Publications by authors named "Anthony J Gill"

349 Publications

Pitfalls and progress in adrenocortical carcinoma diagnosis: the utility of a multidisciplinary approach, immunohistochemistry and genomics.

Endocrinol Diabetes Metab Case Rep 2022 Jan 1;2022. Epub 2022 Jan 1.

Department of Internal Medicine, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia.

Summary: Adrenocortical carcinoma is a rare disease with poor prognosis whose clinical heterogeneity can at times present a challenge to accurate and timely diagnosis. We present the case of a patient who presented with extensive pulmonary lesions, mediastinal and hilar lymphadenopathy and an adrenal mass in whom the oncological diagnosis was initially uncertain. Through the use of immunohistochemistry, biochemistry and genomic testing, an accurate diagnosis of adrenocortical carcinoma was ultimately made which resulted in more directed treatment being administered. The use of multidisciplinary input and genomics to aid in diagnosis and prognosis of adrenocortical carcinoma is discussed.

Learning Points: Adrenocortical carcinomas can present a diagnostic challenge to clinicians given it is a rare malignancy with significant clinical heterogeneity. Specialist multidisciplinary team input is vital in the diagnosis and management of adrenocortical carcinomas. Hormonal testing is recommended in the diagnostic workup of adrenal masses, even in the absence of overt clinical signs/symptoms of hormone excess. Immunostaining for the highly sensitive and specific steroidogenic factor-1 is vital for accurate diagnosis. Genomics can provide prognostic utility in management of adrenocortical carcinoma.
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http://dx.doi.org/10.1530/EDM-21-0081DOI Listing
January 2022

A single domain i-body (AD-114) attenuates renal fibrosis through blockade of CXCR4.

JCI Insight 2022 Jan 11. Epub 2022 Jan 11.

Renal Medicine, Kolling Institute of Medical Research, University of Sydney, Sydney, Australia.

The G-protein coupled C-X-C chemokine receptor 4 (CXCR4) is a candidate therapeutic target for tissue fibrosis. A novel fully human single-domain antibody-like scaffold i-body AD-114-PA600 (AD-114) with specific high binding affinity to CXCR4 has been developed. To define the renoprotective role, AD-114 was administrated in a mouse model of renal fibrosis induced by folic acid (FA). Increased extracellular matrix (ECM) accumulation, macrophage infiltration, inflammatory response, transforming growth factor beta-1 (TGF-β1) expression and fibroblasts activation were observed in kidneys of mice with FA-induced nephropathy. These markers were normalized or partially reversed by AD-114 treatment. In vitro studies demonstrated AD-114 blocked TGF-β1-induced upregulated expression of ECM, matrix metallopeptidase-2 (MMP-2) and downstream p38 mitogen-activated protein kinases (p38 MAPK) and Phosphoinositide 3-kinases (PI3K)/AKT/ mammalian target of rapamycin (mTOR) signaling pathways in a renal proximal tubular cell line. Additionally, these renoprotective effects were validated in a second model of unilateral ureteral obstruction (UUO) using a second generation of AD-114 (Fc-fused AD-114, also named AD-214). Collectively, these results suggest a renoprotective role of AD-114 as it inhibited the chemotactic function of CXCR4 as well as blocked CXCR4 downstream p38 MAPK and PI3K/AKT/mTOR signaling, which establish a therapeutic strategy for AD-114 targeting CXCR4 to limit renal fibrosis.
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http://dx.doi.org/10.1172/jci.insight.143018DOI Listing
January 2022

SWI/SNF complex (SMARCA4, SMARCA2, INI1/SMARCB1) deficient colorectal carcinomas are strongly associated with microsatellite instability: An incidence study in 4508 colorectal carcinomas.

Histopathology 2021 Dec 24. Epub 2021 Dec 24.

Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia.

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http://dx.doi.org/10.1111/his.14612DOI Listing
December 2021

Expanding the clinicopathological spectrum of succinate dehydrogenase-deficient renal cell carcinoma with a focus on variant morphologies: a study of 62 new tumors in 59 patients.

