Signet-ring cell appearance of atrophic fat cells.

Cells with 'signet-ring' appearance were found at post-mortem examination of a man with a history of chronic illness, weight loss and multiple regions of 'bowel thickening' during life. Due to the decedent's history, the finding raised the possibility of disseminated signet-ring adenocarcinoma. However, the vacuoles did not stain for mucin and the cells did not stain for keratin. The cells did stain for calretinin and so a diagnosis of signet ring mesothelioma was considered. However, it was suggested that the cells with a cytoplasmic vacuole displacing the nucleus to one side producing the signet-ring appearance were instead atrophic fat cells. This was subsequently proven by Oil Red O staining.

Usefulness of Aquaporin 1 as a Prognostic Marker in a Prospective Cohort of Malignant Mesotheliomas.

(1) BACKGROUND: Malignant mesothelioma (MM) is an aggressive tumour of the serosal membranes, associated with exposure to asbestos. Survival is generally poor, but prognostication for individual patients is difficult. We recently described Aquaporin 1 (AQP1) as independent prognostic factor in two separate retrospective cohorts of MM patients. Here we assess the usefulness of AQP1 prospectively, and determine the inter-observer agreement in assessing AQP1 scores; (2) METHODS: A total of 104 consecutive cases of MM were included. Sufficient tissue for immunohistochemistry was available for 100 cases, and these cases were labelled for AQP1. Labelling was assessed by two pathologists. Complete clinical information and follow up was available for 91 cases; (3) RESULTS: Labelling of ≥50% of tumour cells for AQP indicated improved prognosis in a univariate model (median survival 13 versus 8 months, p = 0.008), but the significance was decreased in a multivariate analysis. Scoring for AQP1 was robust, with an inter-observer kappa value of 0.722, indicating substantial agreement between observers; (4) CONCLUSION: AQP1 is a useful prognostic marker that can be easily incorporated in existing diagnostic immunohistochemical panels and which can be reliably interpreted by different pathologists.

Nonmesothelial Spindle Cell Tumors of Pleura and Pericardium.

Spindle cell lesions of the pleura and pericardium are rare. Distinction from sarcomatoid mesothelioma, which has a range of morphologic patterns, can be difficult, but accurate diagnosis matters. This article provides practical guidance for the diagnosis of pleural spindle cell neoplasms, focusing on primary lesions.

Mucus extravasation into the orbit during frontal sinus irrigation.

During minitrephination and irrigation of the frontal sinus, mucus extravasated into the orbit through a defect in the sinus floor. The mucus incited a foreign body reaction and became encapsulated within the orbit necessitating excision via an anterior orbitotomy.

Changes in audiovestibular handicap following treatment of vestibular schwannomas.

OBJECTIVE: This study aimed to assess degree of audiovestibular handicap in patients with vestibular schwannoma. METHODS: Audiovestibular handicap was assessed using the Hearing Handicap Inventory, Tinnitus Handicap Inventory and Dizziness Handicap Inventory. Patients completed questionnaires at presentation and at least one year following treatment with microsurgery, stereotactic radiosurgery or observation. Changes in audiovestibular handicap and factors affecting audiovestibular handicap were assessed. RESULTS: All handicap scores increased at follow up, but not significantly. The Tinnitus Handicap Inventory and Dizziness Handicap Inventory scores predicted tinnitus and dizziness respectively. The Hearing Handicap Inventory was not predictive of hearing loss. Age predicted Tinnitus Handicap Inventory score and microsurgery was associated with a deterioration in Dizziness Handicap Inventory score. CONCLUSION: Audiovestibular handicap is common in patients with vestibular schwannoma, with 75 per cent having some degree of handicap in at least one inventory. The overall burden of handicap was, however, low. The increased audiovestibular handicap over time was not statistically significant, irrespective of treatment modality.

Real-world prevalence of PD-L1 expression in non-small cell lung cancer: an Australia-wide multi-centre retrospective observational study.

