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Objective: To develop evidence‐based recommendations to guide the surgical management and postoperative follow‐up of adults with primary hyperparathyroidism. Methods: Representatives from relevant Australian and New Zealand Societies used a systematic approach for adaptation of guidelines (ADAPTE) to derive an evidence‐informed position statement addressing eight key questions. Results: Diagnostic imaging does not determine suitability for surgery but can guide the planning of surgery in suitable candidates. First‐line imaging includes ultrasound and either parathyroid 4DCT or scintigraphy, depending on local availability and expertise. Minimally invasive parathyroidectomy is appropriate in most patients with concordant imaging. Bilateral neck exploration should be considered in those with discordant/negative imaging findings, multi‐gland disease and genetic/familial risk factors. Parathyroid surgery, especially re‐operative surgery, has better outcomes in the hands of higher volume surgeons. Neuromonitoring is generally not required for initial surgery but should be considered for re‐operative surgery. Following parathyroidectomy, calcium and parathyroid hormone levels should be re‐checked in the first 24 h and repeated early if there are risk factors for hypocalcaemia. Eucalcaemia at 6 months is consistent with surgical cure; parathyroid hormone levels do not need to be re‐checked in the absence of other clinical indications. Longer‐term surveillance of skeletal health is recommended. Conclusions: This position statement provides up‐to‐date guidance on evidence‐based best practice surgical and postoperative management of adults with primary hyperparathyroidism. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Late presentation of disease at the time of diagnosis is one of the major reasons for dismal prognostic outcomes for PDAC patients. Currently, there is a lack of clinical biomarkers, which can be used to diagnose PDAC patients at an early resectable stage. This study performed proteomic mass spectrometry to identify novel blood‐based biomarkers for early diagnosis of PDAC. Serum specimens from 88 PDAC patients and 88 healthy controls (60 discovery cohort and 28 validation cohort) were analyzed using data independent acquisition high resolution mass spectrometry to identify candidate biomarker proteins. A total of 249 proteins were identified and quantified by the mass spectrometric analysis. Six proteins were markedly (>1.5 fold) and significantly (p <.05; q < 0.1) increased in PDAC patients compared to healthy controls in discovery cohort. Notably, four of these six proteins were significantly upregulated in an independent validation cohort. The top three upregulated proteins (i.e., Polymeric Immunoglobulin Receptor [PIGR], von Willebrand Factor [vWF], and Fibrinogen) were validated using enzyme linked immunosorbent assay, which led to selection of PIGR and vWF as a diagnostic biomarker panel for PDAC. The panel showed high ability to diagnose early stage (stage I and II) PDAC patients (area under the curve [AUC]: 0.8926), which was further improved after the addition of clinically used prognostic biomarker (Ca 19‐9) to the panel (AUC: 0.9798). In conclusion, a novel serum protein biomarker panel for early diagnosis of PDAC was identified. [ABSTRACT FROM AUTHOR]

Background: Australia's National Bowel Cancer Screening Program consists of an immunohistochemical faecal occult blood test, targeting adults aged 50–74. Existing literature supports the principle of early detection of colorectal cancer (CRC) via national screening, but little is known about the association between colonoscopy or polypectomy rates and CRC stage over time. The aim of this study is to identify the longitudinal change to colonoscopy and polypectomy rates, and any stage shift associated with this screening program. Methods: A retrospective data‐linkage study was performed using the Australian national health database (Medicare) to obtain colonoscopy and polypectomy rates between 1998 and 2017. A second prospective database of CRC resection specimens was analysed for this period. The cohort was divided based on time intervals related to the National Bowel Cancer Screening Program: pre‐commencement 1998–2006 (Period A), immediately post‐commencement 2007–2011 (Period B), and subsequent years 2012–2017 (Period C). Linear regression was used to test relation between annualized predictor and response variables. Results: Annual colonoscopy rates doubled, and polypectomy rates tripled during the study (P < 0.001). Annual colonoscopy rate correlated to a lower T‐stage (P = 0.038) and lower N‐stage (P = 0.026), and there was a 7% increase in early CRC (stage I–II) in Period C (P < 0.001). Across the study period there was also a significant increase in right‐sided tumours, and concurrent MMR deficiency and BRAF mutation. Conclusion: Polypectomy and colonoscopy rates increased after the introduction of the National Bowel Cancer screening program. There was a clinically significant shift to earlier CRC stage which manifested 5 years after its implementation. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) patients have late presentation at the time of diagnosis and a poor prognosis. Metal dyshomeostasis is known to play a role in cancer progression. However, the blood and tissue metallome of PDAC patients has not been assessed. This study aimed to determine the levels of essential and toxic metals in the serum and pancreatic tissue from PDAC patients. Serum samples were obtained from PDAC patients before surgical resection. Tissue (tumor and adjacent normal pancreas) were obtained from the surgically resected specimen. Inductively coupled plasma–mass spectrometry (ICP‐MS) analysis was performed to quantify the levels of 10 essential and 3 toxic metals in these samples. Statistical analysis was performed to identify dysregulated metals in PDAC and their role as potential diagnostic and prognostic biomarkers. Significantly decreased serum levels of magnesium, potassium, calcium, iron, zinc, selenium, arsenic, and mercury and increased levels of molybdenum were shown to be associated with PDAC. There were significantly decreased levels of zinc, manganese and molybdenum, and increased levels of calcium and selenium in the pancreatic tumor tissue compared with the adjacent normal pancreas. Notably, lower serum levels of calcium, iron, and selenium, and higher levels of manganese, were significantly associated with a poor prognosis (i.e., overall survival) in PDAC patients. In conclusion, this is the first study to comprehensively assess the serum and tissue metallome of PDAC patients. It identified the association of metals with PDAC diagnosis and prognosis. [ABSTRACT FROM AUTHOR]

Objective: To formulate clinical consensus recommendations on the presentation, assessment, and management of primary hyperparathyroidism (PHPT) in adults. Methods: Representatives from relevant Australian and New Zealand Societies used a systematic approach for adaptation of guidelines (ADAPTE) to derive an evidence‐informed position statement addressing nine key questions. Results: PHPT is a biochemical diagnosis. Serum calcium should be measured in patients with suggestive symptoms, reduced bone mineral density or minimal trauma fractures, and in those with renal stones. Other indications are detailed in the manuscript. In patients with hypercalcaemia, intact parathyroid hormone, 25‐hydroxy vitamin D, phosphate, and renal function should be measured. In established PHPT, assessment of bone mineral density, vertebral fractures, urinary tract calculi/nephrocalcinosis and quantification of urinary calcium excretion is warranted. Parathyroidectomy is the only definitive treatment and is warranted for all symptomatic patients and should be considered for asymptomatic patients without contraindications to surgery and with >10 years life expectancy. In patients who do not undergo surgery, we recommend annual evaluation for disease progression. Where the diagnosis is not clear or the risk‐benefit ratio is not obvious, multidisciplinary discussion and formulation of a consensus management plan is appropriate. Genetic testing for familial hyperparathyroidism is recommended in selected patients. Conclusions: These clinical consensus recommendations were developed to provide clinicians with contemporary guidance on the assessment and management of PHPT in adults. It is anticipated that improved health outcomes for individuals and the population will be achieved at a decreased cost to the community. [ABSTRACT FROM AUTHOR]

Aims: The International Medullary Thyroid Carcinoma Grading System, introduced in 2022, mandates evaluation of the Ki67 proliferation index to assign a histological grade for medullary thyroid carcinoma. However, manual counting remains a tedious and time‐consuming task. Methods and results: We aimed to evaluate the performance of three other counting techniques for the Ki67 index, eyeballing by a trained experienced investigator, a machine learning‐based deep learning algorithm (DeepLIIF) and an image analysis software with internal thresholding compared to the gold standard manual counting in a large cohort of 260 primarily resected medullary thyroid carcinoma. The Ki67 proliferation index generated by all three methods correlate near‐perfectly with the manual Ki67 index, with kappa values ranging from 0.884 to 0.979 and interclass correlation coefficients ranging from 0.969 to 0.983. Discrepant Ki67 results were only observed in cases with borderline manual Ki67 readings, ranging from 3 to 7%. Medullary thyroid carcinomas with a high Ki67 index (≥ 5%) determined using any of the four methods were associated with significantly decreased disease‐specific survival and distant metastasis‐free survival. Conclusions: We herein validate a machine learning‐based deep‐learning platform and an image analysis software with internal thresholding to generate accurate automatic Ki67 proliferation indices in medullary thyroid carcinoma. Manual Ki67 count remains useful when facing a tumour with a borderline Ki67 proliferation index of 3–7%. In daily practice, validation of alternative evaluation methods for the Ki67 index in MTC is required prior to implementation. [ABSTRACT FROM AUTHOR]

