Distribution of prostatic markers in glands of the female urethra and anterior vaginal wall-a rapid autopsy study.

BACKGROUND: There are varying reports of immunohistochemically detected prostatic marker protein distribution in glands associated with the female urethra that may be related to tissue integrity at the time of fixation. AIM: In this study we used tissue derived from rapid autopsies of female patients to determine the distribution of glandular structures expressing prostate-specific antigen (PSA) and prostate-specific acid phosphatase (PSAP) along the female urethra and in surrounding tissues, including the anterior vaginal wall (AVW). METHODS: Tissue blocks from 7 donors that contained the entire urethra and adjacent AVW were analyzed. These tissue samples were fixed within 4-12 hours of death and divided into 5-mm transverse slices that were paraffin embedded. Sections cut from each slice were immunolabeled for PSA or PSAP and a neighboring section was stained with hematoxylin and eosin. The sections were reviewed by light microscopy and analyzed using QuPath software. OBSERVATIONS: In tissue from all donors, glandular structures expressing PSA and/or PSAP were located within the wall of the urethra and were present along its whole length. RESULTS: In the proximal half of the urethra from all donors, small glands expressing PSAP, but not PSA, were observed adjacent to the and emptying into the lumen. In the distal half of the urethra from 5 of the 7 donors, tubuloacinar structures lined by a glandular epithelium expressed both PSA and PSAP. In addition, columnar cells at the surface of structures with a multilayered transitional epithelium in the distal half of the urethra from all donors expressed PSAP. No glands expressing PSA or PSAP were found in tissues surrounding the urethra, including the AVW. CLINICAL IMPLICATIONS: Greater understanding of the distribution of urethral glands expressing prostatic proteins in female patients is important because these glands are reported to contribute to the female sexual response and to urethral pathology, including urethral cysts, diverticula, and adenocarcinoma. STRENGTHS AND LIMITATIONS: Strengths of the present study include the use of rapid autopsy to minimize protein degradation and autolysis, and the preparation of large tissue sections to demonstrate precise anatomical relations within all the tissues surrounding the urethral lumen. Limitations include the sample size and that all donors had advanced malignancy and had undergone previous therapy which may have had unknown tissue effects. CONCLUSION: Proximal and distal glands expressing prostate-specific proteins were observed in tissue from all donors, and these glands were located only within the wall of the urethra.

BRCA1 and BRCA2 carriers with breast, ovarian and prostate cancer demonstrate a different pattern of metastatic disease compared with non-carriers: results from a rapid autopsy programme.

AIM: To catalogue and compare the pattern of metastatic disease in germline BRCA1/2 pathogenic mutation carriers and non-carriers with breast, ovarian and prostate cancer from a rapid autopsy programme. METHODS AND RESULTS: The number of metastases in the major body systems and the proportion of participants with metastases were documented in 50 participants (19 germline mutation carriers). Analysis was conducted on the participants' pattern of disease for the different cancers and mutation subgroups. The four commonly affected organ systems were the digestive (liver only) (82%), respiratory (76%), gastrointestinal (65%) and reticuloendothelial (42%). There were significant differences in the pattern of metastatic breast cancer in BRCA1/2 germline carriers compared with non-carriers. Breast cancer carriers had significantly fewer organ systems involved (median n = 3, range = 1-3) compared with non-carriers (median n = 9, range = 1-7) (P = 0.03). BRCA1/2 carriers with ovarian carcinomas had significantly more organ systems with metastatic carcinoma (median n = 10, range = 3-8) than non-carriers (median n = 5, range = 3-5) (P < 0.001). There were no significant differences in the number of involved systems in BRCA2 carriers compared with non-carriers with prostate cancer (P = 1.0). There was an absence of locoregional disease (6.5%) compared with distant disease (93.5%) among the three cancer subtypes (P < 0.001). The majority of metastatic deposits (97%) collected during the autopsy were identified by recent diagnostic imaging. CONCLUSION: Even though a major limitation of this study is that our numbers are small, especially in the breast cancer carrier group, the metastatic patterns of breast and ovarian cancers may be impacted by BRCA1/2 carrier status, suggesting that tumours derived from patients with these mutations use different mechanisms of dissemination. The findings may focus clinical diagnostic imaging for monitoring metastases where whole-body imaging resources are scant.