An investigator-initiated, Australia-wide multi-centre retrospective observational study was undertaken to investigate the real-world prevalence of programmed death ligand-1 (PD-L1) expression in non-small cell lung carcinoma (NSCLC). Multiple centres around Australia performing PD-L1 immunohistochemistry (IHC) were invited to participate. Histologically confirmed NSCLC of any stage with a PD-L1 IHC test performed for persons aged ≥18 years between 1 January 2018 and 1 January 2020, and eligible for review, were identified at each centre, followed by data extraction and de-identification, after which data were submitted to a central site for collation and analysis. In total data from 6690 eligible PD-L1 IHC tests from histologically (75%) or cytologically (24%) confirmed NSCLC of any stage were reviewed from persons with a median age of 70 years, 43% of which were female. The majority (81%) of tests were performed using the PD-L1 IHC SP263 antibody with the Ventana BenchMark Ultra platform and 19% were performed using Dako PD-L1 IHC 22C3 pharmDx assay. Reported PD-L1 tumour proportion score (TPS) was ≥50% for 30% of all tests, with 62% and 38% scoring PD-L1 ≥1% and <1%, respectively. Relative prevalence of clinicopathological features with PD-L1 scores dichotomised to <50% and ≥50%, or to <1% and ≥1%, were examined. Females scored ≥1% slightly more often than males (64% vs 61%, respectively, p=0.013). However, there was no difference between sexes or age groups (<70 or ≥70 years) where PD-L1 scored ≥50%. Specimens from patients with higher stage (III/IV) scored ≥1% or ≥50% marginally more often compared to specimens from patients with lower stage (I/II) (p≤0.002). Proportions of primary and metastatic specimens did not differ where PD-L1 TPS was ≥1%, however more metastatic samples scored TPS ≥50% than primary samples (metastatic vs primary; 34% vs 27%, p<0.001). Cytology and biopsy specimens were equally reported, at 63% of specimens, to score TPS ≥1%, whereas cytology samples scored TPS ≥50% slightly more often than biopsy samples (34% vs 30%, respectively, p=0.004). Resection specimens (16% of samples tested) were reported to score TPS ≥50% or ≥1% less often than either biopsy or cytology samples (p<0.001). There was no difference in the proportion of tests with TPS ≥1% between PD-L1 IHC assays used, however the proportion of tests scored at TPS ≥50% was marginally higher for 22C3 compared to SP263 (34% vs 29%, respectively, p<0.001). These real-world Australian data are comparable to some previously published global real-world data, with some differences noted.

Facial Nerve Function Outcome and Risk Factors in Resection of Large Cystic Vestibular Schwannomas.

Objective Cystic vestibular schwannomas (VS) in contrast to solid VS tend to have accelerated growth, larger volume, rapid/atypical presentation, lobulated/adherent surface, and unpredictable course of the cranial nerves. Cystic VS are surgically challenging, with worse clinical outcomes and higher rate of subtotal resection (STR). Methods We retrospectively analyzed postoperative outcomes of 125 patients with cystic VS, operated between years 2005 and 2019 in our center. We confronted the extent of the resection and House-Brackmann (HB) grade of facial palsy with the results of comparable cohort of patients with solid VS operated in our center and literature review by Thakur et al. 1 Results Translabyrinthine approach was preferred for resection of large, cystic VS (97.6%). Gross-total resection (GTR) was achieved in 78 patients (62.4%), near-total resection (NTR) with remnant (<4 × 4 × 2 mm) in 43 patients (34.4%), and STR in 4 patients (3.2%). NTR/STR were significantly associated with higher age, tumor volume >5 cm 3 , retrosigmoid approach, high-riding jugular bulb, tumor adherence to the brain stem, and facial nerve ( p = 0.016; 0.003; 0.005; 0.025; 0.001; and <0.00001, respectively). One year after the surgery, 76% of patients had HB grades 1 to 2, 16% had HB grades 3 to 4, and 8% had HB grades 5 to 6 palsy. Worse outcome (HB grades 3 to 6) was associated with preoperative facial palsy, tumor volume >25 cm 3 , and cyst over the brain stem ( p = 0.045; 0.014; and 0.05, respectively). Comparable solid VS operated in our center had significantly higher HB grades 1 to 2 rate than our cystic VS (94% versus 76%; p = 0.03). Comparing our results with literature review, our HB grades 1 to 2 rate was significantly higher (76% versus 39%; p = 0.0001). Tumor control rate 5 years after surgery was 95.8%. Conclusion Our study confirmed that microsurgery of cystic VS has worse outcomes of facial nerve preservation and extent of resection compared with solid VS. Greater attention should be paid to the above-mentioned risk factors.