Aims: Colorectal carcinoma (CRC) arising in a colorectal polyp with invasion limited to the submucosa is sufficiently treated by complete endoscopic resection alone in many cases. Histological features of the carcinoma including tumour size, vascular invasion and poor tumour differentiation or evidence of de‐differentiation, such as tumour budding, are associated with a higher risk for metastasis such that oncological resection is recommended. However, most malignant polyps with these features do not have lymph node metastases at the time of resection, so there is a need for better refinement of the histological risk features. Methods and results: A total of 437 consecutive colorectal polyps with submucosal invasive carcinoma from a single centre, 57 of which had metastatic disease, were supplemented by 30 cases with known metastatic disease from two additional centres. Clinical and histological features of the polyp cancers were reviewed looking for differences between the 87 cancers with metastatic disease and the remaining cases without metastasis. A subgroup of 204 polyps removed intact was also analysed to ensure maximum histological accuracy. Conclusions: This study confirmed larger invasive tumour size, vascular invasion and poor tumour differentiation as adverse predictive features. Prominent peritumoral desmoplasia and high cytological grade were additional adverse features. A predictive logistic regression model comprised of (i) presence of any form of vascular invasion; (ii) presence of high tumour budding (BD3); (iii) width of invasive tumour component > 8 mm; (iv) depth of invasive tumour > 1.5 mm; and (v) the finding of prominent expansile desmoplasia located within and beyond the deep invasive edge of the carcinoma, showed excellent performance in predicting metastatic disease. [ABSTRACT FROM AUTHOR]

Aim: Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all major cancers. Chemotherapy is the mainstay systemic therapy for PDAC, and chemoresistance is a major clinical problem leading to therapeutic failure. This study aimed to identify key differences in gene expression profile in tumors from chemoresponsive and chemoresistant patients. Methods: Archived formalin‐fixed paraffin‐embedded tumor tissue samples from patients treated with neoadjuvant chemotherapy were obtained during surgical resection. Specimens were macrodissected and gene expression analysis was performed. Multi‐ and univariate statistical analysis was performed to identify differential gene expression profile of tumors from good (0%–30% residual viable tumor [RVT]) and poor (>30% RVT) chemotherapy‐responders. Results: Initially, unsupervised multivariate modeling was performed by principal component analysis, which demonstrated a distinct gene expression profile between good‐ and poor‐chemotherapy responders. There were 396 genes that were significantly (p < 0.05) downregulated (200 genes) or upregulated (196 genes) in tumors from good responders compared to poor responders. Further supervised multivariate analysis of significant genes by partial least square (PLS) demonstrated a highly distinct gene expression profile between good‐ and poor responders. A gene biomarker of panel (IL18, SPA17, CD58, PTTG1, MTBP, ABL1, SFRP1, CHRDL1, IGF1, and CFD) was selected based on PLS model, and univariate regression analysis of individual genes was performed. The identified biomarker panel demonstrated a very high ability to diagnose good‐responding PDAC patients (AUROC: 0.977, sensitivity: 82.4%; specificity: 87.0%). Conclusion: A distinct tumor biological profile between PDAC patients who either respond or not respond to chemotherapy was identified. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies in the world, for which the mortality is almost as high as the disease incidence and is predicted to be the second‐highest cause of cancer‐related deaths by 2030. These cancerous tumors consist of diversified gene expressions within the different cellular subpopulations that include neoplastic ductal cells, cancer‐associated fibroblasts, and immune cells, all of which collectively facilitate cellular heterogeneity in the PDAC tumor microenvironment (TME). Active intratumoral interaction within the cell populations in TME induces the proliferation of cancerous cells, accounting for tumorigenesis and rapid metastasis. Methods: This review will focus on novel findings uncovering PDAC heterogeneity in different cellular subpopulations using single‐cell RNA‐sequencing (scRNA‐seq) and other single‐cell analysis technologies. It will further explore the emerging role of single‐cell technologies in assessing the role of different subpopulations of neoplastic ductal cells, cancer‐associated fibroblasts, and immune cells in PDAC progression. Results and Conclusion: The application of scRNA‐seq in PDAC has started to unveil associations between disease progression and heterogeneity in pancreatic TME and could influence future PDAC treatment. Recent advances in scRNA‐seq have uncovered comprehensive analyses of heterogeneous ecosystems present within the TME. These emerging findings underpins further need for a more in‐depth understanding of intratumoral heterogeneity in the PDAC microenvironment. [ABSTRACT FROM AUTHOR]

Background: Meckels diverticulum (MD) causes a number of acute surgical pathologies and can contain ectopic tissue with the surgical aim to resect all ectopic mucosa. This has traditionally implied a small bowel resection (BR); though contemporary literature has demonstrated Meckel's diverticulectomy to be safe. The aim of this study was to determine optimal resection strategy, and assess MD histopathological features and their relationship to outcomes. Methods: A 19‐year retrospective review of patient medical records across seven hospitals was conducted with demographic, clinical and pathological data collected. Analysis was conducted using a student's t‐test for continuous variables and chi‐squared test for categorical variables. Univariate regression was performed to identify risk factors. P < 0.05 was considered statistically significant. Results: One hundred and sixty patients underwent resection of MD, 70 (44%) had Meckel's diverticulectomy and 90 (56%) had BR. No significant difference in length (P = 0.486), width (P = 0.238), or ratio (P = 0.188) of diverticulectomy compared to BR, with fewer complications in diverticulectomy. In all, 24 (15.3%) MD were perforated, of whom 5 had gastric mucosa, 2 had mixed ectopic mucosa and 1 carcinoid tissue. There were no cases of ectopic mucosa in the resection margin requiring re‐operation, or causing base perforation. MD specimen with greater length: width ratio was a risk factor for perforation OR 1.437 P = 0.042 but not for malignancy P = 0.813 or ectopic tissue P = 0.185. Conclusion: Meckel's diverticulectomy is safe via laparoscopic or open approach compared with BR. Despite higher perforation rates in MD with greater length: width ratio, no malignancy or ectopic risk was identified, supporting diverticulectomy as a safe operative approach. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of follicular carcinoma is often difficult to make on pathological analysis, as the histological distinction from follicular adenoma rests solely on the presence of capsular or vascular invasion. Even on retrospective review of the histopathology after the disease biology has declared itself as malignant, the pathological diagnosis of malignancy may not be possible to make. Methods: We report three cases in which patients were initially diagnosed with benign follicular lesions, but re‐presented with locally recurrent disease and a subsequent malignant disease course. Results: We describe a rare entity of follicular thyroid carcinoma that demonstrates a locally recurrent and eventually metastatic disease phenotype, despite persistently benign pathological findings. Conclusion: We highlight that if local recurrence occurs in discrete anatomical tissue planes, or in the thyroid bed following open total thyroidectomy for 'benign multinodular goitre', the possibility of this rare presentation of follicular thyroid carcinoma should be considered. [ABSTRACT FROM AUTHOR]

Background: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumours, often associated with germline mutations that influence the disease biology and clinical course. We aimed to describe the genotypic and phenotypic characteristics of a consecutive series of PPGL patients and correlate mutation status with clinical outcomes. Methods: We performed a retrospective cohort study of all PPGL patients who presented to a tertiary referral centre between March 2005 and February 2022. Genotypic, phenotypic and follow-up data were analysed. Results: A total of 140 patients were included. Of these, 94 (67%) patients underwent genetic testing and a mutation was detected in 36 (38%) patients. Mutation presence was associated with younger age, smaller tumour size and bilateral adrenal tumours. Disease recurrence occurred at a median time of 5.4 (IQR 2.8–11.0) years after treatment in 21 (15%) patients, of which 14 (67%) had a mutation in a susceptibility gene. Recurrence pattern was influenced by mutation type; higher local recurrence risk for SDHA, SDHB, and MEN2B disease, and higher metastatic risk for SDHB, VHL and MEN2A disease. Recurrence occurred in three (3%) patients with mutation absence. Multivariate analysis revealed that age ≤40 years and mutation presence were associated with increased risk of disease recurrence. Conclusions: Genotypic characteristics strongly influence disease presentation and recurrence risk, which may occur more than 5 years after initial treatment. Routine genetic testing of PPGL patients is warranted given the high prevalence of mutations, allowing for prognostication and tailored follow-up. In the presence of germline mutations, follow-up should be life-long. [ABSTRACT FROM AUTHOR]