Mod Pathol 2021 Dec 23. Epub 2021 Dec 23.

Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Most succinate dehydrogenase (SDH)-deficient renal cell carcinomas (RCCs) demonstrate stereotypical morphology characterized by bland eosinophilic cells with frequent intracytoplasmic inclusions. However, variant morphologic features have been increasingly recognized. We therefore sought to investigate the incidence and characteristics of SDH-deficient RCC with variant morphologies. We studied a multi-institutional cohort of 62 new SDH-deficient RCCs from 59 patients. The median age at presentation was 39 years (range 19-80), with a slight male predominance (M:F = 1.6:1). A relevant family history was reported in 9 patients (15%). Multifocal or bilateral tumors were identified radiologically in 5 patients (8%). Typical morphology was present at least focally in 59 tumors (95%). Variant morphologies were seen in 13 (21%) and included high-grade nuclear features and various combinations of papillary, solid, and tubular architecture. Necrosis was present in 13 tumors, 7 of which showed variant morphology. All 62 tumors demonstrated loss of SDHB expression by immunohistochemistry. None showed loss of SDHA expression. Germline SDH mutations were reported in all 18 patients for whom the results of testing were known. Among patients for whom follow-up data was available, metastatic disease was reported in 9 cases, 8 of whom had necrosis and/or variant morphology in their primary tumor. Three patients died of disease. In conclusion, variant morphologies and high-grade nuclear features occur in a subset of SDH-deficient RCCs and are associated with more aggressive behavior. We therefore recommend grading all SDH-deficient RCCs and emphasize the need for a low threshold for performing SDHB immunohistochemistry in any difficult to classify renal tumor, particularly if occurring at a younger age.
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http://dx.doi.org/10.1038/s41379-021-00998-1DOI Listing
December 2021

BRAF mutation testing for patients diagnosed with stage III or stage IV melanoma: practical guidance for the Australian setting.

Pathology 2021 Dec 19. Epub 2021 Dec 19.

Anatomical Pathology Department, Alfred Hospital, Melbourne, Vic, Australia; Department of Medicine Central Clinical School, Monash University, Melbourne, Vic, Australia.

Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAF mutation testing does not need to be requested by the treating clinician). When performed in centres with appropriate expertise and experience, immunohistochemistry (IHC) using the anti-BRAF V600E monoclonal antibody (VE1) can be a highly sensitive and specific means of detecting BRAF mutations, and may be used as a rapid and relatively inexpensive initial screening test. However, VE1 immunostaining can be technically challenging and difficult to interpret, particularly in heavily pigmented tumours; melanomas with weak, moderate or focal BRAF immunostaining should be regarded as equivocal. It must also be remembered that other activating BRAF mutations (including BRAF), which account for ∼10-20% of BRAF mutations, are not detected with currently available IHC antibodies. For these reasons, if available and practicable, we recommend that DNA-based BRAF mutation testing always be performed, regardless of whether IHC-based testing is also conducted. Advice about tissue/specimen selection for BRAF mutation testing of patients diagnosed with stage III or IV melanoma is also offered in this article; and potential pitfalls when interpreting BRAF mutation tests are highlighted.
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http://dx.doi.org/10.1016/j.pathol.2021.11.002DOI Listing
December 2021

Primary hyperparathyroidism in adults-(Part I) assessment and medical management: Position statement of the endocrine society of Australia, the Australian & New Zealand endocrine surgeons, and the Australian & New Zealand bone and mineral society.

Clin Endocrinol (Oxf) 2021 Dec 21. Epub 2021 Dec 21.

Department of Endocrinology, Austin Health, Victoria, Australia.

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.
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http://dx.doi.org/10.1111/cen.14659DOI Listing
December 2021

Primary hyperparathyroidism in adults-(Part II) surgical management and postoperative follow-up: Position statement of the Endocrine Society of Australia, The Australian & New Zealand Endocrine Surgeons, and The Australian & New Zealand Bone and Mineral Society.