Drug targeting to monocytes and macrophages using esterase-sensitive chemical motifs.

The therapeutic and toxic effects of drugs are often generated through effects on distinct cell types in the body. Selective delivery of drugs to specific cells or cell lineages would, therefore, have major advantages, in particular, the potential to significantly improve the therapeutic window of an agent. Cells of the monocyte-macrophage lineage represent an important target for many therapeutic agents because of their central involvement in a wide range of diseases including inflammation, cancer, atherosclerosis, and diabetes. We have developed a versatile chemistry platform that is designed to enhance the potency and delivery of small-molecule drugs to intracellular molecular targets. One facet of the technology involves the selective delivery of drugs to cells of the monocyte-macrophage lineage, using the intracellular carboxylesterase, human carboxylesterase-1 (hCE-1), which is expressed predominantly in these cells. Here, we demonstrate selective delivery of many types of intracellularly targeted small molecules to monocytes and macrophages by attaching a small esterase-sensitive chemical motif (ESM) that is selectively hydrolyzed within these cells to a charged, pharmacologically active drug. ESM versions of histone deacetylase (HDAC) inhibitors, for example, are extremely potent anticytokine and antiarthritic agents with a wider therapeutic window than conventional HDAC inhibitors. In human blood, effects on monocytes (hCE-1-positive) are seen at concentrations 1000-fold lower than those that affect other cell types (hCE-1-negative). Chemical conjugates of this type, by limiting effects on other cells, could find widespread applicability in the treatment of human diseases where monocyte-macrophages play a key role in disease pathology.

Design and synthesis of novel pyrimidine hydroxamic acid inhibitors of histone deacetylases.

Inhibition of histone deacetylase activity represents a promising new modality in the treatment of a number of cancers. A novel HDAC series demonstrating inhibitory activity in cell proliferation assays is described. Optimisation based on the introduction of basic amine linkers to effect good drug distribution to tumour led to the identification of a compound with oral activity in a human colon cancer xenograft study associated with increased histone H3 acetylation in tumour tissue.

The Incidence of Labelling of Non-Lung Adenocarcinomas With Antibodies Against TTF-1 and Diagnostic Implications.

Thyroid transcription factor 1 (TTF-1) is an immunohistochemical marker in the identification of lung and thyroid tumors. However, positive labelling for TTF-1 can occur in tumors from other sites, and this can result in misdiagnosis if only a limited panel of antibodies is used. We assessed the frequency of expression of 3 TTF-1 antibody clones, namely, 8G7G3/1, SPT24, and SP141 on a tissue microarray of 104 colorectal cancer (CRC), and whole-tumor sections of 165 CRC with known microsatellite instability (MSI) status. We also analyzed the expression of TTF-1 in a tissue microarray of 112 prostatic adenocarcinomas. The association of TTF-1 expression with clinicopathologic parameters and patient survival was analyzed. Six of 104 (5.7%) primary colorectal carcinomas expressed TTF-1 with SPT24 and SP141 clones, whereas only 2 (2%) of these tumors labeled positive for TTF-1 with clone 8G7G3/1. A significant association of TTF-1 expression with younger age at diagnosis (P=0.001) was found, but not with stage, or survival. The SP141 clone also labelled 24/165 (14.5%) of 165 CRC with known MSI status. There was an association with younger age (P<0.001), but not with MSI status or survival. TTF-1 expression was found in 39/112 (34%) prostate adenocarcinomas with 6/112 (5.3%) labelling with clone 8G7G3/1, 26/112 (23%) with clone SP141, and 31/112 (28%) with clone SPT24. TTF-1 expression appeared to be associated with extracapsular extension (P=0.022) and with higher stage (P=0.039). Here too TTF-1 expression was not associated with survival. The mRNA expression of TTF-1 in these tumors was confirmed by RTPCR, indicating that this is not false-positive labelling. Depending on the clone used, TTF-1 expression can vary with the SP141 and SPT24 clones exhibiting higher incidence of labelling. Pathologists should be aware of the differences in performance profiles of the different TTF-1 clones in diagnostic practice.