Background: Encapsulated angioinvasive follicular thyroid carcinoma (EAFTC) is associated with an increased risk of distant metastasis and reduced survival compared to minimally invasive follicular thyroid carcinoma (MIFTC). There is controversy regarding the extent of surgery and adjuvant radioactive iodine therapy for angioinvasive follicular thyroid carcinoma when stratified by number of foci of angioinvasion. Methods: All follicular thyroid carcinoma cases from 1990–2018 were identified from a thyroid cancer database. Primary outcomes were distant metastasis-free survival (DMFS) and disease-specific survival (DSS) with factors of interest being age, gender, tumour size, treatment, foci of angioinvasion and histological subtype. Results: A total of 292 cases were identified; 139 MIFTC, 141 EAFTC and 12 widely invasive follicular thyroid carcinoma (WIFTC). Over a follow-up period of 6.25 years, DMFS was significantly reduced (p < 0.001) with 14.2% (EAFTC) and 50% of WIFTC developing metastasis. The risk of metastasis in EAFTC with ≥ 4 foci of angioinvasion was 31.7% (HR = 5.89, p = 0.004), 6.3% for EAFTC with < 4 foci of angioinvasion (HR = 1.74, p = 0.47), compared to 3.6% MIFTC. Age ≥ 50 years (HR = 4.24, p = 0.005) and tumour size (HR = 1.27, p = 0.014) were significantly associated with increased risk of distant metastasis. DSS was reduced significantly (p < 0.001), with 7.8% EAFTC patients dying of disease. For EAFTC patients, DSS was 96.8% for < 4 foci and 82.6% for ≥ 4 foci of angioinvasion (p = 0.003). Conclusion: EAFTC is at increased risk of distant metastasis related to the extent of angioinvasion. Tumours with < 4 foci of angioinvasion should be considered for a total thyroidectomy, particularly in older patients. [ABSTRACT FROM AUTHOR]

Background: Advances in technology and techniques have allowed for robotic distal pancreatectomies to be readily performed in patients at high volume centres. This study describes the experience of a single surgeon during the learning curve and transition from open to robotic distal pancreatectomy in Australia, a traditionally low volume pancreatic surgery country. Methods: All patients undergoing distal pancreatectomy at an Australian-based tertiary referral centre between 2010 and 2021 were reviewed retrospectively. Demographic, clinicopathologic and survival data were analysed to compare perioperative and oncological outcomes between patients who underwent open, laparoscopic and robotic distal pancreatectomies. Results: A total of 178 distal pancreatectomies were identified for analysis during the study period. Ninety-one open distal pancreatectomies (ODP), 48 laparoscopic distal pancreatectomies (LDP), and 39 robotic distal pancreatectomies (RDP) were performed. Robotic distal pancreatectomy was non-inferior with respect to perioperative outcomes and yielded statistically non-significant advantages over LDP and ODP. Conclusion: RDP is feasible and can be performed safely in well-selected patients during the learning phase at large pancreatic centres in a traditionally low-volume country like Australia. Referral to large pancreatic centres where access to the robotic platform and surgeon experience is not a barrier, and where a robust multidisciplinary team meeting can take place, remains pivotal in the introduction and transition toward the robotic approach for management of patients with pancreatic body or tail lesions. [ABSTRACT FROM AUTHOR]

The fifth edition of the WHO Classification of Tumours of the Urinary and Male Genital Systems encompasses several updates to the classification and diagnosis of prostatic carcinoma as well as incorporating advancements in the assessment of its prognosis, including recent grading modifications. Some of the salient aspects include: (1) recognition that prostatic intraepithelial neoplasia (PIN)‐like carcinoma is not synonymous with a pattern of ductal carcinoma, but better classified as a subtype of acinar adenocarcinoma; (2) a specific section on treatment‐related neuroendocrine prostatic carcinoma in view of the tight correlation between androgen deprivation therapy and the development of prostatic carcinoma with neuroendocrine morphology, and the emerging data on lineage plasticity; (3) a terminology change of basal cell carcinoma to "adenoid cystic (basal cell) cell carcinoma" given the presence of an underlying MYB::NFIB gene fusion in many cases; (4) discussion of the current issues in the grading of acinar adenocarcinoma and the prognostic significance of cribriform growth patterns; and (5) more detailed coverage of intraductal carcinoma of prostate (IDC‐P) reflecting our increased knowledge of this entity, while recommending the descriptive term atypical intraductal proliferation (AIP) for lesions falling short of IDC‐P but containing more atypia than typically seen in high‐grade prostatic intraepithelial neoplasia (HGPIN). Lesions previously regarded as cribriform patterns of HGPIN are now included in the AIP category. This review discusses these developments, summarising the existing literature, as well as the emerging morphological and molecular data that underpins the classification and prognostication of prostatic carcinoma. [ABSTRACT FROM AUTHOR]

The 5th edition of the WHO Classification of Tumours of the Urinary and Male Genital Systems contains relevant revisions and introduces a group of molecularly defined renal tumour subtypes. Herein we present the World Health Organization (WHO) 2022 perspectives on papillary and chromophobe renal cell carcinoma with emphasis on their evolving classification, differential diagnosis, and emerging entities. The WHO 2022 classification eliminated the type 1/2 papillary renal cell carcinoma (pRCC) subcategorization, given the recognition of frequent mixed tumour phenotypes and the existence of entities with a different molecular background within the type 2 pRCC category. Additionally, emerging entities such as biphasic squamoid alveolar RCC, biphasic hyalinising psammomatous RCC, papillary renal neoplasm with reverse polarity, and Warthin‐like pRCC are included as part of the pRCC spectrum, while additional morphological and molecular data are being gathered. In addition to oncocytomas and chromophobe renal cell carcinoma (chRCC), a category of 'other oncocytic tumours' with oncocytoma/chRCC‐like features has been introduced, including emerging entities, most with TSC/mTOR pathway alterations (eosinophilic vacuolated tumour and so‐called 'low‐grade' oncocytic tumour), deserving additional research. Eosinophilic solid and cystic RCC was accepted as a new and independent tumour entity. Finally, a highly reproducible and clinically relevant universal grading system for chRCC is still missing and is another niche of ongoing investigation. This review discusses these developments and highlights emerging morphological and molecular data relevant for the classification of renal cell carcinoma. [ABSTRACT FROM AUTHOR]

I Sir i : Proliferative fasciitis (PF) and proliferative myositis (PM) are benign mass-forming proliferations composed of ganglion-like cells and plump myofibroblastic cells occurring in the subcutaneous tissue (PF) or skeletal muscle (PM).1 Makise and colleagues2 recently identified I FOS i rearrangements and protein overexpression in five cases of adult PF/PM. Although the specificity of FOS in our series was high (98.9%), full sections were not employed for most of the TMA cases, and in the previous study2 sarcomas with epithelioid morphology (and nodular fasciitis) were described to show moderate to strong FOS expression below the 50% cut-off. Due to the nature of our sarcoma cohort studied on TMAs, and considering the heterogeneous expression of FOS, it is possible that the true prevalence of FOS immunostaining in sarcomas and entities unrelated to PF/PM could be significantly higher. [Extracted from the article]

Myeloid sarcoma (MS), also termed 'chloroma' or 'granulocytic sarcoma', is a tumour mass consisting of myeloid blasts occurring at an anatomical site other than the bone marrow. MS occurs in up to 8% of patients with acute myeloid leukaemia. While MS typically involves the skin or lymph nodes, almost any tissue can be affected, and symptoms largely depend on the organ involved and subsequent mass effect. We present a case series of patients that presented to a tertiary hospital with MS affecting the central nervous system over a 4‐month period. These three cases demonstrate the vast spectrum of clinical presentations of MS and, furthermore, show rare examples of intramedullary spinal cord involvement and disseminated intraparenchymal brain disease. [ABSTRACT FROM AUTHOR]

