Ectopic intralaryngo-tracheal thyroid tissue causing neonatal death

Introduction: Ectopic thyroid tissue can be found anywhere along the embryologic path of thyroid descent. Intralaryngo-tracheal thyroid tissue is the least common site of ectopia and can present with upper airways obstruction. Its presentation in the neonate is exceptional. Case Report: We describe a term female neonate with subglottic thyroid tissue causing near-total occlusion of the larynx, which led to upper airways obstruction and neonatal death. Conclusion: This emphasizes the importance of considering intralaryngo-tracheal tumors as a cause of acute and otherwise unexplainable respiratory distress immediately after birth. The cause of this neonatal death would not have been elucidated without careful autopsy examination

Artificial intelligence‐based digital scores of stromal tumour‐infiltrating lymphocytes and tumour‐associated stroma predict disease‐specific survival in triple‐negative breast cancer

Triple-negative breast cancer (TNBC) is known to have a relatively poor outcome with variable prognoses, raising the need for more informative risk stratification. We investigated a set of digital, artificial intelligence (AI)-based spatial tumour microenvironment (sTME) features and explored their prognostic value in TNBC. After performing tissue classification on digitised haematoxylin and eosin (H&E) slides of TNBC cases, we employed a deep learning-based algorithm to segment tissue regions into tumour, stroma, and lymphocytes in order to compute quantitative features concerning the spatial relationship of tumour with lymphocytes and stroma. The prognostic value of the digital features was explored using survival analysis with Cox proportional hazard models in a cross-validation setting on two independent international multi-centric TNBC cohorts: The Australian Breast Cancer Tissue Bank (AUBC) cohort (n = 318) and The Cancer Genome Atlas Breast Cancer (TCGA) cohort (n = 111). The proposed digital stromal tumour-infiltrating lymphocytes (Digi-sTILs) score and the digital tumour-associated stroma (Digi-TAS) score were found to carry strong prognostic value for disease-specific survival, with the Digi-sTILs and Digi-TAS scores giving C-index values of 0.65 (p = 0.0189) and 0.60 (p = 0.0437), respectively, on the TCGA cohort as a validation set. Combining the Digi-sTILs feature with the patient's positivity status for axillary lymph nodes yielded a C-index of 0.76 on unseen validation cohorts. We surmise that the proposed digital features could potentially be used for better risk stratification and management of TNBC patients. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

Frequency of the ATM IVS10-6T→G variant in Australian multiple-case breast cancer families

BACKGROUND: Germline mutations in the genes BRCA1 and BRCA2 account for only a proportion of hereditary breast cancer, suggesting that additional genes contribute to hereditary breast cancer. Recently a heterozygous variant in the ataxia–telangiectasia mutated (ATM) gene, IVS10-6T→G, was reported by an Australian multiple-case breast cancer family cohort study (the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer) to confer a substantial breast cancer risk. Although this variant can result in a truncated ATM product, its clinical significance as a high-penetrance breast cancer allele or its role as a low-penetrance risk-modifier is controversial. METHODS: We determined the frequency of ATM IVS10-6T→G variants in a cohort of individuals affected by breast and/or ovarian cancer who underwent BRCA1 and BRCA2 genetic testing at four major Australian familial cancer clinics. RESULTS: Seven of 495 patients (1.4%) were heterozygous for the IVS10-6T→G variant; the carrier rate in unselected Australian women with no family history of breast cancer is reported to be 6 of 725 (0.83%) (P = 0.4). Two of the seven probands also harboured a pathogenic BRCA1 mutation and one patient had a BRCA1 unclassified variant of uncertain significance. CONCLUSION: These findings indicate that the ATM IVS10-6T→G variant does not seem to occur at a significantly higher frequency in affected individuals from high-risk families than in the general population. A role for this variant as a low-penetrance allele or as a modifying gene in association with other genes (such as BRCA1) remains possible. Routine testing for ATM IVS10-6T→G is not warranted in mutation screening of affected individuals from high-risk families

Polymersome-Mediated Delivery of Combination Anticancer Therapy to Head and Neck Cancer Cells: 2D and 3D in Vitro Evaluation

Polymersomes have the potential to encapsulate and deliver chemotherapeutic drugs into tumor cells, reducing off-target toxicity that often compromises anticancer treatment. Here, we assess the ability of the pH-sensitive poly 2-(methacryloyloxy)ethyl phosphorylcholine (PMPC)- poly 2-(diisopropylamino)ethyl methacrylate (PDPA) polymersomes to encapsulate chemotherapeutic agents for effective combinational anticancer therapy. Polymersome uptake and ability to deliver encapsulated drugs into healthy normal oral cells and oral head and neck squamous cell carcinoma (HNSCC) cells was measured in two and three-dimensional culture systems. PMPC-PDPA polymersomes were more rapidly internalized by HNSCC cells compared to normal oral cells. Polymersome cellular uptake was found to be mediated by class B scavenger receptors. We also observed that these receptors are more highly expressed by cancer cells compared to normal oral cells, enabling polymersome-mediated targeting. Doxorubicin and paclitaxel were encapsulated into pH-sensitive PMPC-PDPA polymersomes with high efficiencies either in isolation or as a dual-load for both singular and combinational delivery. In monolayer culture, only a short exposure to drug-loaded polymersomes was required to elicit a strong cytotoxic effect. When delivered to three-dimensional tumor models, PMPC-PDPA polymersomes were able to penetrate deep into the center of the spheroid resulting in extensive cell damage when loaded with both singular and dual-loaded chemotherapeutics. PMPC-PDPA polymersomes offer a novel system for the effective delivery of chemotherapeutics for the treatment of HNSCC. Moreover, the preferential internalization of PMPC polymersomes by exploiting elevated scavenger receptor expression on cancer cells opens up the opportunity to target polymersomes to tumors