Clin Endocrinol (Oxf) 2021 Dec 19. Epub 2021 Dec 19.

Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia.

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.
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http://dx.doi.org/10.1111/cen.14650DOI Listing
December 2021

A Critical Assessment of Current Grading Schemes for Diffuse Pleural Mesothelioma With a Proposal for a Novel Mesothelioma Weighted Grading Scheme (MWGS).

Am J Surg Pathol 2021 Dec 15. Epub 2021 Dec 15.

Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards Department of Anatomical Pathology, NSW Health Pathology, Royal North Shore Hospital Sydney Medical School, University of Sydney, Sydney, NSW, Australia.

Although there is early support for schemes based on nuclear grade, necrosis and mitotic rate, there is currently no widely implemented grading system for diffuse pleural mesothelioma (DPM). We investigated current systems and propose a novel Mesothelioma Weighted Grading Scheme (MWGS). The MWGS assigns weighted scores from 0 to 10 based on age (≤74, >74 yrs: 0,1); histologic type (epithelioid, biphasic, sarcomatoid: 0,1,2); necrosis (absent, present: 0,2); mitotic count per 2 mm2 (≤1, 2 to 4, ≥5: 0,1,2); nuclear atypia (mild, moderate, severe: 0,1,2); and BRCA1-associated protein 1 (BAP1) expression (lost, retained: 0,1). A score of 0 to 3 is low grade, 4 to 6 intermediate grade, and 7 to 10 high grade. In 369 consecutive DPMs, median survival was 17.1, 10.1, and 4.1 months for low, intermediate, and high grades (P<0.0001). A progressive increase in score correlated with worsening overall survival (P<0.0001). Interobserver concordance was substantial (κ=0.588), with assessment of nuclear grade being the most subjective parameter (κ=0.195). We compared the MWGS to the 2-tiered system discussed in the World Health Organization (WHO) fifth edition. The WHO system predicted median survival in epithelioid (median 18.0 vs. 11.3 mo, P=0.003) and biphasic (16.2 vs. 4.2 mo, P=0.002), but not sarcomatoid DPM (5.4 vs. 4.7 mo, P=0.407). Interestingly, the WHO grading system was prognostic in cases with BAP1 loss (median survival 18.7 vs. 10.4 mo, P<0.0001), but not retained BAP1 expression (8.9 vs. 6.2 mo, P=0.061). In conclusion, the WHO scheme has merit in epithelioid/biphasic and BAP1-deficient DPM, however, the MWGS can be used for risk stratification of all DPMs, regardless of histologic subtype and BAP1 status.
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http://dx.doi.org/10.1097/PAS.0000000000001854DOI Listing
December 2021

Interobserver agreement of estimating the extent of intestinal metaplasia in patients with chronic atrophic gastritis.

Virchows Arch 2021 Dec 13. Epub 2021 Dec 13.

Diagnostic and Research Institute of Pathology, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria.

The extent of gastric intestinal metaplasia (GIM) can be used to determine the risk of gastric cancer. Eleven international gastrointestinal expert pathologists estimated the extent of GIM on haematoxylin and eosin (H&E)- and Alcian blue-Periodic acid Schiff (AB-PAS)-stained slides of 46 antrum biopsies in 5% increments. Interobserver agreement was tested with the intraclass correlation coefficient (ICC). Correlation between standard deviation and extent of GIM was evaluated with the Spearman correlation. The interobserver agreement was very good (ICC = 0.983, 95% confidence interval (CI) 0.975-0.990). The use of AB-PAS did not increase the agreement (ICC = 0.975, 95% CI 0.961-0.985). Cases with a higher amount of metaplastic epithelium demonstrated a higher standard deviation (rs = 0.644; p < 0.01), suggesting lower diagnostic accuracy in cases with extensive GIM. In conclusion, estimating the extent of GIM on H&E-stained slides in patients with chronic atrophic gastritis can be achieved satisfactorily with high interobserver agreement, at least among international expert gastrointestinal pathologists.
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http://dx.doi.org/10.1007/s00428-021-03245-9DOI Listing
December 2021

Cancer-associated stroma reveals prognostic biomarkers and novel insights into the tumour microenvironment of colorectal cancer and colorectal liver metastases.