Aims: Loss of expression of mammalian switch/sucrose‐non‐fermentable (SWI/SNF) [BRG1/BRM‐associated factor (BAF)] complex subunits, including SMARCA4, SMARCA2 and INI1/SMARCB1 (termed SWI/SNF complex deficiency), has been reported in colorectal carcinomas (CRCs) but its frequency and clinical significance are uncertain. Methods and results: We performed immunohistochemistry for SMARCA4, SMARCA2 and SMARCB1 on 4508 consecutive resected CRCs. Loss of SMARCA4 expression was found in 13 cases (0.3%), loss of SMARCA2 expression was found in 59 cases (1.3%), and loss of SMARCB1 expression was found in 21 cases (0.4%). Some CRCs showed loss of expression of more than one subunit, so that 84 CRCs (1.7%) were deficient for at least one component. SWI/SNF complex deficiency was associated with higher grade, a right‐sided location, mismatch repair deficiency, and BRAF V600E mutation (P < 0.05); 5.8% of mismatch repair‐deficient (MMRd) cases and 5.4% of BRAF V600E‐mutant cases were SWI/SNF complex‐deficient, as compared with 0.9% and 0.4% of mismatch repair‐proficient and BRAF‐wild‐type cases (P < 0.001). Any loss of SMARCB1 expression and global loss of SMARCA2 expression were associated with statistically significant worse overall survival, whereas SMARCA4‐deficient cases showed a trend only towards poor overall survival (P = 0.121). In multivariate analysis, any loss of SMARCA4 expression and global loss of SMARCA2 expression were associated with worse survival [odds ratio (OR) 3.33, P = 0.019; and OR 3.39, P < 0.001]. Of particular note, among the subgroup of cases that were MMRd and BRAF V600E‐mutated (otherwise considered to be a good prognostic group), loss of SMARCA4 expression was associated with much worse median survival (10.5 months versus 110.9 months; P = 0.003). Conclusions: SWI/SNF complex deficiency is rare in CRC but is enriched in MMRd cases. Identifying these cases has morphological associations and prognostic significance, and in the future may have potential therapeutic implications. [ABSTRACT FROM AUTHOR]

Aims: Amplification of the murine double minute-2 (MDM2) gene, which is usually detected with fluorescence in-situ hybridisation (FISH), is the key driving event for atypical lipomatous tumours (ALTs)/welldifferentiated liposarcomas (WDLs). We sought to determine the concordance between the histopathological findings and MDM2 FISH in the diagnosis of ALT/WDL, and to identify the histological features of MDM2-amplified tumours lacking classic atypia. Methods and results: We performed a retrospective analysis of all mature lipomatous lesions subjected to MDM2 FISH analysis at our institution. MDM2 FISH analysis was performed on 439 mature lipomatous lesions: 364 (82.9%) were negative and 75 (17%) were positive. In 17 of 75 (22.6%) ALTs/WDLs, cytological atypia was not identified on initial histological assessment, thus favouring lipoma. On review, these cases shared common histological features, consisting of a very low number of relatively small stromal cells within the tumour lobules, with mildly coarse chromatin and oval nuclei, admixed with unremarkable adipocytes in a tumour background devoid of fibroconnective septa, areas of fibrosis, or blood vessels. These cells matched the cells in which FISH showed MDM2 amplification. In contrast, 13 cases (3.5%) regarded as suspicious for ALT/WDL on the basis of histology lacked MDM2 amplification and were reclassified following the FISH findings. Conclusions: We conclude that a subset of lipomalike ALTs/WDLs are not associated with any of the features typically described in ALT/WDL. Our study also showed that tumours >100 mm are more likely to be ALT/WDL; however, a history of recurrence or concerning clinical/radiological features was not significantly associated with classification as ALT/WDL. [ABSTRACT FROM AUTHOR]

Background and Aims: Cancer‐associated stroma (CAS) is emerging as a key determinant of metastasis in colorectal cancer (CRC); however, little is known about CAS in colorectal liver metastases (CRLM). This study aimed to validate the prognostic significance of stromal protein biomarkers in primary CRC and CRLM. Secondly, this study aimed to describe the transcriptome of the CAS of CRLM and identify novel targetable pathways of metastasis. Methods: A case–control study design from a prospectively maintained database was adopted. The prognostic value of epithelial and stromal CALD1, IGFBP7, POSTN, FAP, TGF‐β and pSMAD2 expression was assessed by immunohistochemistry (IHC) in multivariate models. Pathway enrichment and sparse partial least square‐discriminant analysis (sPLS‐DA) were performed on a nested cohort after isolating epithelial tumour and CAS by laser capture microdissection. Results: 110 CRCs with 124 paired CRLMs, and 110 matched non‐metastatic control CRCs were included. Median follow‐up was 62 and 45 months for primary and CRLM groups, respectively. Stromal FAP and POSTN were independent predictors for the development of CRLM. After CRLM resection, stromal IGFBP7 and POSTN were predictors of poorer survival. sPLS‐DA on the nested cohort identified a number of novel targetable stromal genes and pathways that defined poor prognosis CRC and the CAS of CRLM. Conclusions: This study is the first to describe key differences in stromal gene expression between paired primary CRC and CRLM as well as identifying several targetable biomarkers and transcriptomic pathways whose relevance specifically in the CAS of CRC and CRLM have not been previously described. [ABSTRACT FROM AUTHOR]

Aims: Amplification of the murine double minute‐2 (MDM2) gene, which is usually detected with fluorescence in‐situ hybridisation (FISH), is the key driving event for atypical lipomatous tumours (ALTs)/well‐differentiated liposarcomas (WDLs). We sought to determine the concordance between the histopathological findings and MDM2 FISH in the diagnosis of ALT/WDL, and to identify the histological features of MDM2‐amplified tumours lacking classic atypia. Methods and results: We performed a retrospective analysis of all mature lipomatous lesions subjected to MDM2 FISH analysis at our institution. MDM2 FISH analysis was performed on 439 mature lipomatous lesions: 364 (82.9%) were negative and 75 (17%) were positive. In 17 of 75 (22.6%) ALTs/WDLs, cytological atypia was not identified on initial histological assessment, thus favouring lipoma. On review, these cases shared common histological features, consisting of a very low number of relatively small stromal cells within the tumour lobules, with mildly coarse chromatin and oval nuclei, admixed with unremarkable adipocytes in a tumour background devoid of fibroconnective septa, areas of fibrosis, or blood vessels. These cells matched the cells in which FISH showed MDM2 amplification. In contrast, 13 cases (3.5%) regarded as suspicious for ALT/WDL on the basis of histology lacked MDM2 amplification and were reclassified following the FISH findings. Conclusions: We conclude that a subset of lipoma‐like ALTs/WDLs are not associated with any of the features typically described in ALT/WDL. Our study also showed that tumours >100 mm are more likely to be ALT/WDL; however, a history of recurrence or concerning clinical/radiological features was not significantly associated with classification as ALT/WDL. [ABSTRACT FROM AUTHOR]

Background: The early and accurate diagnosis of pancreatic ductal adenocarcinoma is vital for improving the efficacy of therapeutic interventions and to provide patients with the best chance of survival. While endoscopic ultrasound‐fine needle aspiration (EUS‐FNA) has been demonstrated to be a reliable and accurate diagnostic tool for solid pancreatic neoplasms, the ongoing management of patients with a high clinical suspicion for malignancy but with a negative EUS‐FNA biopsy result can prove a challenge. Methods: We describe five patients from a single centre who presented for further work‐up of a pancreatic mass and/or imaging features concerning for a periampullary malignancy. Results: All patients had at least one EUS‐FNA biopsy performed which returned no malignant cells on cytology. Despite these negative cytology results, all patients underwent further invasive investigation through upfront resection (pancreaticoduodenectomy) or extra‐pancreatic biopsy (laparoscopic biopsy of peritoneal nodule) due to worrisome features on imaging, biochemical factors and clinical presentation culminating in a high degree of suspicion for malignancy. The final tissue histopathological diagnosis in all patients was pancreatic ductal adenocarcinoma. Conclusion: This case series highlights the important clinical findings, imaging and biochemical features which need to be considered in patients who have high suspicion for malignancy despite having a negative EUS‐FNA cytology result. In these patients with a high index of suspicion, surgical intervention through an upfront resection or further invasive investigation should not be delayed. [ABSTRACT FROM AUTHOR]