Hearing improvement in a growing vestibular schwannoma.

Vestibular schwannomas are benign, slow-growing tumors that originate from Schwann cells lining the vestibular nerves, most commonly the superior vestibular nerve. They arise at the neurilemmal/neuroglial junction which is situated within the internal auditory canal. They have an incidence of 1 per 100,000 per year and a prevalence of around 700 per million. A case of a patient undergoing a period of observation for a vestibular schwannoma whose hearing improved despite growth of the tumor is described. This raises interesting questions regarding the pathophysiology of hearing loss in patients with vestibular schwannomas. Possible hypotheses are discussed.

Headache, Cerebrospinal Fluid Leaks, and Pseudomeningoceles after Resection of Vestibular Schwannomas: Efficacy of Venous Sinus Stenting Suggests Cranial Venous Outflow Compromise as a Unifying Pathophysiological Mechanism.

Background Regardless of the operative approach, headache, cerebrospinal fluid (CSF) leaks, and pseudomeningoceles remain disproportionately common problems after surgery for vestibular schwannomas and have a significant negative impact on quality of life and potential to return to full employment. Recent work has raised the possibility that these problems may, in part, be related to acquired obstruction of cranial venous outflow. This article explores this idea further with respect to a group of patients with severe and intractable symptoms. Objective The main objective of this article is to describe our experience diagnosing, investigating, and treating cranial venous outflow obstruction following translabyrinthine resection of vestibular schwannomas. Methods Retrospective review of all patients ( n = 9) at our institution referred for sigmoid sinus stenting following translabyrinthine surgery. Results Headache resolved or improved after sigmoid stenting in all five patients in whom it was the primary symptom. CSF leak was the primary problem in two patients. In one, the leak was unchanged, but headache improved. In the other, the leak resolved, and headache improved. Two patients had symptomatic pseudomeningoceles and both resolved Conclusion Assuming a meticulous approach to wound closure, a CSF leak following surgery for vestibular schwannoma can be viewed as a pathological, but essentially homeostatic, response to raised intracranial pressure caused by acquired obstruction to cranial venous outflow. Postoperative headache (from high or low intracranial pressure) and CSF leaks, therefore, may all respond to measures aimed at eliminating the obstructing lesion.

Petrous temporal bone cholesteatoma: a new classification and long-term surgical outcomes.

The goals of this retrospective case review were to analyze the long-term results of surgery for petrous temporal bone cholesteatomas and to propose a new classification system for these lesions. Patients with a surgically confirmed petrous temporal bone cholesteatoma were treated at Addenbrooke's Hospital, a tertiary referral center. Postoperative facial function, hearing, residual/recurrent cholesteatoma, and other complications were assessed in relation to preoperative signs, intraoperative findings, and surgical approach. Between 1983 and 2004, 43 patients were treated. There were no perioperative deaths. There was no long-term recurrence in 95.4% of the patients, possibly because of meticulous surgical technique, bipolar diathermy, and use of the laser to denature the cholesteatoma matrix that was adherent to the dura. At presentation, 95% of the patients had no socially useful hearing in the affected ear. Facial nerve function, however, was usually preserved. Both direct anastomosis and nerve grafting can improve facial nerve function from House-Brackmann grade VI to grade III if the palsy is not longstanding. Four patients had cerebrospinal fluid leakage; other complications were rare. The proposed classification facilitates surgical planning and predicts the postoperative outcome with regards to hearing.

Review of diagnostic error in anatomical pathology and the role and value of second opinions in error prevention.