Cancer Med 2022 01 7;11(2):492-506. Epub 2021 Dec 7.

Cancer Surgery and Metabolism Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, New South Wales, Australia.

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.
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http://dx.doi.org/10.1002/cam4.4452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8729056PMC
January 2022

Malignant Peritoneal Mesothelioma With EWSR1-ATF1 Fusion: A Case Report.

JTO Clin Res Rep 2021 Nov 11;2(11):100236. Epub 2021 Oct 11.

University of Sydney, Sydney, Australia.

Malignant mesothelioma with EWSR1-ATF1 fusion is a rare malignancy described in young adults without asbestos exposure. To the best of our knowledge, outcomes to local and systemic therapies for this subtype of malignant mesothelioma have not been described. This case report describes the clinical course of a 19-year-old man diagnosed with malignant peritoneal mesothelioma with EWSR1-ATF1 fusion localized to the abdomen. His disease followed an aggressive course and resulted in limited survival (18 mo). There was treatment resistance to several lines of conventional local and systemic treatments for peritoneal mesothelioma and biologically targeted MET inhibition with crizotinib. More research is required in this rare subtype of peritoneal mesothelioma.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8569551PMC
November 2021

International Medullary Thyroid Carcinoma Grading System: A Validated Grading System for Medullary Thyroid Carcinoma.

J Clin Oncol 2022 Jan 3;40(1):96-104. Epub 2021 Nov 3.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Medullary thyroid carcinoma (MTC) is an aggressive neuroendocrine tumor (NET) arising from the calcitonin-producing C cells. Unlike other NETs, there is no widely accepted pathologic grading scheme. In 2020, two groups separately developed slightly different schemes (the Memorial Sloan Kettering Cancer Center and Sydney grade) on the basis of proliferative activity (mitotic index and/or Ki67 proliferative index) and tumor necrosis. Building on this work, we sought to unify and validate an internationally accepted grading scheme for MTC.

Patients And Methods: Tumor tissue from 327 patients with MTC from five centers across the United States, Europe, and Australia were reviewed for mitotic activity, Ki67 proliferative index, and necrosis using uniform criteria and blinded to other clinicopathologic features. After reviewing different cutoffs, a two-tiered consensus grading system was developed. High-grade MTCs were defined as tumors with at least one of the following features: mitotic index ≥ 5 per 2 mm, Ki67 proliferative index ≥ 5%, or tumor necrosis.

Results: Eighty-one (24.8%) MTCs were high-grade using this scheme. In multivariate analysis, these patients demonstrated decreased overall (hazard ratio [HR] = 11.490; 95% CI, 3.118 to 32.333; < .001), disease-specific (HR = 8.491; 95% CI, 1.461 to 49.327; = .017), distant metastasis-free (HR = 2.489; 95% CI, 1.178 to 5.261; = .017), and locoregional recurrence-free (HR = 2.114; 95% CI, 1.065 to 4.193; = .032) survivals. This prognostic power was maintained in subgroup analyses of cohorts from each of the five centers.

Conclusion: This simple two-tiered international grading system is a powerful predictor of adverse outcomes in MTC. As it is based solely on morphologic assessment in conjunction with Ki67 immunohistochemistry, it brings the grading of MTCs in line with other NETs and can be readily applied in routine practice. We therefore recommend grading of MTCs on the basis of mitotic count, Ki67 proliferative index, and tumor necrosis.
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http://dx.doi.org/10.1200/JCO.21.01329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683221PMC
January 2022

The Anatomy of Nerve Transfers Used in Tetraplegic Hand Reconstruction.