Quadriceps tendon malalignment is an independent anatomical deformity which is the primary abnormality associated with lateral facet patellofemoral joint osteoarthritis.

PURPOSE: The purposes of this study are to, firstly, develop techniques to accurately identify extensor mechanism malalignment by measuring the alignment of the quadriceps tendon (QTA) with computerized tomography (CT) scans. Secondly, to investigate correlations between QTA and lower limb bony anatomical variations within a representative normal population. Lastly, to evaluate the clinical significance of QTA by establishing its potential connection with lateral facet patellofemoral joint osteoarthritis (LFPFJOA). METHOD: CT scans were orientated to a mechanical axis reference frame and three techniques developed to measure the alignment of the quadriceps tendon. Multiple measurement of bony alignment from the hip to the ankle were performed on each scan. A series of 110 cadaveric CT scans were measured to determine normal values, reproducibility, and correlations with bony anatomy. Secondly, a comparison between 2 groups of 25 patients, 1 group with LFPFJOA and 1 group with isolated medial OA and no LFPFJOA. RESULTS: From the cadaveric study, it was determined that the alignment of the quadriceps tendon is on average 4.3° (SD 3.9) varus and the apex of the tendon is 9.1 mm (SD 7.7 mm) lateral to the trochlear groove and externally rotated 1.9° (SD 12.4°) from the centre of the femoral shaft. There was no association between the quadriceps tendon alignment and any other bony measurements including tibial tubercle trochlear groove distance (TTTG), coronal alignment, trochlear groove alignment and femoral neck anteversion. A lateralized QTA was significantly associated with LFPFJOA. QTA in the LFPFJOA group was 9.6° varus (SD 2.8°), 21.3 mm (SD 6.6) lateralised and 17.3° ER (SD 11°) compared to 5.5° (SD 2.3°), 10.7 mm (SD 4.9) and 3.3° (SD 7.2°), respectively, in the control group (p < 0.001). A significant association with LFPFJOA was also found for TTTG (17.2 mm (SD 5.7) vs 12.1 mm (SD 4.3), p < 0.01). Logistic regression analysis confirmed the QTA as having the stronger association with LFPFJOA than TTTG (AUC 0.87 to 0.92 for QTA vs 0.79 for TTTG). CONCLUSION: These studies have confirmed the ability to accurately determine QTA on CT scans. The normal values indicate that the QTA is highly variable and unrelated to bony anatomy. The comparative study has determined that QTA is clinically relevant and a lateralised QTA is the dominant predictor of severe LFPFJOA. This deformity should be considered when assessing patella maltracking associated with patella osteoarthritis, patella instability and arthroplasty. LEVEL OF EVIDENCE: III (retrospective cohort study).

Post-mortem CT lung findings at a medicolegal institute in SARS-CoV-2 RT-PCR positive cases with autopsy correlation.

CoVID-19 is a novel viral infection with now well-established clinical radiological findings. There is limited data on post-mortem imaging. We explore the proposition that PMCT could be used as screening test. In an 11-week period, 39 deceased persons were referred for medicolegal investigation with pre-existing or subsequent nasopharyngeal swabs showing positivity on SARS-CoV-2 RT-PCR testing. All 39 had routine whole-body CT scans on admission and 12 underwent medicolegal autopsy. These cases were contrasted with 4 others which were negative on nasopharyngeal swabs despite PMCT findings suggestive of CoVID-19 pneumonia (designated false positive). Nine of the 12 autopsies showed lung histology consistent with those reported in CoVID-19 pneumonia. Typical clinical CoVID-19 lung findings on PMCT were only detected in 5 (42%). In 3 of the 4 false positive cases, lung findings showed non-COVID-19 histology but in 1, findings were identical. PMCT CoVID-19 findings in the lungs are therefore not specific and may not be detected in all cases due to obscuration by expected agonal CT findings or other pathologies that pre-dated SARS-CoV-2 infection. PMCT findings may otherwise be subtle. Although PMCT may hint at CoVID-19, we believe that nasopharyngeal swabs are still required for definitive diagnosis. Even with positive swabs, clinical CoVID-19 lung findings on PMCT are often not detected. PMCT findings can be subtle, extreme or obscured by agonal changes. Given this range of PMCT changes, the challenge for pathologists is to determine whether death has been caused by, or merely associated with, SARS-CoV-2 infection.

