studies investigating numbers, phenotype, and function of CAR-T in the different body compartments of SNSCL patients receiving CAR-T will help to improve local delivery of "fit" and highly tumor-reactive CAR-T with low off-target reactivity into the CNS., (© 2024. The Author(s).)

The classification of haematological neoplasms recently underwent revision, generating two separate schemes-the International Consensus Classification and the fifth edition of the WHO classification. The new division into separate classification systems presents challenges for haematopathologists, haematologists/oncologists and patients. While it is too early to assess the full clinical impact, we sought to identify diagnostic discordance which may arise from applying separate classification schemes in myeloid neoplasia, and particularly in the challenging category of myelodysplastic syndrome/myeloproliferative neoplasms. A review of 64 such cases found 1 case with a significant discrepancy between the WHO and International Consensus Classification systems, and 9 cases with nominal discrepancies. Confusion from the use of conflicting diagnostic terms represents a potential source of patient harm, increased pathologist workload and burnout and erosion of clinician and patient trust., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Arthroplasty-related pseudotumors are nonneoplastic and noninfectious inflammatory masses that are typically associated with adverse reaction to metal debris. Pseudotumors most commonly occur in the setting of metal-on-metal joint replacements at the hip. However, the presentation of pseudotumor at the shoulder is exceedingly rare. In this article, we reported a case of arthroplasty-related pseudotumor of the scapula. Clinical history, radiologic signs, and tissue analysis are described. Knowledge of this rare diagnosis will support clinical decision making for teams of radiologists, pathologists, oncologists, and orthopaedic surgeons who provide care for patients presenting with suspicious shoulder masses., Competing Interests: Conflict of Interest None declared., (Indian Radiological Association. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication following kidney transplantation, and there is a critical and unmet need for PTLD treatments associated with more pronounced and durable responses. To date, reports on the use of CD19-targeted chimeric antigen receptor (CAR) T (CAR-T) cells in patients after solid organ transplant (SOT) have been anecdotal, clinical presentations and outcomes have been heterogenous, and a longitudinal analysis of CAR-T cell expansion and persistence in PTLD patients has not been reported. Our report describes a patient with a history of renal transplant who received CD19-directed CAR-T cell therapy for the treatment of refractory PTLD, diffuse large B cell lymphoma (DLBCL)-type. We show that even with the background of prolonged immunosuppression for SOT, it is possible to generate autologous CAR-T products capable of expansion and persistence in vivo, without evidence of excess T-cell exhaustion. Our data indicate that CAR-T cells generated from a SOT recipient with PTLD can yield deep remissions without increased toxicity or renal allograft dysfunction. Future clinical studies should build on these findings to investigate CAR-T therapy, including longitudinal monitoring of CAR-T phenotype and function, for PTLD in SOT recipients.

Calcified chondroid mesenchymal neoplasm is a term proposed for tumors with a spectrum of morphologic features, including cartilage/chondroid matrix formation, that frequently harbor FN1 gene fusions. We report a series of 33 cases of putative calcified chondroid mesenchymal neoplasms, mostly referred for expert consultation out of concern for malignancy. Patients included 17 males and 16 females, with a mean age of 51.3 years. Anatomic locations include the hands and fingers, feet and toes, head and neck, and temporomandibular joint; 1 patient presented with multifocal disease. Radiologic review showed soft tissue masses with variable internal calcification, which occasionally scalloped bone but in all cases appeared indolent/benign. Tumors had a mean gross size of 2.1 cm and a homogenous rubbery to fibrous/gritty tan-white cut surface. Histology demonstrated multinodular architecture with a prominent chondroid matrix and increased cellularity towards the periphery of the nodules. The tumor cells were polygonal with eccentric nuclei and bland cytologic features and showed a variable amount of increased spindled / fibroblastic forms in the perinodular septa. The majority of cases had notable grungy and/or lacy calcifications. A subset of cases demonstrated at least focal areas of increased cellularity and osteoclast-like giant cells. Herein, we confirm the distinct morphologic and clinicopathologic features associated with this entity with the largest series to date, with a focus on practical diagnostic separation from similar chondroid neoplasms. Awareness of these features is critical in avoiding pitfalls, including a malignant diagnosis of chondrosarcoma., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

New therapies for multiple myeloma have improved outcomes, but are associated with therapy-related hematologic malignancies. We report eight patients with therapy-related B-lymphoblastic leukemias (t-B-ALL) in the setting of therapy for multiple myeloma, which included lenalidomide maintenance. A subset of patients had pancytopenia and low-level marrow involvement by acute leukemia, an unusual finding in de novo B-ALL. One patient died of chemotherapy complications; the other seven responded. No patient died of B-ALL (median follow up of 1.0 years). Our series suggests that t-B-ALL is clonally unrelated to myeloma, presents with diverse cytogenetic abnormalities, and responds well to B-ALL therapy., Competing Interests: The authors have no conflicts of interest to disclose., (© 2022 The Author(s).)

Round cell sarcomas include a diverse group of bone and soft tissue tumors, which comprise well-defined entities as well as several nascent categories presented in the 2020 World Health Organization classification. The morphologic overlap yet disparate nosology, prognostic implications, and management strategies places a high value on ancillary testing, including a strategic immunohistochemical approach and directed confirmation by cytogenetic and molecular genetic methods. We review the diagnostic categories that have emerged from the former wastebasket "undifferentiated round cell sarcoma" ("Ewing-like" sarcomas), with an emphasis on algorithmic exclusion of nonsarcomatous entities, diagnostic stratification of well-defined entities (Ewing sarcoma, rhabdomyosarcomas, poorly differentiated synovial sarcoma), and a discussion of the new categories with novel genetic alterations (CIC-rearranged sarcomas, sarcomas with BCOR genetic alterations, and round cell sarcomas with EWSR1-non-ETS fusions)., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Rhabdomyosarcoma is the most common soft tissue sarcoma in children and adolescents. Embryonal rhabdomyosarcoma (ERMS), its most common subtype, is a malignant soft tissue tumor with morphologic and immunophenotypic features of embryonic skeletal muscle. The histologic findings in ERMS typically include a range of differentiation in rhabdomyoblasts from primitive to terminally differentiated forms, and the latter become more prominent after chemotherapy-induced cytodifferentiation. Several reports have shown therapy-related cytodifferentiation to portend a good prognosis in ERMS. We discuss the case of a pediatric patient who presented with ERMS of the orbit. Although her tumor showed extensive posttreatment cytodifferentiation and several other good prognostic clinicopathologic factors, it pursued an aggressive course, resulting in early metastasis and death. This case represents an unusual course and may be instructive as to the clinicopathologic features impacting prognostication, and ultimately the biology, of this aggressive family of tumors., Competing Interests: The authors have no financial relationships to disclose., (Copyright © 2021 Maniraj Jeyaraju et al.)

Purpose of Review: Rare malignancies developing from lymphocyte precursor cells, lymphoblastic leukemia (LBL), and acute lymphoblastic lymphoma (ALL) have historically been viewed as different manifestations of the same disease process. This review examines data on their epidemiology, genetics, clinical presentation, and response to treatment while highlighting areas of similarity and divergence between these two clinical entities., Recent Findings: Pediatric-type ALL chemotherapy regimens, compared to both lymphoma-type chemotherapy and adult-type ALL regimens, have led to improved outcomes for children, adolescents, and young adults with ALL. BCR-ABL-targeting tyrosine kinase inhibitors (TKIs) have improved outcomes in Philadelphia chromosome-positive (Ph +) ALL and in rare cases of Ph + LBL. Newer therapies including blinatumomab, inotuzumab, CAR-T therapy, and nelarabine have improved outcomes in selected cases of ALL and have an emerging role in the management of LBL. Better understanding of ALL and LBL biology allows for the development of therapies that target immunophenotypic or genetic features found in subsets of both diseases. Novel therapies are leading to improved outcomes in Ph + and relapsed and refractory disease., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The fifth edition of the World Health Organization Classification of Tumors of Soft Tissue and Bone was published in early 2020. The revisions reflect a consensus among an international expert editorial board composed of soft tissue and bone pathologists, geneticists, a medical oncologist, surgeon, and radiologist. The changes in the soft tissue tumor chapter notably include diverse, recently described tumor types (eg, atypical spindle cell/pleomorphic lipomatous tumor, angiofibroma of soft tissue, and CIC-rearranged sarcoma), new clinically significant prognostic information for a variety of existing entities (eg, dedifferentiated liposarcoma and solitary fibrous tumor), and a plethora of novel genetic alterations, some of practical diagnostic relevance (eg, NAB2-STAT6 in solitary fibrous tumor, FOSB rearrangements in epithelioid hemangioma and pseudomyogenic hemangioendothelioma, and SUZ12 or EED mutations in malignant peripheral nerve sheath tumor, leading to loss of H3K27 trimethylation). In this review, we highlight the major changes to the soft tissue chapter in the 2020 World Health Organization Classification, as well as the new chapter on undifferentiated small round cell sarcomas, with a focus on updates in diagnostic categories, prognostication, and novel markers. Recent discoveries in molecular genetics are also discussed, particularly those of immediate utility in differential diagnosis, including protein correlates detectable using immunohistochemistry.

Hyperprogression associated with immunotherapy has been reported previously with melanoma, non-small cell lung cancer (NSCLC), renal, and urothelial cancers but not with sarcoma. A 63-year old man with a biopsy-proven, localized 13 cm high-grade myxoid/round cell liposarcoma of the thigh was treated with concurrent, neoadjuvant checkpoint inhibitor immunotherapy and radiotherapy. After his subsequent wide surgical resection, he developed small hepatic lesions that rapidly progressed and caused his death, raising the possibility of hyperprogression in this entity., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Chan et al.)

Introduction: The rise in primary surgical management of oropharyngeal squamous cell carcinoma has led to varying interpretations of the histopathologic evaluation following a radical tonsillectomy. The oncologic margin may be significantly influenced by the morphologic relations and anatomic dimensions of the palatine tonsil and superior pharyngeal constrictor (SPC) muscle., Objective: The aim of this study was to characterize the gross and histologic anatomic features of the palatine tonsil and SPC muscle following an en bloc radical tonsillectomy., Methods: Radical tonsillectomy specimens were collected from cadaveric and oncologic subjects. Specimens were processed using standard histopathologic techniques and were analyzed by a board-certified head and neck pathologist. The thickness of the SPC muscle and relationship to the tonsillar carcinoma were assessed., Results: Six cadaveric and 10 oncologic specimens were analyzed. The mean minimum SPC width for all cadaveric specimens was 1.02 ± 0.50 mm. The mean minimum width for oncologic specimens was 0.76 ± 0.46 mm. The mean distance from tonsil carcinoma to the lateral specimen margin was 1.79 ± 1.39 mm., Conclusion: Due to the limited width of the SPC muscle, a margin in excess of 2 mm may not be attainable in a transoral radical tonsillectomy. Margin status may be ideally determined by the integrity of the SPC muscle in future oncologic studies, rather than an adequate distance measurement., (© 2020 S. Karger AG, Basel.)

Bone marrow failure and related syndromes are rare disorders characterized by ineffective bone marrow hematopoiesis and peripheral cytopenias. Although many are associated with characteristic clinical features, recent advances have shown a more complicated picture with a spectrum of broad and overlapping phenotypes and imperfect genotype-phenotype correlations. Distinguishing acquired from inherited forms of marrow failure can be challenging, but is of crucial importance given differences in the risk of disease progression to myelodysplastic syndrome, acute myeloid leukemia, and other malignancies, as well as the potential to genetically screen relatives and select the appropriate donor if hematopoietic stem cell transplantation becomes necessary. Flow cytometry patterns in combination with morphology, cytogenetics, and history can help differentiate several diagnostic marrow failure and/or insufficiency entities and guide genetic testing. Herein we review several overlapping acquired marrow failure entities including aplastic anemia, hypoplastic myelodysplasia, and large granular lymphocyte disorders; and several bone marrow disorders with germline predisposition, including GATA2 deficiency, CTLA4 haploinsufficiency, dyskeratosis congenita and/or telomeropathies, Fanconi anemia, Shwachman-Diamond syndrome, congenital amegakaryocytic thrombocytopenia, severe congenital neutropenia, and Diamond-Blackfan anemia with a focus on advances related to pathophysiology, diagnosis, and management., (Published by Elsevier Inc.)

Triple hit lymphomas are a subset of so-called double hit non-Hodgkin lymphomas exhibiting simultaneous gene translocations/disruption of MYC, BCL2, and BCL6; however, their overlapping morphologic features and complex genetic rearrangements can render classification and prognostication vexing. Clinically triple hit lymphomas are thought to demonstrate aggressive behavior, similar to or worse than that of double hit lymphomas. Only rare reports of long term survivors exist and raise the possibility that unidentified morphologic, immunologic, or cytogenetic differences may impart a less adverse prognosis than current literature and opinion may suggest. Here we report 3 such cases with less aggressive behavior. Cases such as these may prove useful in comparing outcomes, and underlying mechanisms of tumor progression, in aggressive non-Hodgkin lymphomas., (© The Author(s) 2016.)

Intraductal oncocytic papillary neoplasms (IOPNs) are cystic neoplasms with intraductal growth and complex papillae composed of oncocytic cells. IOPNs have been reported both in the pancreas and biliary tree, and are most likely closely related in these 2 locations. In the pancreas, these rare tumors are now considered 1 of the 4 histologic subtypes of intraductal papillary mucinous neoplasm (IPMN). Significant differences in histology, immunophenotype, and molecular genetics have been reported between IOPNs and other IPMN subtypes. However, there are limited data regarding the clinical behavior and prognosis of IOPNs in comparison to other subtypes of IPMN. We review features of pancreatic IOPNs and discuss the differential diagnosis of other intraductal lesions in the pancreas.

Case 1: A 67-year-old Asian female was diagnosed with locally advanced high-grade salivary duct carcinoma in June 2011. Molecular analysis revealed human epidermal growth factor receptor 2 (HER-2) amplification. She received adjuvant therapy with carboplatin/paclitaxel/ trastuzumab and maintenance of trastuzumab. Upon disease progression, trastuzumab could not be continued due to lack of financial coverage. Instead, she was treated with compassionate use of lapatinib from April 2013 and standard 5-fluorouracil. Her disease ultimately progressed and she expired later in 2013., Case 2: A 68-year-old Asian male was diagnosed with extramammary Paget's disease of the scrotum with HER-2 amplification in May 2011. He received 6 cycles of adjuvant trastuzumab/docetaxel/carboplatin followed by maintenance trastuzumab, which was changed to compassionate use of lapatinib as his insurance did not cover further administration of trastuzumab. He showed clinical benefits from single-agent lapatinib and a combination of lapatinib/capecitabine upon progression to the single-agent lapatinib. Ultimately, he was started on ado-trastuzumab emtansine, which was approved at that time by the FDA for HER-2-positive breast cancer progressed on trastuzumab. He is having clinical and radiographic complete response based on current imaging and normalization of his tumor markers., Conclusion: HER-2-targeted therapy should be considered for tumors with HER-2 amplification. In our case series, we would like to emphasize this approach in other rare histologies. Specifically, our patient with extramammary Paget's disease of the scrotum represents the first reported case of a non-breast, non-gastric tumor with HER-2 overexpression with complete clinical and radiographic response to HER-2-targeted therapy.

Breast pathology relies on gross dissection for accurate diagnostic work, but challenges can necessitate submission of high tissue volumes resulting in excess labor, laboratory costs, and delays. To address these issues, a quality initiative was created through implementation of the Faxitron PathVision specimen radiography system as part of the breast gross dissection protocol; this report documents its impact on workflow and clinical care. Retrospective data from 459 patients who underwent simple or modified radical mastectomy at our institution between May 2012 and December 2014 were collected. Comparison was made between the mastectomy specimen control group before radiography use (233 patients, 340 breasts) and Faxitron group that underwent postoperative radiography (226 patients, 338 breasts). We observed a statistically significant decrease in mean number of blocks between control and Faxitron groups (47.0 vs 39.7 blocks; P<.0001), for calculated cost savings of US $146 per mastectomy. A statistically significant decrease in pathology report turnaround time was also observed (4.2 vs 3.8days; P=.038). Postoperative mastectomy specimen radiography has increased workflow efficiency and decreased histology costs and pathology report turnaround time. These findings may underestimate actual benefits and highlight the importance of quality improvement projects in anatomical pathology., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Major histocompatibility complex class II (MHCII) deficiency is a rare autosomal recessive immunodeficiency disorder characterized by lack of expression of MHCII molecules, causing defective CD4 lymphocyte function and an impaired immune response. Clinical manifestations include susceptibility to severe bacterial, viral, and fungal infections which can lead to failure to thrive and childhood death. The only definitive treatment to date is allogeneic stem cell transplantation. Here, we share our experience of 2 patients who presented with MHCII deficiency. We will discuss the role of diagnostic modalities and stem cell transplantation.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm composed of monomorphic small to medium-sized atypical lymphocytes arising from naïve mantle zone B-cells, with a generally aggressive and incurable clinical course. The t(11;14)(q13;q32) between IGH@ and CCND1 is present in almost all cases of MCL. Secondary cytogenetic abnormalities are common, and have been associated in some cases with clinical progression. Variant and cryptic t(11;14) translocations have been reported as well. Herein, we present the case of an 80-year old woman with classical MCL, and a cryptic t(11;14) translocation detected by fluorescence in situ hybridization (FISH), and not by conventional cytogenetics. FISH on previously G-banded metaphases showed a cryptic CCND1-IGH@ fusion signal on a derivative chromosome 10, and another fusion signal on one of the abnormal copies of chromosome 11. Cases such as this highlight the importance of FISH studies as part of an algorithmic and multidisciplinary approach to diagnosis.

Prostate cancer (PCa) is the one of the most commonly diagnosed cancers in males living in the United States, and approximately 222,800 men will contract PCa in 2015. Recent molecular studies have found novel genetic associations with PCa and genetic changes of potential clinical relevance in cancer detection and treatment. Single nucleotide polymorphism (SNP) arrays have revealed unique SNPs connected with patient ethnicity and other medical conditions, as well as uncovered new information on genes such as KLK3, which produces prostate specific antigen (PSA) and promotes PCa metastasis. Identification of embryonic stem cell gene predictors serve as more accurate indicators when used with clinical parameters (e.g., PSA levels, biopsy Gleason score, clinical stage) in determining the risk of developing prostate cancer and survival times than clinical parameters alone. Studies utilizing exome sequencing have linked mutations in specific genes with PCa progression. In this review, we summarize the most recent and significant molecular and cytogenetic PCa literature, and discuss directions for future research focused on improving diagnostic utility and supplanting PSA testing.

Expression of the p63 tumor suppressor protein has been reported in the mononuclear stromal cells of giant cell tumor of the bone, which may represent osteoblast-precursor cells. Only a limited number of osteoblastic tumors have been studied for p63 expression thus far. We therefore examined whether p63 may serve as a marker for osteoblastic differentiation in osteosarcomas or as a differential diagnostic marker to distinguish osteoblastoma from osteosarcoma. Immunohistochemical stains for p63 were performed on a tissue microarray containing 71 chemotherapy naïve biopsy samples of osteosarcoma, 21 whole sections of osteosarcoma, and 8 osteoblastomas. Nuclear p63 was detected in seven of eight osteoblastomas but was restricted to stromal cells within primitive, immature-appearing areas of osteoid deposition. Although only 7 of 71 (10 %) biopsy samples of osteosarcoma represented on the tissue microarray were positive for p63, 7 of 21 (33 %) osteosarcomas were positive when whole tissue sections were evaluated. Although p63 is detected in most osteoblastomas, it is also observed in a significant subset of osteosarcomas, severely limiting its utility in distinguishing between benign and malignant osteoblastic tumors. The relatively low prevalence of p63 expression in osteosarcoma would also seem to preclude its use as a marker of osteoblastic differentiation in skeletal sarcomas.

Expression of p63, a putative marker for epithelial or myoepithelial differentiation, has been used to distinguish spindle cell carcinoma from sarcoma. The specificity of p63 for epithelial differentiation has not been thoroughly evaluated however, since p63 expression has been explored in only a handful of mesenchymal tumors. After observing unexpected immunohistochemical staining for p63 in an angiosarcoma of the breast, we evaluated a series of benign and malignant vascular tumors to determine the frequency of such a finding. Nuclear immunoreactivity to p63 was detected, at least focally, in 24% of malignant vascular tumors other than Kaposi sarcoma, which was uniformly negative. Benign vascular tumors were also negative for p63. Although p63 expression in tumors of vascular differentiation is unusual, it may be seen occasionally in some malignant vascular tumors. Thus, p63 is not entirely specific for epithelial differentiation. Since soft tissue angiosarcomas and hemangioendotheliomas sometimes express cytokeratins, the finding of nuclear p63 represents another potential pitfall in the differential diagnosis between poorly-differentiated carcinomas and vascular neoplasms.