Aims: Current guidelines for pathology reporting on pancreatic cancer differ in certain aspects, resulting in divergent reporting practices and a lack of comparability of data. Here, we report on a new international dataset for pathology reporting on resection specimens with cancer of the exocrine pancreas (ductal adenocarcinoma and acinar cell carcinoma). The dataset was produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), which is a global alliance of major (inter)national pathology and cancer organisations. Methods and results: According to the ICCR's rigorous process for dataset development, an international expert panel consisting of pancreatic pathologists, a pancreatic surgeon and an oncologist produced a set of core and non‐core data items based on a critical review and discussion of current evidence. Commentary was provided for each data item to explain the rationale for selecting it as a core or non‐core element and its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the document was finalised and ratified, and the dataset, which includes a synoptic reporting guide, was published on the ICCR website. Conclusions: This first international dataset for cancer of the exocrine pancreas is intended to promote high‐quality, standardised pathology reporting. Its widespread adoption will improve the consistency of reporting, facilitate multidisciplinary communication, and enhance the comparability of data, all of which will help to improve the management of pancreatic cancer patients. [ABSTRACT FROM AUTHOR]

Backgrounds: Solid pseudopapillary neoplasms (SPNs) are a distinct but rare form of lowgrade pancreatic neoplasia, accounting for 0.3%–2.7% of all pancreatic tumours. They are most common in young females. Local recurrence and distant metastasis are reported but extremely rare, and are usually resectable with curative intent. We report the clinicopathological features and long-term outcomes of SPNs following surgical resection from a single institution. Methods: A total of 1296 patients undergoing pancreatic resection during the 30 years period from 1991 to 2020 were retrospectively reviewed, and those with a confirmed pathological diagnosis of pancreatic SPN on review were included. Results: Twenty-two patients (1.7% of all patients undergoing resection), were identified. Twenty patients (91%) were female. Unlike previous studies, most patients (91%) were symptomatic at diagnosis. On diagnostic CT, cystic components were visible in 16 patients (73%), calcifications were found in two patients (9%), haemorrhage in one patient (5%) and a defined capsule was seen in four patients (18%). Surgical resection was undertaken on all cases, with distal pancreatectomy the most commonly performed (n = 11, 50%). One patient (4.7%) had nodal involvement, nine patients had an incomplete tumour capsule (41%) and seven patients (32%) had tumour extension into the pancreatic parenchyma. Despite this, no patients had disease recurrence at 10 years. One patient died within 5 years of heart failure unrelated to the SPN process; no patients died within 10 years of the disease. Conclusion: We confirm a high proportion of female patients. Interestingly, a high proportion of our cohort was investigated for symptomatic disease. Despite a high proportion of tumours with an incomplete capsule, and extension into the pancreatic parenchyma, our findings indicated that SPN patients have excellent survival after margin-negative surgical resection. [ABSTRACT FROM AUTHOR]

Aims: Myxoid liposarcoma (MLPS) is characterised by DNA damage‐inducible transcript 3 (DDIT3) gene rearrangements, confirmation of which is commonly used diagnostically. Recently, DDIT3 immunohistochemistry (IHC) has been reported to be highly sensitive and, when strict criteria are employed, specific for the diagnosis of MLPS. The aim of this study was to independently investigate DDIT3 IHC as a diagnostic marker for MLPS. Methods and results: DDIT3 IHC was performed on 52 MLPS and on 152 mimics on whole sections, and on 515 non‐MLPS sarcomas in tissue microarray format. Only one MLPS (which had undergone acid‐based decalcification) was completely negative. With inclusion of this case if any nuclear expression is considered to indicate positivity, the overall sensitivity of DDIT3 is 98% (51 of 52 cases) and the specificity is 94% (633 of 667 non‐MLPS cases are negative). If a cut‐off of >10% of neoplastic cells is required for positivity, then the sensitivity remains 98% (51/52) and the specificity is 98.5% (657 of 667 non‐MLPS cases are negative). If a cut‐off of >50% of cells is required for positivity, then the sensitivity is 96% (50 of 52 cases) but the specificity improves to 100%. Conclusions: Diffuse nuclear DDIT3 expression occurs in the overwhelming majority of MLPSs, and can be used to confirm the diagnosis in most cases without the need for molecular testing. A complete absence of expression argues strongly against MLPS, and almost completely excludes this diagnosis, particularly if there is consideration of technical factors such as decalcification. The significance of focal DDIT3 expression should be interpreted in the morphological and clinical context, although most tumours showing only focal expression are not MLPS. [ABSTRACT FROM AUTHOR]

Aims: NTRK‐rearranged sarcomas are emerging as a distinct class of sarcomas of particular importance in the era of targeted therapy. The aim of this study was to use array comparative genomic hybridisation (aCGH) to explore the cytogenetic profile of six adult soft tissue sarcomas harbouring NTRK gene fusions. Methods and results: aCGH was performed on six adult soft tissue sarcomas with proven NTRK rearrangements [NTRK1, n = 1 (TPM3–NTRK1); NTRK2, n = 1 (MTMR2–NTRK2); NTRK3, n = 4 (two ETV6–NTRK3; two with unknown partners). The morphological patterns of these cases included inflammatory myofibroblastic tumour‐like, fibrosarcoma/malignant peripheral nerve sheath tumour‐like, and Ewing sarcoma‐like. On the basis of the number of chromosomal copy number variations (CNVs), ranging from two to 15 per sample, NTRK‐associated sarcomas could be subdivided into two groups: one with a relatively simple karyotype (n = 2; median of three genomic alterations), and those with a more complex karyotype (n = 4; median of 11 genomic imbalances). Recurrent chromosomal CNVs included gains at chromosomes 6p, 1q, 7 (whole chromosome), and 12p, and losses at chromosomes 10q, 13q, 19q, and 9p. Conclusions: NTRK‐rearranged sarcomas constitute a heterogeneous group of tumours that can show a relatively simple or a complex karyotype. Although there were some, but inconsistent, associations between karyotype complexity and morphology, our study showed that a more complex karyotype in this group of tumours appeared to correlate with more aggressive clinical behaviour. Gains at chromosome 6p and 1q were the most common recurrent genomic alterations, being present in 67% of the samples (4/6), followed by gains at chromosome 7, which were present in 50% of the samples (3/6). [ABSTRACT FROM AUTHOR]

Background: Postoperative pancreatic fistula (POPF) is a potentially lethal complication of pancreatic surgery. POPF rate is consistently higher after distal pancreatectomy (DP) compared with pancreatoduodenectomy (PD). The acinar score of the remnant pancreas is associated with postoperative pancreatitis and POPF. This study aimed to: (i) confirm the difference in POPF rate after DP vs PD; (ii) confirm the association between acinar score and POPF; and (iii) evaluate the difference in acinar scores between DP and PD. Methods: Patients undergoing DP or PD at a single institution from 2011 to 2017 were included. Hematoxylin and eosin‐stained slides of the pancreatic resection margin were evaluated for all patients and scored for acinar cell density. Clinicopathological data were retrieved from a prospectively maintained database. Results: Two hundred and ninety‐four patients were included in the analysis (206 PD, 88 DP). The POPF rate was significantly higher after DP than PD (20.4% vs 11.2%, P =.043). Acinar score >50 was independently associated with the development of POPF (OR 6.457, P =.003). DP was associated with a higher median acinar score than PD (65 vs 50, P <.001). Conclusion: The POPF rate is significantly higher after DP compared with PD and is attributable to a higher acinar score of the pancreatic resection margin. [ABSTRACT FROM AUTHOR]

The clinical implication of a misdiagnosis renders SCPD as an important differential for patients presenting with cystic lesions of the pancreas. A 57-year-old female with a background of melanoma and bilateral mastectomy for breast cancer presented with multiple pancreatic cysts detected on abdominal ultrasound. On immunohistochemistry, the epithelium was positive for markers of ductal differentiation (c - CK-19) and squamous differentiation (d - p40). gl This is the first reported Australian case of SCPDs, which are rare benign intraductal lesions lined by non-keratinized squamous epithelium. [Extracted from the article]