Survey on postmortem screening and management of COVID-19 related deaths.

The COVID-19 pandemic is associated with a high case fatality rate in some countries even thought the majority of cases are asymptomatic. Scientific studies on this novel virus is limited and there is uncertainty regarding the best practices for death investigations both in terms of detection of the disease as well as autopsy safety. An online survey was conducted to identify how different institutions responded to the screening and management of dead bodies during the early phase of the pandemic from January to May. A questionnaire was developed using Google Forms and data was collected from 14 different forensic and pathological institutions in 9 countries. None of the institutions had performed any screening prior to March. Four institutions stated that screening was done routinely. In total, 322 cases had been screened using RT-PCR, out of which 40 positive cases were detected among four institutions. The commonest types of samples obtained were nasopharyngeal and oropharyngeal swabs which also had the highest rates of positivity followed by tracheal swab. Blood, swabs from cut surfaces of lung and lung tissue also gave positive results in some cases. Majority of the positive cases were > 65 years with a history suggestive of respiratory infection and were clinically suspected to have COVID-19 before death. Except for one institution which performed limited dissections, standard autopsies were conducted on all positive cases. Disposal of bodies involved the use of sealed body bags and labelling as COVID positive. Funeral rites were restricted and none of the institutions advocated cremation. There were no reports of disease transmission to those who handled COVID positive bodies.

The effect of post-mortem computed tomography angiography (PMCTA) using water-soluble, iodine-based radiographic contrast on histological analysis of the liver, kidneys and left ventricle of the heart.

The purpose of this study was to investigate the impact of post-mortem computed-tomography angiography (PMCTA) on the histology of the liver, kidneys and heart. Multiple tissue cores were collected from the liver, left and right kidneys and left ventricle utilizing CT-guided biopsy. Subsequent whole body PMCTA was performed using a solution of polyethylene glycol and iodinated radiographic contrast, and an embalming pump. Corresponding biopsy cores were collected at autopsy, and blinded histology analysis assessing for PMCTA-induced histology artefact was performed. The blinded analysis of pre-PMCTA and post-PMCTA biopsy samples demonstrated that whole body PMCTA had no effect on the histological analyses of the liver (0%, CI = 0-13.7%), left ventricle of the heart (0%, CI = 0-36.9%) and right kidney (0%, CI = 13.2%), however likely caused increased Bowman's capsule spaces in the left kidney of one case (4%, CI = 0.01-20.4%). Other artefactual histological changes identified included eosinophilic material in the liver, whiter interstitium and dilated tubules in kidney samples, and autolysis-related changes, however these could not be categorically attributed to the PMCTA procedure. PMCTA causes zero or minimal effect to the histological examination of the liver, left kidney, right kidney and left ventricle, and as such performing PMCTA prior to autopsy is unlikely to impact autopsy histological results in these organs.

The development of a protocol for post-mortem management of Ebola virus disease in the setting of developed countries.

The management of the recent Ebola virus disease (EVD) epidemic continues to pose currently insuperable challenges to health care providers in the resource-deprived countries of West Africa. In an age where air travel facilitates rapid movement of people between countries and continents, there is an urgent requirement for health systems around the globe to develop management strategies and protocols in the event that EVD cases are suspected or confirmed. Departments of forensic pathology play an important, and underestimated, role in public health service delivery, particularly at times of novel infectious disease emergence. This role can include disease identification, characterization, and notification, as well as close engagement with agencies responsible for disease surveillance and treatment provision. A mass outbreak of EVD in the Western world is considered highly unlikely; however, there is clear responsibility on departments of forensic pathology to develop protocols for rapid assessment of sporadic or suspected cases while ensuring the health and safety of mortuary and pathology personnel. The Ontario Forensic Pathology Service and the Victorian Institute of Forensic Medicine have collaborated on the development of a protocol for management of EVD cases presenting at a scene or in the mortuary. It is hoped that this trans-national, inter-departmental exercise will serve as a model for future co-operative endeavors. The protocol has been distributed to forensic pathology departments around Australia and may be modified to accommodate local resource capabilities.

The role of post-mortem imaging in preliminary examinations under the Coroners Act 2008 (Vic): a forensic pathologist's perspective.