AIMS: Diagnostic/interpretative accuracy can be challenging in anatomical pathology due to the subjective element of the diagnostic process. This can lead to false-negative or false-positive diagnoses of malignancy, variations in grading and diagnostic misclassification of a condition.It is imperative that an accurate diagnosis is achieved so that an appropriate and timely treatment is administered to the patient, for example, the success of targeted molecular therapeutic options for treatment of cancer is dependent on accurate anatomical pathology diagnoses being issued. METHODS: A literature review of diagnostic accuracy in selected specimen categories was undertaken and was compared with data on metropolitan and regional pathologist diagnostic proficiency performance in an external quality assurance programme from surveys provided 2015-2017. For each specimen category, cases having attracted a diagnostic inaccuracy (ie, major discordance) of ≥20% and cases attracting a combined error rate (ie, major and minor discordance) of ≥30% are reviewed and discussed. RESULTS: The rate of inaccurate diagnoses (assessed as a major discordance) ranged from 3% to 9% among the different specimen groups, with highest mean percentage of inaccurate diagnoses in gynaecology, dermatopathology and gastrointestinal specimens. CONCLUSIONS: It was possible to ascertain that gynaecology, dermatopathology and gastrointestinal specimens had presented the greatest diagnostic challenge to the participant pathologists, determined as highest rate of diagnostic inaccuracy, that is, major discordance with respective case target diagnoses.Through a combination of routine second opinions, directed retrospective peer review and participation in appropriate external quality assurance schemes, the risk associated with these diagnoses can be minimised.

Accuracy of rapid on-site evaluation of endobronchial ultrasound guided transbronchial needle aspirates by respiratory registrars in training and medical scientists compared to specialist pathologists-an initial pilot study.

BACKGROUND: Rapid on-site evaluation (ROSE) of endobronchial ultrasound guided transbronchial needle aspirates (EBUS-TBNA) increases diagnostic accuracy but in many institutions requires a specialist pathologist. This study aimed to determine if medical scientists or respiratory registrars could adequately perform ROSE to determine sufficiency of EBUS samples. METHODS: ROSE was performed on the first two EBUS-TBNA passes per patient by a pathologist, a medical scientist and two respiratory registrars. The medical scientists involved had all previously performed ROSE on over 50 procedures. The two respiratory registrars received cytology education from a pathologist in four separate hour-long training sessions. Each ROSE reviewer recorded whether each sample was sufficient or insufficient. Pathologist interpretation was taken as gold standard. Specific diagnosis was not required. Final diagnosis and the total number of passes were also recorded. This study recruited 25 patients (50 passes) for statistical evaluation. RESULTS: Assessment by specialist pathologists deemed 16/50 (32%) to be sufficient and 34/50 (68%) insufficient respectively. Medical scientists were 90% concordant with the pathologist (K =0.774; 95% CI, 0.587-0.961). The two respiratory registrars were 78% (K =0.568; 95% CI, 0.338-0.798) and 72% (K =0.448; 95% CI, 0.222-0.674) concordant, respectively. The mean number of passes per patient was 4.9 (range, 3-7). A diagnosis was established in 21/25 (82%) patients from the first EBUS-TBNA procedures with the remaining four patients requiring a further procedure or monitoring with serial CT scans to establish the diagnosis. Malignancy was found in 14/25 (56%) patients and a benign process in 11/25 (44%) patients. CONCLUSIONS: Medical scientist review of ROSE samples is not significantly different to a specialist pathologist and is an acceptable alternative. Respiratory registrars are not a realistic alternative for ROSE without more intensive training, which may be difficult to facilitate in addition to existing respiratory training commitments.

Cranial nerve involvement in malignant external otitis: implications for clinical outcome.

BACKGROUND: Malignant external otitis is an uncommon, potentially lethal infection of the temporal bone primarily affecting elderly diabetic patients. OBJECTIVE: To determine whether cranial nerve involvement in malignant external otitis affects or predicts the clinical outcome in terms of morbidity and mortality. METHODS: Diagnosis of malignant external otitis was established in 23 patients (average age, 71 yr; range, 39-87) based on inclusion criteria of severe pain, otitis externa refractory to conventional treatments, diabetes mellitus, and Pseudomonas aeruginosa detection. Computed tomography confirmed temporal bone involvement extending outside the external auditory canal. DATA ANALYSIS: Retrospective analysis of hospital records. RESULTS: Ten of 23 (43.5%) patients showed cranial nerve involvement. The following cranial nerves were affected: facial nerve (6/10), lower cranial nerves (combination of IX, X, XI, XII) (3/10), and extended nerve palsy (VI, VII, IX, X, XI) (1/10). Thirteen of 23 (56.5%) patients displayed no cranial nerve involvement. All patients were treated with long-term, high-dose antibiotic treatment dependent on the microbiological findings. CONCLUSIONS: All patients with lower cranial nerve palsy recovered normal function; however, the facial nerve palsy was significantly less likely to improve by medical treatment. Cranial nerve involvement did not affect the patient survival rate under an optimized medical treatment in our series.