J Hand Surg Am 2021 Oct 23. Epub 2021 Oct 23.

Department of Hand Surgery and Peripheral Nerve Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia. Electronic address:

Purpose: To evaluate the anatomy of nerve transfers used to reconstruct wrist extension, hand opening, and hand closing in tetraplegic patients.

Methods: Nerve transfers were completed on 18 paired cadaveric upper limbs. The overlap of donor and recipient nerves was measured, as well as the distance to the target muscle. Axons were counted in each nerve and branch, with the axon percentage calculated by dividing the donor nerve count by that of the recipient.

Results: Transfers with overlap of the donor and recipient nerve were from the radial nerve branch to extensor carpi radialis brevis to anterior interosseous nerve (AIN) and from the branch(es) to supinator to posterior interosseous nerve. The extensor carpi radialis brevis to AIN had the shortest distance to the target, with the branch to brachialis to AIN being the longest. The nerve transfers for wrist extension had the highest axon percentage. Of the transfers for hand closing, the brachialis to AIN had the highest axon percentage, and the branch to brachioradialis to AIN had the lowest.

Conclusions: The anatomical features of nerve transfers used in tetraplegic hand reconstruction are variable. Differences may help explain clinical outcomes.

Clinical Relevance: This study demonstrates which nerve transfers may be anatomically favorable for restoring hand function in tetraplegic patients.
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http://dx.doi.org/10.1016/j.jhsa.2021.09.003DOI Listing
October 2021

Corrigendum: Serum Biomarker Panel for Diagnosis and Prognosis of Pancreatic Ductal Adenocarcinomas.

Front Oncol 2021 6;11:774861. Epub 2021 Oct 6.

Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.

[This corrects the article DOI: 10.3389/fonc.2021.708963.].
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http://dx.doi.org/10.3389/fonc.2021.774861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527849PMC
October 2021

Clinical suspicion of pancreatic cancer despite negative endoscopic ultrasound-guided fine-needle aspiration biopsy.

ANZ J Surg 2021 Oct 11. Epub 2021 Oct 11.

Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia.

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.
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http://dx.doi.org/10.1111/ans.17256DOI Listing
October 2021

Sheep in wolf's clothing: squamoid cysts of the pancreatic ducts.

ANZ J Surg 2021 Oct 3. Epub 2021 Oct 3.

Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, New South Wales, Australia.

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http://dx.doi.org/10.1111/ans.17239DOI Listing
October 2021

Lessons learnt from MDM2 fluorescence in-situ hybridisation analysis of 439 mature lipomatous lesions with an emphasis on atypical lipomatous tumour/well-differentiated liposarcoma lacking cytological atypia.

Histopathology 2022 Jan 11;80(2):369-380. Epub 2021 Nov 11.

Department of Anatomical Pathology, Sonic Healthcare-Douglass Hanly Moir Pathology, Macquarie Park, Australia.

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.
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http://dx.doi.org/10.1111/his.14558DOI Listing
January 2022

Eosinophilic vacuolated tumor (EVT) of kidney demonstrates sporadic TSC/MTOR mutations: next-generation sequencing multi-institutional study of 19 cases.

Mod Pathol 2021 Sep 14. Epub 2021 Sep 14.

Department of Pathology, University of Toronto, Toronto, ON, Canada.