Changing community attitudes and expectations, allied to the recent incorporation of sophisticated clinical imaging techniques into the medico-legal death investigation process, have presented significant challenges for Coroners and pathologists alike. The traditional functions of coronial systems have expanded from the relatively narrow confines of a judicial determination as to the cause of death on the basis of autopsy findings. Today they include broader responsibilities in death and disease prevention and a more enlightened approach to the social and familial consequences of a death. The Coroners Act 2008 (Vic) reflects this evolution with the introduction of a so-called preliminary examination process allowing for the performance of certain initial processes and procedures in relation to the medical investigation into a death, and with the aim of increasing the quality and robustness of the pathologist's advice to the Coroner before a decision is made as to whether the Coroner will order an autopsy. The post-mortem computed tomography scan (PMCT) is an important component of the preliminary examination process and significantly increases the information available in the early stages of a death investigation. The use of such new technology carries with it the necessity for a re-evaluation of the roles and responsibilities of the participants in the coronial death investigation system, including those of the next of kin. Three coronial case studies are presented to illustrate the impact and consequences of these developments.

Sudden unexpected death in the setting of undiagnosed Graves' disease.

Graves' disease is the most common cause of hyperthyroidism and is classically characterized by the clinical triad of diffuse toxic goiter, infiltrative ophthalmopathy with exophthalmos and an infiltrative dermopathy. While the name of the Irishman Robert Graves has received the eponymous honor, the first description of the condition in the English language can be attributed to the Englishman Caleb Perry, while in continental Europe the entity in name once honored Karl von Basedow. We present the case of a previously well 43 year old woman who presented in supraventricular tachycardia and acute pulmonary edema and died despite treatment and without a diagnosis for cause of death. At autopsy the significant positive macroscopic findings were confined to the lungs (acute pulmonary edema) and thyroid (diffusely enlarged). Histology revealed features typical of Graves' disease while post mortem thyroid function tests supported a diagnosis of thyrotoxic crisis in the setting of undiagnosed Graves' disease.

Fatal Intoxications from a Combination of 4-Fluoroamphetamine and 25C-NBOMe.

Six fatalities have occurred from the ingestion of a combination of new psychoactive substances (NPSs), 4-fluoroamphetamine (4FA) and 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25C-NBOMe) over a 9-month period. Four of these fatalities (one older female and three young males) were from direct adverse effects of drugs, and one each from a fall while being intoxicated and during restraint. All cases were subject to full postmortem examinations that included collection of femoral blood. The four drug-caused fatalities had postmortem blood concentrations for 4FA and 25C-NBOMe of 330-682 ng/L (median 417) and 1.4-12 ng/mL (median 4.3), respectively. The other two cases (both young males) where death was considered to have been caused indirectly by drug intoxication had 4FA and 25C-NBOMe postmortem concentrations of 21 and 123 ng/mL, and 1.8 and 4.5 ng/mL, respectively. None of these cases showed concentrations of drugs that suggested use of high recreational doses. In one drug-caused death, capsules and a brown powder obtained from the scene were found to contain a mixture of these two NPSs. With the exception of one drug-caused death, other drugs were detected; however, the effects of the two NPSs together were regarded as the primary triggers for the deaths. There were no consistent symptoms or pathology in these cases; however, agitation/aggression was observed in two cases prior to their collapse, with seizures in possibly three cases. Pulmonary and/or cerebral edema was noted in three cases. Potentially significant natural disease (a mildly enlarged heart) was only observed in one drug-caused case. These cases illustrate a possible increased risk of sudden death with this combination of drugs, both of which can elevate serotonin concentrations as well as act as strong stimulants. These cases also illustrate the difficulty in detecting NPS in cases where no prior information is available that might suggest their use.

Demonstration of liver metastases on postmortem whole body CT angiography following inadvertent systemic venous infusion of the contrast medium.