Change in hearing and tinnitus in conservatively managed vestibular schwannomas.

OBJECTIVES: The aim of this study was to evaluate the change of hearing and tinnitus in a group of conservatively managed unilateral vestibular schwannomas (VS). DESIGN: Retrospective case series review. SETTING: Tertiary referral otoneurological and skull base surgery department. PARTICIPANTS: Seventy patients affected by unilateral VS with at least two audiograms available were retrospectively evaluated. MAIN OUTCOME MEASURES: Changes in pure tone average (PTA), speech discrimination score (SDS), and tinnitus were analyzed. RESULTS: At diagnosis 16 patients (22.9%) had a PTA of 0 to 30 dB and 38 (54.4%) a PTA of 0 to 50 dB. At the end of the follow-up period, 9 patients (12.9%) had a PTA of 0 to 30 dB and 27 (38.7%) had a PTA of 0 to 50 dB, representing a hearing preservation rate of 56% and 70%, respectively. Of patients with both tonal and speech audiometry, 71.4% with class A hearing (PTA < 30 dB/SDS > 70%) maintained their initial hearing and 60% with class A or B hearing (PTA < 50 dB/SDS > 50%) maintained this useful hearing. Forty-two patients (60%) did not show a significant growth in their tumor over the period of observation. In this group of patients the mean PTA after a mean follow-up time of 40 months decreased from 44 dB HL to 50.8 dB HL, with a yearly rate of 2.47 dB HL. The chance of maintaining a PTA of 0 to 30 dB in this group of patients was 57.1% and a PTA of 0 to 50 dB was 81.4%. CONCLUSIONS: In this group of patients affected by VS and managed conservatively with a mean follow-up of 33.3 months, the risk of losing eligibility for hearing preservation surgery was lower than 30%.

Are facial nerve outcomes worse following surgery for cystic vestibular schwannoma?

OBJECTIVES: This study sought to determine explicitly whether postsurgical facial nerve outcomes for patients with a cystic component to a vestibular schwannoma were significantly different from those with a solid tumor. DESIGN: Seventy patients who underwent translabyrinthine surgery for a cystic vestibular schwannoma between May 1981 and the present, and who had complete records in our database, were identified. These were compared with a group of patients with solid tumors matched to the study group on the following parameters: House-Brackmann grade at presentation, tumor size, surgical approach, age. SETTING: Regional tertiary referral center. PARTICIPANTS: Adult patients with vestibular schwannomas. MAIN OUTCOME MEASURES: House-Brackmann score 2 years following surgery. RESULTS: No significant difference was found between the two groups. CONCLUSIONS: The perceived difference in outcomes between cystic and solid vestibular schwannomas cannot be demonstrated when confounding factors such as tumor size are taken into account.

Malignant Mesothelioma, BAP1 Immunohistochemistry, and VEGFA: Does BAP1 Have Potential for Early Diagnosis and Assessment of Prognosis?

Malignant mesothelioma (MM) is an aggressive malignancy of the serosal membranes. Early diagnosis and accurate prognostication remain problematic. BAP1 is a tumour suppressor gene commonly mutated in MM. Germline BAP1 mutation has been associated with early onset and less aggressive disease compared with sporadic MM. Sporadic BAP1 mutations are common and are associated with improved survival in MM, contrary to other malignancies. This study investigated the prognostic role of BAP1 in matched cytology and surgical specimens and aimed to investigate the association between BAP1 and the established prognostic marker VEGFA from a cohort of 81 patients. BAP1 mutation was found in 58% of histology and 59% of cytology specimens. Loss of BAP1 expression in both surgical and cytology specimens was significantly associated with poorer survival in a multivariate analysis when controlling for known prognostic indicators. Increased levels of VEGFA in pleural effusions were associated with poor survival. We conclude that the prognostic significance of BAP1 mutations in MM cannot be determined in isolation of other prognostic factors, which may vary between patients. Pathologists should employ caution when commenting on prognostic implications of BAP1 status of MM patients in diagnostic pathology reports, but it may be useful for early diagnosis.