Background: This study aimed to examine the presentation, treatment, and long‐term outcomes of patients with gallbladder carcinoma (GBC) managed in a surgical unit of an Australian tertiary referral hospital of a 19‐year period. Methods: A retrospective review of prospectively collected data of patients with GBC managed in the Royal North Shore Upper GI Surgical department from October 1999 to March 2018. Results: A total of 104 patients with GBC were identified: 36 patients underwent palliative treatment, 61 patients with gallbladder adenocarcinoma underwent resection with curative intent. Seven patients were excluded. 'Simple cholecystectomy' was undertaken in eight patients, 'standard radical cholecystectomy' in 37 and 'extended radical resection' in 16. The median survival in these patients was 35 months (95% confidence interval (CI) 21.29–55.10), with a median follow up of 60 months (95% CI 38.18–78.39). This compares with an overall median survival of only 4.00 months (95% CI 2.79–6.24) in patients who did not undergo a potentially curative resection. Independent predictors of poor long‐term survival included an elevated preoperative serum tumour marker, advanced tumour stage (T3/T4) or node positive disease (N1/N2). Conclusion: The biology and stage of GBC at presentation are major factors in determining patient outcome. There is a need for better pre‐ and post‐operative predictors to improve risk stratification, and these are likely to be in the form of molecular markers. Although the focus of surgery should be to ensure an R0 resection, patients with advanced stage disease need to be carefully selected for surgical intervention, and ideally should be managed by a multidisciplinary team in a specialist centre. [ABSTRACT FROM AUTHOR]

Background: The occurrence of distant metastasis (DM) is the most important prognostic factor influencing survival outcomes in differentiated thyroid cancer (DTC). Identifying patients who are likely to develop DM and offering these cases more aggressive surgical approaches and I‐131 therapy, is paramount to achieving the best possible outcomes. DM on presentation in DTC are uncommon, with an incidence of 1–9%. However, the incidence of DTC is rising and the disease affects a relatively young cohort of patients. The aims of this study were to investigate predictive factors in the development of DM by comparing a homogenous group of DTC patients with and without DM, and to illustrate the overall and disease‐specific survival (DSS) rates of DTC patients presenting with DM. Methods: A matched case–control study of patients with DTC and DM was undertaken. The study group comprised a consecutive series of cases with DM treated in the period 1968–2014. Patients with DM at initial presentation were identified (DTC‐DM group). A control group of patients without DM were matched based on age, gender, tumour size and histological subtype. The primary outcome measures were overall and disease‐free survival. Secondary outcome measures were lymph node involvement (LNI), extra‐thyroidal extension (ETE) of tumour and presence of BRAFV600E mutation identified on immunohistochemistry. Results: A total of 2547 patients with DTC were reviewed and of these 83 (3.26%) had DM at initial presentation. At 5 and 10 years, the overall survival rates for DTC‐DM patients were 89.6% and 64%, respectively. The 5 and 10 year DSS rates for DTC‐DM cases were 90.2% and 67.3%, respectively. When compared to the DTC group, the DTC‐DM group had significantly higher rates of ETE (63% vs. 29.5%, P < 0.0001) and LNI (32.5% vs. 18.8%, P = 0.044). Among patients with papillary thyroid cancer (PTC), the presence of BRAFV600E mutation was significantly associated with DM (62.2% vs. 36.8%, P = 0.028). Conclusion: ETE, LNI and BRAFV600E mutation in PTC are significant predictors for the development of distant metastatic disease. [ABSTRACT FROM AUTHOR]

Our study aimed to identify a urinary metabolite panel for the detection/diagnosis of pancreatic ductal adenocarcinoma (PDAC). PDAC continues to have poor survival outcomes. One of the major reasons for poor prognosis is the advanced stage of the disease at diagnosis. Hence, identification of a novel and cost‐effective biomarker signature for early detection/diagnosis of PDAC could lead to better survival outcomes. Untargeted metabolomics was employed to identify a novel metabolite‐based biomarker signature for PDAC diagnosis. Urinary metabolites from 92 PDAC patients (56 discovery cohort and 36 validation cohort) were compared with 56 healthy volunteers using 1H nuclear magnetic resonance spectroscopy. Multivariate (partial‐least squares discriminate analysis) and univariate (Mann‐Whitney's U‐test) analyses were performed to identify a metabolite panel which can be used to detect PDAC. The selected metabolites were further validated for their diagnostic potential using the area under the receiver operating characteristic (AUROC) curve. Statistical analysis identified a six‐metabolite panel (trigonelline, glycolate, hippurate, creatine, myoinositol and hydroxyacetone), which demonstrated high potential to diagnose PDAC, with AUROC of 0.933 and 0.864 in the discovery and validation cohort, respectively. Notably, the identified panel also demonstrated very high potential to diagnose early‐stage (I and II) PDAC patients with AUROC of 0.897. These results demonstrate that the selected metabolite signature could be used to detect PDAC and will pave the way for the development of a urinary test for detection/diagnosis of PDAC. What's new?: Although most cases of pancreatic ductal adenocarcinoma (PDAC) are diagnosed after metastasis, roughly 8 years elapse between the initial mutation and the development of metastasis, representing a potential screening window. The current lack of sensitive and inexpensive diagnostic tests for early PDAC makes population screening impractical. However, this study using 1H nuclear magnetic resonance spectroscopy identifies a six‐metabolite panel (trigonelline, glycolate, hippurate, creatine, myoinositol and hydroxyacetone) that shows good sensitivity and specificity in both the discovery cohort and an independent validation cohort, demonstrating its potential for development into a clinically useful diagnostic test for PDAC. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) of the gastrointestinal tract (GIT) comprise neuroendocrine tumours (NETs) and neuroendocrine carcinomas (NECs). During the last decade the classification and grading of GIT NENs has undergone significant changes, culminating in the World Health Organisation (WHO) 2019 classification. These changes, some of which are attributable to an only partially successful attempt to achieve uniform nomenclature among different organs, include: slight changes to the cut‐off used for the Ki‐67 proliferative index to distinguish grade 1 from grade 2 NETs; an emphasis on the distinction between grade 3 NETs (low‐grade NETs with a high proliferative rate) and NECs which, by definition, are all high grade; classification of tumours with mixed non‐neuroendocrine and neuroendocrine differentiation as MiNENs; and replacement of the term 'goblet cell carcinoid' with 'goblet cell adenocarcinoma'. While some of these changes seem minor, even semantic, each was made for very specific reasons which reflect an improved understanding of neuroendocrine neoplasia. The changes have definite implications for pathologists in clinical practice, not all of which may be readily apparent. This review is an attempt to explain the background behind each of the recent changes to the classification of neuroendocrine neoplasms of the gastrointestinal tract and summarise their impact on surgical pathologists – including a guide on how to approach certain recurrent difficulties encountered with the WHO 2019 system in routine clinical practice. [ABSTRACT FROM AUTHOR]

Interestingly, histopathology reported a fibroinflammatory lesion composed of lobules of fat necrosis, consistent with sclerosing mesenteritis (SM), as opposed to the expected diagnosis of a carcinoid tumour (Fig. An 81-year-old man was referred to our unit following an incidental finding of a spiculated lesion in the small bowel mesentery on computed tomography (CT) for investigation of microscopic haematuria. One prospective study of CT scans from 613 patients revealed an incidence of 3.42% when strict criteria were applied.1 SM is seen twice as commonly in men than in women and typically in older, Caucasian men.2 Patients may present with or without symptoms. [Extracted from the article]

Aims: Synovial sarcoma is defined by recurrent t(X;18)(p11;q11) translocations creating SS18–SSX1, SS18–SSX2 or SS18–SSX4 fusions. Recently, a novel rabbit monoclonal antibody designed to identify these fusions (SS18–SSX, clone E9X9V) was proposed to be highly specific (100%), but not completely sensitive (95%) for this diagnosis. Another antibody designed to identify the C‐terminal end of SSX (SSX_CT, clone E5A2C) was proposed to be highly sensitive (100%), but not completely specific (96%). We sought to validate these antibodies in an independent cohort. Methods and results: We performed immunohistochemistry for SS18–SSX and SSX_CT on 39 synovial sarcoma samples from 25 patients with confirmed gene rearrangements. Thirty‐four (87%) and 36 (92%) were positive for SS18–SSX and SSX_CT, respectively. False‐negative staining was associated with suboptimally handled small biopsies and decalcified specimens, even when staining was diffuse and strong in subsequent optimally processed excisions and non‐decalcified areas. None of 580 non‐synovial sarcoma tumours (76 whole sections, 504 TMA samples) were positive for SS18–SSX (100% specificity), whereas 39 (93% specificity) were positive for SSX_CT. Conclusions: SS18–SSX fusion‐specific IHC is 87–95% sensitive for the diagnosis of synovial sarcoma and highly (perhaps perfectly) specific. Therefore, positive SS18–SSX staining definitively confirms the diagnosis of synovial sarcoma. SSX_CT is less specific (93–96%) but highly sensitive (92%, but approaching 100% when suboptimally processed biopsies and decalcified specimens are excluded). Negative SSX_CT staining may therefore have an ancillary role as a rule‐out test for synovial sarcoma. We caution that both antibodies are prone to false‐negative staining in decalcified specimens. [ABSTRACT FROM AUTHOR]

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours with a hereditary background in over one‐third of patients. Mutations in succinate dehydrogenase (SDH) genes increase the risk for PPGLs and several other tumours. Mutations in subunit B (SDHB) in particular are a risk factor for metastatic disease, further highlighting the importance of identifying SDHx mutations for patient management. Genetic variants of unknown significance, where implications for the patient and family members are unclear, are a problem for interpretation. For such cases, reliable methods for evaluating protein functionality are required. Immunohistochemistry for SDHB (SDHB‐IHC) is the method of choice but does not assess functionality at the enzymatic level. Liquid chromatography–mass spectrometry‐based measurements of metabolite precursors and products of enzymatic reactions provide an alternative method. Here, we compare SDHB‐IHC with metabolite profiling in 189 tumours from 187 PPGL patients. Besides evaluating succinate:fumarate ratios (SFRs), machine learning algorithms were developed to establish predictive models for interpreting metabolite data. Metabolite profiling showed higher diagnostic specificity compared to SDHB‐IHC (99.2% versus 92.5%, p = 0.021), whereas sensitivity was comparable. Application of machine learning algorithms to metabolite profiles improved predictive ability over that of the SFR, in particular for hard‐to‐interpret cases of head and neck paragangliomas (AUC 0.9821 versus 0.9613, p = 0.044). Importantly, the combination of metabolite profiling with SDHB‐IHC has complementary utility, as SDHB‐IHC correctly classified all but one of the false negatives from metabolite profiling strategies, while metabolite profiling correctly classified all but one of the false negatives/positives from SDHB‐IHC. From 186 tumours with confirmed status of SDHx variant pathogenicity, the combination of the two methods resulted in 185 correct predictions, highlighting the benefits of both strategies for patient management. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Stromal tumour-infiltrating lymphocytes (TILs) assessed using the ITWG system do not predict overall survival in a cohort of 337 cases of mesothelioma Keywords: International TILs Working Group; mesothelioma; tumour-infiltrating lymphocytes (TILs) EN International TILs Working Group mesothelioma tumour-infiltrating lymphocytes (TILs) 1095 1101 7 06/04/20 20200601 NES 200601 I Sir i : Assessment of tumour-infiltrating lymphocytes (TILs) is a subject of considerable interest, as accumulating evidence supports its prognostic value in a range of different malignancies.[[1]] With the ever-increasing use of immunotherapeutic agents, TILs, together with other components of the tumour microenvironment, present an opportunity to identify patients who are most likely to respond to these agents. In conclusion, we were unable to demonstrate a statistically significant association between stromal TILs, scored using the ITWG methodology, and overall survival in our cohort of 337 mesothelioma patients. Assessment of tumor infiltrating lymphocytes using International TILs Working Group (ITWG) system is a strong predictor of overall survival in colorectal carcinoma - a study of 1034 patients. [Extracted from the article]

Aims: Ameloblastic fibrosarcoma (AFS) is an aggressive odontogenic neoplasm featuring malignant mesenchymal stroma in addition to an ameloblastic epithelial component, and is hence considered to be the malignant counterpart of ameloblastic fibroma (AF). AFS is exceedingly rare, with <110 cases having been reported so far. Although BRAF mutations are recognised driver mutations in ameloblastoma, the molecular pathogenesis of AFS remains elusive. Methods and results: We herein describe seven AFSs that were analysed, for the first time, for mutations in the BRAF–NRAS pathway. The patients were four females and three males aged 23–57 years (median, 26 years). Three tumours developed after one or multiple recurrences of AF (4–20 years after initial diagnosis), two showed transition from AF‐like bland areas, and two developed de novo. All patients were treated with surgery; adjuvant chemotherapy was given to one patient. At the last follow‐up, five patients were alive and well (19–344 months). The remainder were lost to follow‐up. Histological examination showed variable sarcomatous overgrowth with varying degrees of atypia and increased mitotic activity. The epithelial component varied greatly according to the degree of sarcomatous overgrowth. Molecular testing revealed BRAF V600E mutations in five cases and NRAS p.Gln61Lys mutation in one case. One tumour was wild‐type. Conclusion: To our knowledge, this is the first study on BRAF/NRAS mutations in AFS. Given the activity of RAF and MEK inhibitors across different cancers harbouring V600E mutations, our data strongly suggest that all AFS cases should be genetically tested, and that targeted treatment approaches for this extremely rare sarcoma subtype should be clinically investigated. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular adenoma (HCA) is a rare benign liver tumour that may cause diagnostic and management dilemmas. This study describes the clinical and histopathological characteristics of patients who were treated for HCA in a tertiary referral hospital over a 17‐year period. Methods: A retrospective review was performed of prospectively collected data of all patients treated for HCA within the Northern Upper GI Surgical unit between 2002 and 2018. Immunohistochemical β‐catenin expression was evaluated. Results: Thirty‐two patients had histological or radiologically confirmed HCA. Twenty‐eight patients underwent 30 operations and four patients were treated conservatively. The median age of the operative group was 43 years (range 19–83) and most patients were female (95%). The median body mass index was 28.7 (range 20–51), and nine patients (33%) were obese. Seven patients (25%) had multifocal HCA. Evidence of prior bleed or rupture or a perceived risk of either a bleed or malignant change (i.e. tumours ≥50 mm) were the most common indications for resection. There were no perioperative mortalities. Nuclear expression of β‐catenin by immunohistochemical staining was negative in all cases and there was no malignancy identified in any of the resected lesions. Two patients required transarterial embolization and two patients required a second liver resection for residual HCA. Conclusion: HCA is a rare lesion predominantly affecting females. Haemorrhage is seen frequently on imaging studies, occasionally requiring urgent angioembolization and/or surgical intervention. Malignant transformation and immunohistochemical β‐catenin expression are uncommon. HCA may be multifocal and residual tumours usually require ongoing surveillance and occasionally further intervention. [ABSTRACT FROM AUTHOR]

Introduction: We investigated outcomes in a cohort of patients with a biochemical diagnosis of primary hyperparathyroidism (pHPT) undergoing surgery for asymptomatic disease or target organ damage, where a focussed or four-gland operation was undertaken and the histopathology only reported a "large normal" parathyroid gland (LNP). Methods and materials: Patients subjected to a parathyroidectomy for pHPT between 2012 and 2018 with a pathology of LNP were included. Patients with fat depletion or additional histological features of adenoma or hyperplasia in any of the resected glands were excluded. A control group was formed from 50 consecutive patients with the histological finding of adenoma or hyperplasia during the same study period. The primary outcome was biochemical normalisation of pHPT at 1–2 weeks and after 6 months post-operatively. Results: Forty-eight LNP patients (2% of all parathyroidectomies) were included in the study group with 50 matched controls. LNP patients had a lower biochemical cure rate (81% vs. 98% P < 0.05) and a higher risk of recurrence (10% vs. 0%, P = 0.06). LNP patients had a milder form of pHPT (Ca2+ 2.63 vs. 2.68 P < 0.05) with a smaller PTH and Ca2+ drop post-operatively. For LNP patients with failure, a definite additional cause of pHPT was found in only two patients. Conclusion: This study highlights a controversial area in pHPT and reports LNP as a cause of pHPT. The biochemical analysis of this LNP group supports a benefit in resection in the setting of pHPT, although the risk of failure (persistence/recurrence) is higher than those with adenoma or hyperplasia. Stricter post-operative follow-up of LNP patients should be considered. [ABSTRACT FROM AUTHOR]

Background: Patients may present with a resectable pancreatic tumour in the context of a concurrent primary extra‐pancreatic malignancy. These patients pose a dilemma regarding their suitability for surgery. We evaluated our experience with such patients who underwent pancreatic resection with curative intent and detailed their outcomes and rationale for surgical decision‐making. Methods: A retrospective review of patients with pancreatic concurrent extra‐pancreatic primary malignancy who underwent pancreatic resection at our institution over a 12‐year period (2005–2016) was performed. Clinical, histopathological and perioperative outcomes were reviewed. Results: Ten patients with a median age of 74 years (40–85 years) were identified. Secondary primary tumours included thyroid (n = 2), gastrointestinal (n = 4), small bowel neuroendocrine (n = 1), renal (n = 1) and haematological malignancies (n = 2). Pancreatic tumours included pancreatic ductal adenocarcinomas (n = 6), solid pseudopapillary neoplasms (n = 2) and ampullary carcinomas (n = 2). After a median follow up of 41.3 months (31.3–164 months), 8 of 10 patients were still alive. Two patients died due to metastatic disease from the secondary malignancy (small bowel neuroendocrine tumour and sigmoid colon adenocarcinoma). The post‐operative complication rate was 30% with no perioperative 90‐day mortality. Conclusion: Selected patients with a pancreatic and concurrent primary extra‐pancreatic malignancy may undergo curative pancreatic resection with favourable outcomes. [ABSTRACT FROM AUTHOR]

1a, b) showed a 42 × 38 × 50 mm enhancing mass anterior to the left kidney within the small bowel mesentery, containing flecks of calcification with a central region of low attenuation, suggestive of a small bowel carcinoid tumour. 3)[[1], [8]] and on excision speciemens submitted for pathological analysis it is easily distinguished from NET.[[4], [6]] Based on the patients abdominal pain and provisional diagnosis of an NET, surgical resection was planned. [Extracted from the article]

Background: Fumarate hydratase (FH)‐deficient renal cell carcinoma (RCC) is rare and highly aggressive and is believed to arise mostly in the setting of hereditary leiomyomatosis‐RCC syndrome with a germline mutation of FH. Because of the aggressiveness of these tumors and a frequent lack of ascertainable family history, these tumors may first present as metastases and be sampled by cytology. The cytologic findings of FH‐deficient RCC have not previously been reported. Methods: Cytologic and limited biopsy samples from patients with FH‐deficient RCC were reviewed retrospectively. Results: In total, 24 cytologic and limited biopsy samples from 19 patients (6 women and 13 men; age range, 22‐69 years) who had FH‐deficient RCC and metastasis at presentation were evaluated. These included 21 cytology samples ranging from malignant effusions (n = 7) to metastases (n = 11), to samples of primary kidney tumors (n = 3). The samples exhibited cells, often in clusters and abortive papillae, with voluminous, finely vacuolated cytoplasm and large, pleomorphic nuclei with prominent, viral inclusion‐like nucleoli. A distinctive finding of peripheral cytoplasmic clearing frequently was apparent, and intranuclear cytoplasmic pseudoinclusions were less frequent. Of 7 cell block and biopsy samples, several of which represented sampling from the same patient, all demonstrated tissue fragments that had discernable morphologic patterns associated with FH‐deficient RCC, including tubulocystic and intracystic papillary growth. Conclusions: Features characteristic and suggestive of FH‐deficient RCC may be identified in cytologic and small biopsy samples. Although the current samples were identified retrospectively in well characterized cases of FH‐deficient RCC, the authors argue that, with appropriate clinical correlation, these features are sufficiently distinctive to trigger recognition and confirmatory workup. Features suggestive of fumarate hydratase‐deficient renal cell carcinoma may be identified in cytology and small biopsy samples. Cells exhibit large, pleomorphic nuclei with prominent, inclusion‐like macronucleoli and voluminous cytoplasm, often with peripheral cytoplasmic clearing. [ABSTRACT FROM AUTHOR]

Abstract: Aim: To report on the pattern of care and survival of anaplastic lymphoma kinase rearranged non–small cell lung cancer (ALK+NSCLC) in a real‐world retrospective cohort from an Australian tertiary referral center. Methods: Individuals with a pathological diagnosis of ALK+NSCLC via immunohistochemistry and fluorescence in situ hybridization and a radiological diagnosis of stage IV disease were eligible. Patients were identified via the Pathology Department specimen database and electronic patient chart review. Data were collected and analyzed for baseline demographics, radiological pattern of disease and response to treatment, treatment sequencing, toxicity and survival. Results: Thirty‐five patients were identified over a 7‐year period from 2010 to 2016 and followed for a median of 23 months. Median overall survival (OS) in the entire cohort was immature at data cut, 46.0 months (95% confidence interval [CI], 22.53–69.47 months), with the longest surviving patient was alive 62.1 months since diagnosis. Objective radiological response rate overall across six potential treatments and six treatment lines (range 1–6) was 58.2%. Almost 50% received at‐least two lines of ALK inhibitor therapy with median OS in this group estimated to be 53.4 months (95% CI, 35.1 months–not reached). Toxicity was manageable with a low rate of ≥ grade 3 toxicity (n = 7). Forty‐eight percent relapsed within the CNS and 43% overall died due to CNS progression. In those with CNS diagnosis at baseline and/or progression within the CNS (n = 32), median OS was also 46.0 months (95% CI, 24.22–66.78 months). Conclusion: This retrospective cohort analysis of a single tertiary institution experience in treating ALK+NSCLC demonstrates impressive OS and the importance and impact of careful management of CNS disease in this patient population. [ABSTRACT FROM AUTHOR]

Background: The impact of the public and private hospital systems on major abdominal operations that are demanding on clinical resources, such as pancreatic surgery, has not been explored in an Australian setting. This study examines the perioperative outcome of patients undergoing pancreatoduodenectomy (PD) at a major public and private hospital. Methods: Patients undergoing PD between January 2004 and October 2015 were classified based on their health insurance status and location of where the surgery was performed. Clinical variables relating to perioperative outcome were retrieved and compared using univariate and multivariate analyses. Results: Four hundred and twenty patients underwent PD of whom 232 patients (55%) were operated on in the private hospital. Overall, there was no difference in morbidity and mortality in the public versus the private hospital. However, there were variations in public versus private hospital, this included longer duration of surgery (443 min versus 372 min; P < 0.001), increased estimated blood loss (683 mL versus 506 mL; P < 0.001) and more patients requiring perioperative blood transfusion (25% versus 13%; P = 0.001). Of the 10 complications compared, post‐operative bleeding was higher in the private hospital (11% versus 5%; P = 0.051) and intra‐abdominal collections were more common in the public hospital (11% versus 5%; P = 0.028). Independent predictive factors for major complications were American Society of Anesthesiologists score (odds ratio (OR) = 1.91; P = 0.050), patients requiring additional visceral resection (OR = 3.36; P = 0.014) and post‐operative transfusion (OR = 3.37; P < 0.001). The hospital type (public/private) was not associated with perioperative outcome. Conclusion: Comparable perioperative outcomes were observed between patients undergoing PD in a high‐volume specialized unit in both the public and private hospital systems. [ABSTRACT FROM AUTHOR]

Abstract: Background: Temporal artery biopsy is considered the investigation of choice to diagnose definitively giant cell arteritis (GCA) in patients with compatible symptoms. However it is invasive and not completely sensitive. Serum markers, particularly erythrocyte sedimentation rate (ESR), can be supportive, but are not definitive in individual cases. Aims: To investigate whether indices derived from the full blood count, including neutrophil‐to‐lymphocyte ratio (NLR) and platelet‐to‐lymphocyte ratio (PLR) were associated with a positive biopsy in patients with suspected GCA. Methods: The clinical and pathological details of 537 patients undergoing temporal artery biopsy at our institution from 1992 to 2015 were reviewed. Results: In univariate analysis high platelets (odds ratio (OR) 4.44, P < 0.001), NLR (OR 1.81, P = 0.02), PLR (OR 3.25, P < 0.001), C‐reactive protein (CRP) (OR 3.00, P < 0.001), ESR (OR 3.62, P < 0.001) and increased age (OR 1.03, P = 0.006) were strongly associated with a positive biopsy. In multivariate modelling only high platelets (P < 0.001) and ESR (P = 0.049) maintained significance. Conclusions: We conclude that the presence of thrombocytosis and high NLR, PLR, ESR and CRP can all be used clinically to support the diagnosis of GCA prior to biopsy. Of particular note, in multivariate modelling the presence of thrombocytosis is a stronger predictor of a positive temporal artery biopsy than ESR. Therefore, careful consideration of the findings in a full blood count can be used to predict the likelihood of a positive temporal artery biopsy in patients with suspected GCA. [ABSTRACT FROM AUTHOR]