An 86-year-old woman was hospitalized for breathlessness and a large right-sided pleural effusion. Approximately 1 h after thoracentesis, she developed a hemothorax resulting in hypotension and death. Routine postmortem CT scanning showed a large volume right hemothorax and a markedly enlarged liver. In an attempt to determine the origin of bleeding prior to autopsy, a postmortem CT angiogram was performed. Following inadvertent cannulation of the left long saphenous vein and infusion of ∼1,700 mL of a polyethylene glycol 200 and iodine-based radiographic contrast solution into systemic veins using a mechanical pump, CT scanning revealed a dense hepatic "parenchogram" containing multiple large, filling defects indicative of metastases. These were confirmed at autopsy. Microscopic evaluation of the liver using hematoxylin and eosin staining showed marked histological artifact characterized by centrilobular sinusoidal expansion although histology of the adenocarcinoma metastases was typical and apparently unaffected by the contrast solution. Postmortem CT angiography using an aqueous radiographic contrast agent in the so-called venous phase seems to be useful for the identification of hepatic parenchymal metastatic disease although it does cause histological artifact.

The effect of the postmortem interval on the redistribution of drugs: a comparison of mortuary admission and autopsy blood specimens.

Postmortem redistribution (PMR) is an accepted toxicological phenomenon that may affect the interpretation of postmortem blood concentrations. The extent of PMR is not well understood for some drugs. This report describes the PMR of selected substances resulting from the analysis of 149 cases comparing blood specimens taken at admission of the deceased to the mortuary and then at autopsy. Blood was collected in preserved tubes containing 1 % sodium fluoride/potassium oxalate. All cases were subject to a full autopsy and blood extracts were analyzed using a targeted screen by LC-MS/MS. 30 drug or drug metabolites that were detected with an incidence of 6 or more were included in this study. The pre-autopsy interval ranged from 0.5 to 164 h (6.4 days) with an average of 64 h for the cases analyzed. The increase in drug concentration from mortuary admission to autopsy ranged from 30 % for drugs such as citalopram, mirtazapine, and sertraline to 300 % for doxylamine. Only 7 drugs of the 30 studied showed increases of greater than 20 % when comparing autopsy to mortuary admission blood irrespective of the length of the postmortem interval. Drugs including methadone, EDDP, fluoxetine, mirtazapine, and sertraline all showed statistically significant increases during the pre-autopsy interval (p < 0.05) while 6-acetylmorphine, 9-hydroxy-risperidone, and caffeine showed significant decreases (p < 0.05) from mortuary admission to autopsy. While femoral blood is thought to reduce PMR, this data shows that for some drugs significant redistribution can occur even when taking peripheral specimens irrespective of the delay in the postmortem interval.

Stimulant use in suicides: A systematic review.

Suicide remains a global public health concern and the increased supply and use of synthetic stimulants globally may have implications for the burden of suicides attributable to substance use. This systematic review investigated any potential associations of stimulant use detected in post-mortem biological specimens and suicides. We conducted a systematic review and narrative synthesis (CRD42021237966). Medline, EMBASE, TOXLINE, and Scopus databases were searched for terms related to forensic toxicology, post-mortem toxicology, suicide and stimulants. The primary outcome was to estimate the prevalence of stimulant use in suicides. There were 26 studies whichcontributed to prevalence measures; in studies reporting at the individual compound level, suicides involved cocaine (0.1-23%), caffeine (3.2-22%), 3,4-methylenedioxymethamphetamine (0.1-17%), amphetamine (0.2-9.3%), methamphetamine (3.1-7%), and phentermine (0.9-1%). Overall, stimulant use in suicides was over-represented compared to estimates of stimulant use in the general population and has increased over time. Thirteen case reports used to contextualise suicides involving stimulants found no examples of cocaine or methamphetamine mono-intoxication of suicidal intent. This suggests mechanisms other than acute toxicity involved in stimulant-associated suicide. Future research by in-depth psychological autopsies of suicides involving stimulants, in combination with segmental hair analysis to determine the chronicity of stimulant exposure, may contribute to a better understanding of the burden of suicide attributable to stimulant use.

Postmortem Interrogation of Cardiac Implantable Electronic Devices: A 15-Year Experience.