Diffuse lung disease of infancy: a pattern-based, algorithmic approach to histological diagnosis

Diffuse lung disease (DLD) of infancy has multiple aetiologies and the spectrum of disease is substantially different from that seen in older children and adults. In many cases, a specific diagnosis renders a dire prognosis for the infant, with profound management implications. Two recently published series of DLD of infancy, collated from the archives of specialist centres, indicate that the majority of their cases were referred, implying that the majority of biopsies taken for DLD of infancy are first received by less experienced pathologists. The current literature describing DLD of infancy takes a predominantly aetiological approach to classification. We present an algorithmic, histological, pattern-based approach to diagnosis of DLD of infancy, which, with the aid of appropriate multidisciplinary input, including clinical and radiological expertise and ancillary diagnostic studies, may lead to an accurate and useful interim report, with timely exclusion of inappropriate diagnoses. Subsequent referral to a specialist centre for confirmatory diagnosis will be dependent on the individual case and the decision of the multidisciplinary team

The outcome of papillary lesions of the breast diagnosed by standard core needle biopsy within a BreastScreen Australia service

Papillary lesions of the breast are most commonly diagnosed via mammographic screening. The standard practice has been to excise these lesions, since a subset of papillary lesions are neoplastic. However, this approach leads to a high proportion of negative excisions. In order to identify papillary lesions which could be managed by surveillance alone, we assessed the outcome of 103 papillary lesions diagnosed on core needle biopsy in a public screening program. Subsequent excision biopsy led to an upgrade to malignancy in 30% of cases. Segregation via presence or absence of atypia stratified the outcome into 72% upgrade, compared with 7% upgrade, respectively. Further, in the latter group (i.e., no atypia on core needle biopsy with 7% upgrade to malignancy), the neoplasia found in the targeted excision area was low to intermediate grade ductal carcinoma in situ only, with no invasive neoplasia (4 cases). Of the lesions identified due to microcalcification, the microcalcification was present within an adjacent benign lesion in 35% of cases and hence the papillary lesion was detected incidentally. Overall therefore, we have identified a cohort of papillary lesions in which conservative management, rather than excision, could be considered, i.e., those without atypia, including those without atypia in which the papillary lesion was found incidental to microcalcification in an adjacent benign lesion

Pagetoid squamous cell carcinoma in situ of the vulva: Comparison with extramammary Paget disease and nonpagetoid squamous cell neoplasia

Pagetoid squamous cell carcinoma in situ (PSSCIS) is a variant of squamous cell intraepithelial neoplasia. Although PSSCIS is well-documented in the cutaneous skin and esophagus, cases of vulvar PSSCIS are rare. In the vulva, the main differential diagnosis is extramammary Paget disease (EMPD). We report 2 cases of vulvar PSSCIS along with the immunohistochemical and human papillomavirus (HPV) status of this disease compared with primary cutaneous EMPD of the vulva. Although PSSCIS and EMPD share CK7 and CK19 expression, PSSCIS is consistently mucin and carcinoembryonic antigen negative. In contrast to EMPD, both cases of PSSCIS strongly expressed p16 (INK4A) protein, consistent with RB1 protein dysregulation. However, integration of high-risk HPV was found in only 1 of the 2 PSSCIS cases. Given the morphological and immunohistochemical findings, we suggest that PSSCIS arises from a bidirectional stem cell capable of both squamous and glandular differentiation. Additionally, as with nonpagetoid squamous cell neoplasias of the vulvar, integration of high-risk HPV may occur in some, but not all, cases of PSSCIS

Preliminary comparison of tumor biologic factors in breast carcinomas from Australian and Chinese women

OBJECTIVE: To compare the morphologic and immunohistochemical properties of breast carcinomas from Chinese and Australian women in order to define possible biologic differences between these carcinomas

Extracorporeal life support in multisystem smooth muscle dysfunction syndrome

We describe an infant with congenital mydriasis, patent ductus arteriosus (PDA), pulmonary hypertension, and cystic lung disease. She had all the major components of multisystemic smooth muscle dysfunction syndrome. Due to progressive respiratory deterioration, she required surgical PDA interruption, extracorporeal life support, and subsequent prolonged respiratory support. Genetic testing revealed ACTA2 R179H mutation and cystic lung disease on biopsy