A distinct renal tumor has recently been described as "high-grade oncocytic renal tumor" and "sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm". The Genitourinary Pathology Society (GUPS) consensus proposed a unifying name "eosinophilic vacuolated tumor" (EVT) for this emerging entity. In this multi-institutional study, we evaluated 19 EVTs, particularly their molecular features and mutation profile, using next-generation sequencing. All cases were sporadic and none of the patients had a tuberous sclerosis complex. There were 8 men and 11 women, with a mean age of 47 years (median 50; range 15-72 years). Average tumor size was 4.3 cm (median 3.8 cm; range 1.5-11.5 cm). All patients with available follow-up data (18/19) were alive and without evidence of disease recurrence or progression during the follow-up, ranging from 12 to 198 months (mean 56.3, median 41.5 months). The tumors were well circumscribed, but lacked a well-formed capsule, had nested to solid growth, focal tubular architecture, and showed ubiquitous, large intracytoplasmic vacuoles, round to oval nuclei, and prominent nucleoli. Immunohistochemically, cathepsin K, CD117, CD10, and antimitochondrial antigen were expressed in all cases. Other positive stains included: PAX8, AE1/AE3 and CK18. CK7 was typically restricted only to rare scattered cells. Vimentin, HMB45, melan-A, and TFE3 were negative in all cases. All tumors showed retained SDHB. All cases (19/19) showed non-overlapping mutations of the mTOR pathway genes: TSC1 (4), TSC2 (7), and MTOR (8); one case with MTOR mutation showed a coexistent RICTOR missense mutation. Low mutational rates were found in all samples (ranged from 0 to 6 mutations/Mbp). Microsatellite instability and copy number variations were not found in any of the 17 analyzable cases. EVT represents an emerging renal entity that shows a characteristic and readily identifiable morphology, consistent immunohistochemical profile, indolent behavior, and mutations in either TSC1, TSC2, or MTOR genes.
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http://dx.doi.org/10.1038/s41379-021-00923-6DOI Listing
September 2021

Pancreatic solid pseudopapillary neoplasm: a single-institution study.

ANZ J Surg 2021 11 23;91(11):2453-2458. Epub 2021 Aug 23.

Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, St Leonards, New South Wales, Australia.

Backgrounds: Solid pseudopapillary neoplasms (SPNs) are a distinct but rare form of low-grade 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.
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http://dx.doi.org/10.1111/ans.17142DOI Listing
November 2021

Dedifferentiated melanoma with MDM2 gene amplification mimicking dedifferentiated liposarcoma.

Pathology 2021 Aug 19. Epub 2021 Aug 19.

Department of Anatomical Pathology, Douglass Hanly Moir Pathology, NSW, Australia; Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, NSW, Australia; Faculty of Medicine, University of Sydney, NSW, Australia.

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http://dx.doi.org/10.1016/j.pathol.2021.05.096DOI Listing
August 2021

Dataset for the reporting of carcinoma of the exocrine pancreas: recommendations from the International Collaboration on Cancer Reporting (ICCR).

Histopathology 2021 Dec 22;79(6):902-912. Epub 2021 Sep 22.

Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Centre, Nashville, TN, USA.

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.
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http://dx.doi.org/10.1111/his.14540DOI Listing
December 2021

International Validation of a Nomogram to Predict Recurrence after Resection of Grade 1 and 2 Nonfunctioning Pancreatic Neuroendocrine Tumors.

Neuroendocrinology 2021 Jul 29. Epub 2021 Jul 29.

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Despite the low recurrence rate of resected nonfunctional pancreatic neuroendocrine tumors (NF-pNETs), nearly all patients undergo long-term surveillance. A prediction model for recurrence may help select patients for less intensive surveillance or identify patients for adjuvant therapy. The objective of this study was to assess the external validity of a recently published model predicting recurrence within 5 years after surgery for NF-pNET in an international cohort. This prediction model includes tumor grade, lymph node status and perineural invasion as predictors.

Methods: Retrospectively, data were collected from 7 international referral centers on patients who underwent resection for a grade 1-2 NF-pNET between 1992 and 2018. Model performance was evaluated by calibration statistics, Harrel's C-statistic, and area under the curve (AUC) of the receiver operating characteristic curve for 5-year recurrence-free survival (RFS). A sub-analysis was performed in pNETs >2 cm. The model was improved to stratify patients into 3 risk groups (low, medium, high) for recurrence.

Results: Overall, 342 patients were included in the validation cohort with a 5-year RFS of 83% (95% confidence interval [CI]: 78-88%). Fifty-eight patients (17%) developed a recurrence. Calibration showed an intercept of 0 and a slope of 0.74. The C-statistic was 0.77 (95% CI: 0.70-0.83), and the AUC for the prediction of 5-year RFS was 0.74. The prediction model had a better performance in tumors >2 cm (C-statistic 0.80).

Conclusions: External validity of this prediction model for recurrence after curative surgery for grade 1-2 NF-pNET showed accurate overall performance using 3 easily accessible parameters. This model is available via www.pancreascalculator.com.
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http://dx.doi.org/10.1159/000518757DOI Listing
July 2021

Urinary metabolite prognostic biomarker panel for pancreatic ductal adenocarcinomas.

Biochim Biophys Acta Gen Subj 2021 11 27;1865(11):129966. Epub 2021 Jul 27.

Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, St Leonards, Sydney, Australia; Australian Pancreatic Centre, St Leonards, Sydney, Australia. Electronic address:

Background: Patients with pancreatic ductal adenocarcinoma (PDAC) have a very low survival rate and surgical resection is the only curative intent treatment available. However, the majority of patients relapse after surgery and identification of biomarkers for accurate prognostication of PDAC patients is required. We have recently identified a six biomarker (i.e., trigonelline, glycolate, hippurate, creatine, myoinositol and hydroxyacetone) urinary metabolite panel with very high potential to diagnose PDAC (Int J Cancer 2021;148:1508-18). This study aimed to assess the prognostic ability of these previously identified diagnostic metabolites in the urine of PDAC patients.

Methods: Metabolite data from 88 PDAC patients was statistically assessed for their prognostic ability.

Results: A panel of three metabolites (i.e., trigonelline, hippurate and myoinositol) was able to stratify patients with good- or poor-prognosis based on overall survival. The PDAC patients with abnormal levels of 2 or more metabolites in their urine demonstrated significantly lower survival compared to patients with abnormal levels of one or less metabolites.

Conclusion: These results demonstrate that the selected three metabolite panel could be used to stratify patients based on their prognostic outcomes and if independently validated may lead to the development of a urinary prognostic biomarker test for PDAC.

General Significance: This study highlights the potential of using H-nuclear magnetic resonance spectroscopy for the identification of novel metabolites which can prognosticate cancer patients.
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http://dx.doi.org/10.1016/j.bbagen.2021.129966DOI Listing
November 2021

Predicting survival in colorectal carcinoma after curative resection: a new prognostic nomogram.

Pathology 2021 Jul 21. Epub 2021 Jul 21.

Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. Electronic address:

Several prognostic nomograms designed to predict survival after curative resection for colorectal cancer (CRC) have been proposed. Recently, routine pathological assessment has evolved with subtle changes to the AJCC staging system, and routine screening for mismatch repair deficiency (MMRd). Therefore we sought to develop and validate a new prognostic nomogram. All cause survival data from 4517 consecutive patients with primary CRC were used as independent training and validation cohorts to develop a final model including only: age, sex, tumour stage, nodal status, number of lymph nodes resected, apical node status, distant metastases, thin-walled vascular invasion, and MMR status. Patients were stratified into four risk groups to assess model discrimination and calibration. To assess discrimination, the area-under-the-curve (AUC) of a receiver-operator-curve (ROC), concordance-index (C-index), and D-index were calculated. The model was compared to the Memorial Sloan Kettering Cancer Center (MSKCC) CRC nomogram and the AJCC TNM staging. Based on the 5-year ROC analysis, the AUC for our model was 0.81 (0.79 and 0.74 for MSKCC and AJCC, respectively). Moreover, our model demonstrated a concordance index of 0.77 (95% CI 0.70-0.82) compared to 0.75 (95% CI 0.68-0.81) for MSKCC and 0.73 (95% CI 0.65-0.79) for AJCC. In conclusion, our new prognostic nomogram incorporates a larger number of clinically relevant prognostic markers, including MMR status, and therefore demonstrates improved predictive capability. As these factors are routinely assessed, it is hoped that this model will inform prognostication and difficult management decisions, such as patient selection for adjuvant therapy.
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http://dx.doi.org/10.1016/j.pathol.2021.04.012DOI Listing
July 2021

Serum Biomarker Panel for Diagnosis and Prognosis of Pancreatic Ductal Adenocarcinomas.

Front Oncol 2021 5;11:708963. Epub 2021 Jul 5.

Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.

Background: Patients with pancreatic ductal adenocarcinoma (PDAC) have late diagnosis which results in poor prognosis. Currently, surgical resection is the only option for curative intent. Identifying high-risk features for patients with aggressive PDAC is essential for accurate diagnosis, prognostication, and personalised care due to the disease burden and risk of recurrence despite surgical resection. A panel of three biomarkers identified in tumour tissue (S100A4, Ca125 and Mesothelin) have shown an association with poor prognosis and overall survival. The diagnostic and prognostic value of the serum concentration of this particular biomarker panel for patients with PDAC has not been previously studied.

Methods: Retrospectively collected blood samples of PDAC patients (n =120) and healthy controls (n =80) were evaluated for the serum concentration of select biomarkers - S100A4, S100A2, Ca-125, Ca 19-9 and mesothelin. Statistical analyses were performed for diagnostic and prognostic correlation.

Results: A panel of four biomarkers (S100A2, S100A4, Ca-125 and Ca 19-9) achieved high diagnostic potential (AUROC 0.913). Three biomarkers (S100A4, Ca-125 and Ca 19-9) correlated with poor overall survival in a univariable model (). PDAC patients with abnormal levels of 2 or more biomarkers in their serum demonstrated significantly lower survival compared to patients with abnormal levels of one or less biomarker ().

Conclusion And Impact: The identified biomarker panels have shown the potential to diagnose PDAC patients and stratify patients based on their prognostic outcomes. If independently validated, this may lead to the development of a diagnostic and prognosticating blood test for PDAC.
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http://dx.doi.org/10.3389/fonc.2021.708963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287202PMC
July 2021

Optimal Upfront Treatment in Surgically Resectable Pancreatic Cancer Candidates: A High-Volume Center Retrospective Analysis.

J Clin Med 2021 Jun 18;10(12). Epub 2021 Jun 18.

Faculty of Medicine and Health Sciences, Northern Clinical School, The University of Sydney, Sydney, NSW 2065, Australia.

Pancreatic adenocarcinoma is a devastating disease with only 15-20% of patients resectable at diagnosis. Neoadjuvant chemotherapy for this cohort is becoming increasingly popular; however, there are no published randomized trials that support the use of neoadjuvant chemotherapy over upfront surgery in resectable disease. This retrospective cohort analysis was conducted to compare both treatment pathways and to identify any potential prognostic markers. Medical records from one large volume pancreatic cancer center from 2013-2019 were reviewed and 126 patients with upfront resectable disease were analyzed. Due to a change in practice in our center patients treated prior to December 2016 received upfront surgery and those treated after this date received neoadjuvant chemotherapy. Of these, 86 (68%) patients were treated with upfront surgery and 40 (32%) of patients were treated with neoadjuvant chemotherapy. Our results demonstrated that patients treated with upfront surgery with early-stage (1a) disease had a longer median OS compared to those treated with neoadjuvant chemotherapy (24 vs. 21 months, = 0.028). This survival difference was not evident for all patients (regardless of stage). R0 resections were similar between groups ( = 0.605). We identified that both tumor viability (in neoadjuvant chemotherapy-treated patients) and tumor grade were useful prognostic markers. Upfront surgery for certain patients with low volume disease may be suitable despite the global trend towards neoadjuvant chemotherapy for all upfront resectable patients. A prospective clinical trial in this cohort incorporating biomarkers is needed to determine optimal therapy pathway.
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http://dx.doi.org/10.3390/jcm10122700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235361PMC
June 2021
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