OBJECTIVES: This study sought to define the feasibility and utility of postmortem cardiac implantable electronic device (CIED) interrogation. BACKGROUND: The diagnostic yield of routine postmortem interrogation of CIEDs including pacemakers, defibrillators, and implantable loop recorders has not been established. METHODS: The study reviewed all CIED interrogations in deceased individuals undergoing medicolegal investigation of sudden or unexplained death by the Victorian Institute of Forensic Medicine between 2005 and 2020. RESULTS: A total of 260 patients (68.8% male, median age 72.8 years [interquartile range: 62.7-82.2 years]) underwent CIED interrogation (202 pacemakers, 56 defibrillators, and 2 loop recorders) for investigation of sudden (n = 162) or unexplained (n = 98) death. CIEDs were implanted for median of 2.0 years (interquartile range: 0.7-5.0 years), with 19 devices at elective replacement indicator and 5 at end of life. Interrogation was successful in 256 (98.5%) cases. Potential CIED malfunction was identified in 20 (7.7%) cases, including untreated ventricular arrhythmias (n = 13) and lead failures (n = 3, 2 resulting in untreated ventricular arrhythmia). Interrogation directly informed cause of death in 131 (50.4%) cases. A total of 72 (27.7%) patients had abnormalities recorded in 30 days preceding death: nonsustained ventricular tachycardia (n = 26), rapid atrial fibrillation (n = 17), elective replacement indicator or end-of-life status (n = 22), intrathoracic impedance alarms (n = 3), lead issues (n = 3), or therapy delivered (n = 1). In 6 cases in which the patient was found deceased after a prolonged period, interrogation determined time of death. In 1 case, CIED interrogation was the primary means of patient identification. CONCLUSIONS: Postmortem CIED interrogation frequently contributes important information regarding critical device malfunction, premortem abnormalities, mechanism, and time of death or patient identity. Device interrogation should be considered for select patients with CIEDs undergoing autopsy.

Time-Dependent Changes in THC Concentrations in Deceased Persons.

Changes in the concentrations of Δ9-tetrahydrocannabinol (THC) in the postmortem period were investigated in a series of cases by comparing concentrations in blood taken on receipt of the body in the mortuary (admission specimen, AD) with the concentrations obtained in blood taken at autopsy some time later and also from blood specimens taken antemortem. Overall, the median THC concentration in AD blood was 13.7 ng/mL (n = 239, range LOQ-220), while the median concentration at autopsy was 13.8 ng/mL (n = 106, range LOQ-810) and 1.9 ng/mL (n = 147, range LOQ-48) antemortem. Fourteen cases had all three specimens taken from the same decedent. The corresponding AM, AD and PM median concentrations were 4.0 (range LOQ-48), 15.5 (range 4.0-176) and 4.4 ng/mL (LOQ-56), respectively. The median elapsed times from AM to AD and AD to PM were 33 and 97.5 h, respectively. In contrast, acetaminophen showed no change in blood concentration from AM to AD (6.8 and 6.0 mg/L, respectively). These data show large increases in THC concentration in the early postmortem period, followed by a decline, although the median blood concentrations at autopsy were similar to that obtained antemortem. In contrast, when blood was taken from the femoral region, subclavian and heart ventricles sites, in the same case, the THC concentrations, while variable, showed overall no significant difference. These dynamic changes reflect complex phenomenon occurring in deceased persons and will further serve to increase the uncertainty over any interpretation of postmortem THC concentrations.

Postmortem Drug Redistribution: A Compilation of Postmortem/Antemortem Drug Concentration Ratios.

Postmortem drug redistribution (PMR) is a well-known phenomenon in forensic toxicology with implications for medico-legal death investigations. Paired antemortem (AM) specimen and postmortem (PM) mortuary admission femoral blood drug concentrations from 811 coronial cases were used to construct a retrospective compilation of PM/AM drug concentration ratios for 42 parent drugs and metabolites. The median PM/AM ratios for all antidepressants were > 1 and consistent with PMR In contrast, the median PM/AM ratios of most benzodiazepines were < 1. The antipsychotics were varied (0.63-3.3) and suggest the mixed effects of PMR and drug instability. Amphetamines exhibited no trends (0.90-0.95) and are likely confounded by many factors. The PM/AM ratios of cardiovascular drugs, opioids and other drugs are also reported. This research represents an expansive retrospective compilation of paired AM and PM drug concentrations for many toxicologically relevant drugs. While the median PM/AM ratios demonstrate some drug-dependent trends, there was no obvious relationship between AM specimens and PM femoral blood taken at mortuary admission.

Evolution of late-stage metastatic melanoma is dominated by aneuploidy and whole genome doubling.

Although melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by sampling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour samples reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naïve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression.