Research autopsy programmes in oncology: shared experience from 14 centres across the world.

While there is a great clinical need to understand the biology of metastatic cancer in order to treat it more effectively, research is hampered by limited sample availability. Research autopsy programmes can crucially advance the field through synchronous, extensive, and high-volume sample collection. However, it remains an underused strategy in translational research. Via an extensive questionnaire, we collected information on the study design, enrolment strategy, study conduct, sample and data management, and challenges and opportunities of research autopsy programmes in oncology worldwide. Fourteen programmes participated in this study. Eight programmes operated 24 h/7 days, resulting in a lower median postmortem interval (time between death and start of the autopsy, 4 h) compared with those operating during working hours (9 h). Most programmes (n = 10) succeeded in collecting all samples within a median of 12 h after death. A large number of tumour sites were sampled during each autopsy (median 15.5 per patient). The median number of samples collected per patient was 58, including different processing methods for tumour samples but also non-tumour tissues and liquid biopsies. Unique biological insights derived from these samples included metastatic progression, treatment resistance, disease heterogeneity, tumour dormancy, interactions with the tumour micro-environment, and tumour representation in liquid biopsies. Tumour patient-derived xenograft (PDX) or organoid (PDO) models were additionally established, allowing for drug discovery and treatment sensitivity assays. Apart from the opportunities and achievements, we also present the challenges related with postmortem sample collections and strategies to overcome them, based on the shared experience of these 14 programmes. Through this work, we hope to increase the transparency of postmortem tissue donation, to encourage and aid the creation of new programmes, and to foster collaborations on these unique sample collections. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Perfusion Pressure and the Histology of Brain Death: A Unique Case in an Infant Maintained on Life Support.

Brain death is a not uncommon phenomena in the adult and pediatric population. Most cases are removed from life support soon after brain death is declared. Less commonly, systemic perfusion is maintained by life support for some time after neurologic function stops. These cases present uncommon opportunities to explore the histology of necrosis and autolysis in the context of global hypoxic ischemic damage. Here, we describe the unusual case of an infant maintained on life support for 2 weeks after brain death was declared with an emphasis on the resulting gross and histologic findings including a discussion of their underlying physiology.

Gamma-delta T-cell lymphoma of the central nervous system: A case report and review of the literature.

Primary T-cell lymphoma (TCL) of the central nervous system (CNS) is a rare and potentially aggressive entity. We describe a case of TCL presenting in the basal ganglia with γδ receptor expression and a remarkably aggressive clinical course. To the best of our knowledge, this is the fifth reported case of γδ TCL presenting in the CNS. We review existing literature, including the previously reported cases of γδ TCL of the CNS. In our case, a 69-year-old male presented with acute onset dysarthria and right-sided weakness, with initial imaging concerning for stroke. Repeat imaging demonstrated a 2.6-cm mass in the left basal ganglia-corona radiata. Pathologic examination of a stereotactic biopsy revealed TCL with γδ receptor phenotype. The patient suffered rapid clinical decline and passed away within 6 weeks of initial diagnosis. This represents an important differential diagnosis and sheds light on the potentially poor prognosis conferred by γδ TCL of the CNS.

How (Cautious) Social Media Use May Improve Education and Pipeline Efforts of a Growing Postpandemic Forensic Pathologist Workforce Shortage.

ABSTRACT: Many subspecialties of pathology have initiated novel methods and strategies to connect with medical students and residents, stimulate interest, and offer mentorship. Emerging concern about the future of forensic pathology has been highlighted in contemporary literature as recruitment of new fellows has stagnated and workforce shortage concerns have blossomed. Amidst these challenges, the potential role of social networking platforms like social media (SoMe) in enhancing autopsy pathology/forensics education has garnered attention, yet literature focusing specifically on its application in autopsy and forensic pathology remains limited. This review aims to provide a comprehensive narrative overview of the current literature on the established uses of SoMe in forensic pathology. It seeks to build upon existing recommendations, introducing a contemporary compilation of online resources designed to facilitate virtual engagement among pathologists, learners, patients, and families. The review supports the idea that strategic, ethical, and conscientious use of SoMe has a place in addressing the growing workforce shortages and closing educational gaps in forensic pathology by enhancing exposure to the field and dispelling antiquated stereotypes.

A novel method to assess copy number variation in melanoma: Droplet digital PCR for precise quantitation of the RREB1 gene in formalin-fixed, paraffin-embedded melanocytic neoplasms, a proof-of-concept study.

BACKGROUND: Melanocytic neoplasms can be challenging to diagnose. One well-established diagnostic aid is the detection of copy number variation (CNV) in a few key genetic loci using conventional methods such as fluorescence in situ hybridization (FISH) and chromosomal microarray (CMA). Droplet digital polymerase chain reaction (ddPCR) is a novel, cost-effective, rapid, and automated method to detect CNV. METHODS: We perform the first investigation of ddPCR to assay Ras-responsive element-binding protein-1 (RREB1), the most common CNV in melanoma using formalin-fixed, paraffin-embedded (FFPE) melanocytic lesion samples; CMA data are used as the gold standard. Archival samples from 2013 to 2021 were analyzed, including 153 data points from 39 FFPE samples representing 34 patients. Benign, borderline, malignant, and metastatic melanocytic neoplasms were examined. RESULTS: ddPCR showed a sensitivity and specificity of 93.8% and 95.7% using one reference gene, and 87.5% and 100% using a different reference gene for RREB1 gain detection. CONCLUSIONS: Here we show that ddPCR can provide inexpensive, rapid, and robust data on the commonest copy number alteration in melanoma. Future development and validation could provide a useful ancillary tool in the diagnosis of challenging melanocytic lesions.

A Novel Method to Detect Copy Number Variation in Melanoma: Droplet Digital PCR for Quantitation of the CDKN2A Gene, a Proof-of-Concept Study.

ABSTRACT: A definitive diagnosis of nevus or melanoma is not always possible for histologically ambiguous melanocytic neoplasms. In such cases, ancillary molecular testing can support a diagnosis of melanoma if certain chromosomal aberrations are detected. Current technologies for copy number variation (CNV) detection include chromosomal microarray analysis (CMA) and fluorescence in situ hybridization. Although CMA and fluorescence in situ hybridization are effective, their utilization can be limited by cost, turnaround time, and inaccessibility outside of large reference laboratories. Droplet digital polymerase chain reaction (ddPCR) is a rapid, automated, and relatively inexpensive technology for CNV detection. We investigated the ability of ddPCR to quantify CNV in cyclin-dependent kinase inhibitor 2A ( CDKN2A ), the most commonly deleted tumor suppressor gene in melanoma. CMA data were used as the gold standard. We analyzed 57 skin samples from 52 patients diagnosed with benign nevi, borderline lesions, primary melanomas, and metastatic melanomas. In a training cohort comprising 29 randomly selected samples, receiver operator characteristic curve analysis revealed an optimal ddPCR cutoff value of 1.73 for calling CDKN2A loss. In a validation cohort comprising the remaining 28 samples, ddPCR detected CDKN2A loss with a sensitivity and specificity of 94% and 90%, respectively. Significantly, ddPCR could also identify whether CDKN2A losses were monoallelic or biallelic. These pilot data suggest that ddPCR can detect CDKN2A deletions in melanocytic tumors with accuracy comparable with CMA. With further validation, ddPCR could provide an additional CNV assay to aid in the diagnosis of challenging melanocytic neoplasms.

Fatal Retroperitoneal Bleeding in Neurofibromatosis Type 1: A Clinically Occult Complication.

ABSTRACT: Neurofibromatosis type 1 (NF1) is a common, autosomal dominant neurocutaneous syndrome. The most frequent clinical manifestations include multiple neurofibromas, café-au-lait spots, dystrophic scoliosis, benign and malignant peripheral nerve sheath tumors, and paragangliomas. Neurofibromatosis type 1 vasculopathy is a less well-recognized constellation of vascular pathologies that can cause significant medical complications in patients with NF1. A rare manifestation of this process is neurofibroma infiltration of vasculature with resultant bleeding. The case presented herein illustrates a rare example of a massive fatal hemorrhage due to disruption of a large paraspinal artery in the setting of a diffuse, infiltrative neurofibroma. This case highlights the potential of benign neurofibromas to infiltrate major blood vessels, leading to extensive bleeding and death.

Topical Imiquimod for Lentigo Maligna: Survival Analysis of 103 Cases With 17 Years Follow-up.

Topical imiquimod 5% cream has been investigated as off-label primary or adjuvant treatment for melanoma in situ, lentigo maligna type (LM). Herein, we present the largest known case series of lentigo maligna treated with topical imiquimod, with up to 17 years of follow-up, and include a recurrence-free survival analysis. In this case series, 103 lesions were retrospectively evaluated for treatment response and recurrence following a course of topical imiquimod with or without tazarotene gel 0.1% pretreatment between January 1, 2002 and March 31, 2019, and prospectively followed through November 15, 2019. Over median follow-up of 5.1 years (mean = 6.2 years, S = 5.2 years, range, 0.08–17.1 years), including 29.1% LM with >10 years follow-up, we observed a response rate of 97.1% (100/103), with 8 local recurrences (8/100, 8.0%) developing at mean 2.9 years (SD: 2.7 years). Local recurrence was significantly associated with a history of failed excision (P= 0.001), <60 applications of imiquimod (P= 0.04) and partial clinical clearance (P= 0.0003). Recurrence-free survival analysis demonstrated significant risk-stratification for low and high-risk groups (P= 0.0001). Long term risk for recurrence showed significant differences among low- and high-risk cases, with low-risk cases demonstrating favorable long-term outcomes, comparable to conventional and staged surgery. Our observed low recurrence in a large case series with long-term follow-up suggests the efficacy of topical 5% imiquimod for LM and emphasizes the need for randomized control trials comparing imiquimod with, or as an adjunct to, surgical treatment. J Drugs Dermatol. 2021;20(3):346-348. doi:10.36849/JDD.5660.

Molecular genetic profiling reveals novel association between FLT3 mutation and survival in glioma.

INTRODUCTION: Recent molecular characterization of gliomas has uncovered somatic gene variation and DNA methylation changes that are associated with etiology, prognosis, and therapeutic response. Here we describe genomic profiling of gliomas assessed for associations between genetic mutations and patient outcomes, including overall survival (OS) and recurrence-free survival (RFS). METHODS: Mutations in a 50-gene cancer panel, 1p19q co-deletion, and MGMT promoter methylation (MGMT methylation) status were obtained from tumor tissue of 293 glioma patients. Multivariable regression models for overall survival (OS) and recurrence-free survival (RFS) were constructed for MGMT methylation, 1p19q co-deletion, and gene mutations controlling for age, treatment status, and WHO grade. RESULTS: Mutational profiles of gliomas significantly differed based on WHO Grade, such as high prevalence of BRAF V600E, IDH1, and PTEN mutations in WHO Grade I, II/III, and IV tumors, respectively. In multivariate regression analysis, MGMT methylation and IDH1 mutations were significantly associated with improved OS (HR = 0.44, p = 0.0004 and HR = 0.21, p = 0.007, respectively), while FLT3 and TP53 mutations were significantly associated with poorer OS (HR = 19.46, p < 0.0001 and HR = 1.67, p = 0.014, respectively). MGMT methylation and IDH1 mutations were the only significant alterations associated with improved RFS in the model (HR = 0.42, p < 0.0001 and HR = 0.37, p = 0.002, respectively). These factors were then included in a combined model, which significantly exceeded the predictive value of the base model alone (age, surgery, radiation, chemo, grade) (likelihood ratio test OS p = 1.64 × 10-8 and RFS p = 3.80 × 10-7). CONCLUSIONS: This study highlights the genomic landscape of gliomas in a single-institution cohort and identifies a novel association between FLT3 mutation and OS in gliomas.

Expanding the differential of cutaneous epithelioid tumors: A case of dedifferentiated liposarcoma with epithelioid features involving the skin, with review of the literature.

Liposarcomas are categorized into four distinct histopathological subtypes: atypical lipomatous tumors (ALT)/well-differentiated liposarcoma (WDL), dedifferentiated, myxoid, and pleomorphic. Dedifferentiated liposarcomas account for approximately 18% of all liposarcomas, characteristically arising in the deep soft tissue. They are reported to have lower rates of metastasis compared to other pleomorphic sarcomas.1 -3 The classic histopathologic appearance is ALT/WDL admixed or juxtaposed with a predominantly nonlipogenic sarcoma. Epithelioid features are rare, appearing in as few as 3% of tumors, and have not previously been reported in a superficial location. Herein, we present a 57-year-old male with intradermal and subcutaneous metastasis of his known deep dedifferentiated liposarcoma with epithelioid features. By H&E the tumor featured cords and sheets of crowded, plump, epithelioid cells with thick nuclear membranes and prominent nucleoli, which raised a broad differential including carcinoma and melanoma. By immunohistochemistry the tumor was diffusely positive for MDM2 and CDK4, on the other hand stains for Sox10, Melan A, MITF, CKAE1/3, desmin, and S100 protein were negative. This case serves as an opportunity to raise awareness of this rare morphological subtype, which can involve the skin and mimic epithelial and melanocytic malignancies. It can be a potential diagnostic pitfall, especially if metastases are the first presentation.

Outcome Analysis of a Series of Mixed-Grade, Non-muscle Invasive, Papillary Carcinomas of the Bladder.

Introduction. Papillary urothelial carcinomas are currently graded as either low- or high-grade tumors based on World Health Organization (WHO) 2022 guidelines for genitourinary tumors. However, a minority of tumors are mixed-grade tumors, composed predominantly of low-grade cancer with a minor high-grade component. In the 2022 WHO these cancers are recognized as having outcomes comparable to low-grade cancers, although data to date has been limited. Methods. The pathology records of a large academic institution were searched for mixed-grade, non-muscle invasive papillary carcinomas of the bladder and ureter in order to characterize prognosis of these cancers. Results. Of 136 cancers, the majority (n = 104, 76.5%) were solitary, mixed-grade tumors, while 21 (15.4%) had a concurrent low-grade cancer and 11 (8.1%) had multiple mixed-grade tumors at the time of diagnosis. At follow-up (median 48.3 months, range = 1.3 months-18.1 years), 71 cancers recurred (52.2%): 52 (38.2%) as low- or mixed-grade cancers and 18 (13.2%) as high-grade cancers. There were no instances of stage-progression to >pT2. Conclusions. The clinical outcome of mixed-grade carcinomas was similar to what has been reported for low-grade carcinomas. Based on our results, and prior congruent studies of mixed-grade lesions, these lesions may be regarded as a distinct sub-category with a better prognosis than high-grade tumors.

A Droplet Digital Polymerase Chain Reaction-Based Tool to Aid in Melanoma Diagnosis.

CONTEXT.­: Detecting copy number variations (CNVs) at certain loci can aid in the diagnosis of histologically ambiguous melanocytic neoplasms. Droplet digital polymerase chain reaction (ddPCR) is a rapid, automated, and inexpensive method for CNV detection in other cancers, but not yet melanoma. OBJECTIVE.­: To evaluate the performance of a 4-gene ddPCR panel that simultaneously tests for ras responsive binding element protein 1 (RREB1) gain; cyclin-dependent kinase inhibitor 2A (CDKN2A) loss; MYC proto-oncogene, bHLH transcription factor (MYC) gain; and MYB proto-oncogene, transcription factor (MYB) loss in melanocytic neoplasms. DESIGN.­: One hundred sixty-four formalin-fixed, paraffin-embedded skin samples were used to develop the assay, of which 65 were used to evaluate its performance. Chromosomal microarray analysis (CMA) data were used as the gold standard. RESULTS.­: ddPCR demonstrated high concordance with CMA in detecting RREB1 gain (sensitivity, 86.7%; specificity, 88.9%), CDKN2A loss (sensitivity, 80%; specificity, 100%), MYC gain (sensitivity, 70%; specificity, 100%), and MYB loss (sensitivity, 71.4%; specificity, 100%). When one CNV was required to designate the test as positive, the 4-gene ddPCR panel distinguished nevi from melanomas with a sensitivity of 78.4% and a specificity of 71.4%. For reference, CMA had a sensitivity of 86.2% and a specificity of 78.6%. Our data also revealed interesting relationships with histology, namely (1) a positive correlation between RREB1 ddPCR copy number and degree of tumor progression; (2) a statistically significant correlation between MYC gain and nodular growth; and (3) a statistically significant correlation between MYB loss and a sheetlike pattern of growth. CONCLUSIONS.­: With further validation, ddPCR may aid both in our understanding of melanomagenesis and in the diagnosis of challenging melanocytic neoplasms.

Diffuse hemispheric glioma with H3 p.K28M (K27M) mutation: Unusual non-midline presentation of diffuse midline glioma, H3 K27M-altered?

Diffuse midline glioma, H3 K27-altered (DMG-H3 K27) is an aggressive group of diffuse gliomas that predominantly occurs in pediatric patients, involves midline structures, and displays loss of H3 p.K28me3 (K27me3) expression by immunohistochemistry and characteristic genetic/epigenetic profile. Rare examples of a diffuse glioma with an H3 p.K28M (K27M) mutation and without involvement of the midline structures, so-called "diffuse hemispheric glioma with H3 p.K28M (K27M) mutation" (DHG-H3 K27), have been reported. Herein, we describe 2 additional cases of radiologically confirmed DHG-H3 K27 and summarize previously reported cases. We performed histological, immunohistochemical, molecular, and DNA methylation analysis and provided clinical follow-up in both cases. Overall, DHG-H3 K27 is an unusual group of diffuse gliomas that shows similar clinical, histopathological, genomic, and epigenetic features to DMG-H3 K27 as well as enrichment for activating alterations in MAPK pathway genes. These findings suggest that DHG-H3 K27 is closely related to DMG-H3 K27 and may represent an unusual presentation of DMG-H3 K27 without apparent midline involvement and with frequent MAPK pathway activation. Detailed reports of additional cases with clinical follow-up will be important to expand our understanding of this unusual group of diffuse gliomas and to better define the clinical outcome and how to classify DHG-H3 K27.

Squamous Differentiation in the Thyroid: Metaplasia, Neoplasia, or Bystander?

Background. Squamous differentiation within the thyroid is seen in a variety of settings. Squamous epithelium is non-native to the thyroid, and its debated origins span reactive metaplasia and developmental/embryologic remnants. Despite a lack of clarity as to its evolution, squamous epithelium may be associated with both neoplastic and non-neoplastic processes. Methods. Thyroid pathology reports spanning a 30-year period were reviewed for terms indicating squamous features. Associated diagnostic and clinical information was collated. Results. Four hundred and twenty seven of 17,452 (2.4%) thyroid surgical pathology cases during this period utilized terminology indicating squamous differentiation including 243 malignant (58%) and 178 benign (42%) diagnoses. There were 111 (26%) primary thyroid malignancies with squamous differentiation, 116 (28%) malignancies of non-thyroid origin including local extension from nearby cancers, and 16 (4%) malignancies of uncertain primary. Most benign lesions were non-neoplastic (84%). The minor subset representing benign neoplasia was interpreted as secondary reactive changes. Conclusion. While squamous differentiation is seen routinely in the thyroid, it is most commonly reported in malignancy. For primary thyroid malignancies reported to demonstrate a squamous component, biologically aggressive tumors were overrepresented. Available evidence suggests that multiple pathways may contribute to the presence of squamous epithelium in the thyroid including metaplasia of mature follicular cells, development from established embryonic remnants, or inception in putative, incompletely characterized stem-like cells. Our retrospective review presents an institutional landscape from which further investigation into the frequency and unique histologic and molecular context of intrathyroidal squamous differentiation as a driver or terminal event in thyroid pathophysiology.

Cytologic features of a case of mixed medullary and follicular cell-derived thyroid carcinoma with review of the literature.

Mixed medullary and follicular cell-derived thyroid carcinoma (MMFTC) is a rare primary thyroid carcinoma with morphologic and immunophenotypic evidence of admixed parafollicular and follicular cell-derived tumor populations within the same tumor. We herein present the fine-needle aspiration biopsy (FNAB) cytology of a case of MMFTC that was diagnosed histologically and discuss potential clues to the diagnosis for cytologists. We also provide a literature review of this uncommon primary thyroid tumor. The patient was a 47-year-old man with a history of hypothyroidism who presented with ear and neck pain. Imaging demonstrated thyroid nodules with regional lymphadenopathy. FNAB samples of two thyroid nodules and an involved lymph node were diagnosed as papillary thyroid carcinoma (PTC). The subsequent total thyroidectomy specimen demonstrated classic-type PTC which transitioned to a morphologically and immunophenotypically distinct medullary thyroid carcinoma (MTC) component within the same lesion, indicative of MMFTC. The patient experienced recurrence of the medullary component 20 months later and received chemotherapy with subsequent external beam radiation. As in this case, the cytologic diagnosis of MMFTC is almost never made prospectively. Retrospective review of the preoperative FNAB samples showed subtle cytomorphologic features suggestive of MTC in two of three biopsies, an impression confirmed by calcitonin immunohistochemistry on cell block material. In the broader literature, most MMFTCs on FNAB have been diagnosed as MTC, which is usually the more aggressive component of the mixed neoplasm.

Salivary-Like Tumors of the Thyroid: A Comprehensive Review of Three Rare Carcinomas.

Thyroid carcinomas represent 3.2% of all new cases of cancer in the United States. Whereas most thyroid tumors arise from follicular cells or, less commonly, parafollicular cells, the derivation of some rare primary thyroid carcinoma subtypes is less clear and represents an area of evolving knowledge. Primary thyroid carcinomas that resemble neoplasms characteristic of the salivary glands ("salivary-like" primary thyroid carcinomas) arguably represent some of the most unusual primary thyroid tumors. Herein, we have undertaken a review of the literature in order to present a comprehensive overview of salivary-like primary thyroid carcinomas including: mucoepidermoid carcinoma, sclerosing mucoepidermoid carcinoma with eosinophilia, and secretory carcinoma. Awareness of these unusual, distinct primary tumors is important for timely diagnosis and optimal patient management. This review highlights these three salivary-like carcinomas, with special emphasis on developments since publication of the World Health Organization (WHO) 2017 Classification of Tumours of Endocrine Organs.

Fine-needle aspiration biopsy for the diagnosis of bone and soft tissue lesions: a systematic review and meta-analysis.

INTRODUCTION: The workup of musculoskeletal (MSK) lesions utilizes a range of diagnostic tests including incisional biopsy, core needle biopsy, and fine-needle aspiration (FNA). FNA is the most cost-effective and least invasive biopsy method, but variation in its reported diagnostic performance has constrained its use for MSK lesions. Herein, we undertake a meta-analysis to clarify the diagnostic performance of FNA for bone and soft tissue lesions. MATERIALS AND METHODS: A systematic search was run in MEDLINE, EMBASE, and CINAHL. Included studies were aggregated for pooled estimates of adequacy, accuracy, and sensitivity/specificity for all MSK lesions as well as bone and soft tissue independently. Analysis of heterogeneity and risk of bias were assessed across studies. Covariate subgroup analyses were attempted to investigate potential influences on diagnostic accuracy. RESULTS: Twenty-five articles met inclusion criteria, representing 4604 FNAs. Adequacy was 92.3% (range: 59.2%-98.0%, S = 9.4%), and sensitivity/specificity for the nature (malignant or benign) of the lesion was 95.6% (95% CI: 94.5%-96.5%) and 96.9% (95% CI: 95.9%-97.7%). FNA was 75.8% accurate (range: 42.5%-99.3%, S = 17.3%) for definitive diagnosis. FNA provides higher accuracy for benign versus malignant nature in bone lesions but achieves a definitive diagnosis more frequently in soft tissue lesions. CONCLUSIONS: The results of this meta-analysis support the expanded use of FNA in the diagnostic workup of bone and soft tissue lesions, particularly in light of a sensitivity and specificity comparable to incisional and core needle biopsy.