Large cell calcifying Sertoli cell tumour: molecular and immunohistochemical assessment of a series comprising non-metastasising and metastasising neoplasms.

Large cell calcifying Sertoli cell tumour (LCCSCT) is a type of testicular sex cord-stromal tumour that may occur sporadically or in the context of Carney complex and other genetic syndromes. A subset is clinically malignant, and the molecular mechanisms that drive such aggressive behaviour remain unknown. METHODS AND RESULTS: We analysed 21 samples from 20 patients with LCCSCT (12 non-metastasising and eight metastasising) using PRKAR1A immunohistochemistry (IHC) and next-generation sequencing. All tumours except two (cases 17 and 20, both metastasising) demonstrated loss of PRKAR1A expression. Among 11 cases with interpretable sequencing results, all harboured pathogenic single nucleotide variants of PRKAR1A. Evidence of loss of heterozygosity (LOH) of PRKAR1A was present in all tumours with interpretable zygosity data, but the mechanisms of LOH were different for non-metastasising and metastasising tumours. Non-metastasising tumours demonstrated only copy-neutral LOH, while metastasising tumours demonstrated a spectrum of mechanisms of LOH, including copy-loss LOH, two concurrent mutations or copy-neutral LOH. Relevant molecular findings in non-metastasising LCCSCT were limited to PRKAR1A variants. In contrast, all metastasising LCCSCTs with interpretable data harboured additional pathogenic variants, including (but not restricted to) BRCA2 mutations with evidence of LOH and bi-allelic CDKN2A/B deletions. Three patients harboured PRKAR1A variants of inferred germline origin, including one with Carney complex and two without known syndromic features. CONCLUSIONS: This study further confirms that PRKAR1A IHC is a useful diagnostic tool for both non-metastasising and metastasising tumours and suggests that molecular analyses can be helpful to identify non-metastasising tumours with malignant potential in selected patients. Importantly, these results highlight that germline assessment could be beneficial for all patients presenting with LCCSCT.

Myoid gonadal stromal tumours are characterised by recurrent chromosome-level copy number gains: molecular assessment of a multi-institutional series.

Myoid gonadal stromal tumours (MGST) represent a rare type of testicular sex cord-stromal tumour that has recently been recognised as a distinct entity by the World Health Organization (WHO) classification of genitourinary tumours. MGSTs affect adult men and have been reported to behave in an indolent fashion. Histologically, MGSTs are pure spindle cell neoplasms that coexpress SMA and S100 protein. Given that the molecular features of these neoplasms remain largely undescribed, we evaluated a multi-institutional series of MGSTs using DNA and RNA sequencing. This study included 12 tumours from 12 patients aged 28 to 57 years. Tumour sizes ranged from 0.6 to 4.3 cm. Aggressive histologic features, such as vascular invasion, necrosis, invasive growth, and atypical mitoses were invariably absent. Mitotic activity was low, with a median of less than 1 mitosis per 10 high power fields (HPF; maximum: 3 mitoses per 10 HPF). Molecular analyses did not identify recurrent mutations or gene fusions. All cases with interpretable copy number variant data (9/10 cases sequenced successfully) demonstrated a consistent pattern of chromosome arm-level and whole-chromosome-level copy number gains indicative of ploidy shifts, with recurrent gains involving chromosomes 3, 6, 7, 8, 9, 11, 12, 14q, 15q, 17, 18q, 20, and 21q. Similar findings have also been recognised in pure spindle cell and spindle-cell predominant sex cord-stromal tumours without S100 protein expression. MGSTs are characterised by ploidy shifts and may be part of a larger spectrum of spindle cell-predominant sex cord-stromal tumours, including cases without S100 protein expression.

Usefulness of impulse oscillometry for the assessment of airway hyperresponsiveness in mild-to-moderate adult asthma.

BACKGROUND: Impulse oscillometry (IOS) is a novel method of assessing airway resistance. IOS is rarely used in assessing airway resistance after bronchoprovocation in adult asthma. OBJECTIVE: To ascertain the degree of change in IOS measurements seen in patients with asthma undergoing bronchial challenge testing. METHODS: Patients 18 to 65 years old with mild to moderate asthma, forced expiratory volume in 1 second (FEV1) greater than 80% predicted, and diurnal FEV1 variation less than 30% and taking inhaled corticosteroid (≤1,000 µg/day of beclomethasone dipropionate equivalent dose) were recruited. Sequential spirometry and IOS results were measured during bronchial challenge testing to inhaled methacholine and histamine. RESULTS: The magnitude of percentage of change demonstrated in total airway resistance at 5 Hz was greater than that observed for FEV1 in the 2 bronchial challenge tests. For example, at a methacholine provocation concentration that caused a decrease in FEV1 of 20%, a 43.5% change (95% confidence interval 29.4-57.5) was seen in total airway resistance at 5 Hz as measured by IOS compared with a 23.3% change (95% confidence interval 18.7-27.9) in FEV1. The magnitude of change seen with other IOS outcomes, including peripheral airway resistance, area under the curve, and resonant frequency, also was greater compared with spirometry. CONCLUSION: The potential application of IOS in the assessment of airway hyperresponsiveness in adult asthma has been demonstrated. Further population studies are required. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01074853).

Assessment of spirometry and impulse oscillometry in relation to asthma control.

INTRODUCTION: Guidelines advocate the use of spirometry to assess pulmonary function in asthmatic patients. Commonly used measures include forced expiratory volume in 1 s (FEV1), forced expiratory ratio (FEV1/FVC), and forced mid-expiratory flow between 25 and 75 % of forced vital capacity (FEF25-75). Impulse oscillometry (IOS) is an effort-independent test performed during tidal breathing. IOS may be used to assess the total and central airway resistance at 5 Hz (R5) and 20 Hz (R20), respectively, and hence derive the peripheral airway resistance from the difference (R5-R20). We compared spirometry and IOS as tests of global airway function (i.e., FEV1, FEV1/FVC, R5) and putative measures of small airways function (i.e., FEF25-75, R5-R20) and their relationship to oral steroid and short-acting beta-agonist (SABA) use as surrogates for long-term asthma control. METHODS: Spirometry and IOS measurements from physician-diagnosed asthmatics were linked to a health informatics database for oral steroid and SABA use 1 year prior to the index measurements. RESULTS: Four hundred forty-two patients had both spirometry and IOS, mean FEV1 = 86 % predicted, 94 % on ICS, median dose 800 µg/day. IOS and spirometry measures were equally predictive of impaired asthma control for both oral steroid and SABA use. For oral steroid use, the adjusted odds ratio, OR (95 % CI) is as follows: FEV1 < 80 %: 1.56(0.99-2.47), p = 0.056; FEV1/FVC < 0.70: 1.67(1.03-2.69), p = 0.037; FEF25-75 < 60 %: 1.84(1.18-2.86), p = 0.007; R5 > 150 %: 1.91(1.25-2.95), p = 0.003; and R5-R20 > 0.1 kPa L(-1) s 1.73(1.12-2.66), p = 0.013. For SABA use, the adjusted OR (95 % CI) is as follows: FEV1 < 80 %: 2.22(1.43-3.44), p < 0.001; FEV1/FVC < 0.70: 2.26(1.44-3.57), p < 0.001; FEF25-75 < 60 %: 2.51(1.65-3.82), p < 0.001; R5 > 150 %: 1.76(1.18-2.63), p = 0.006; and R5-R20 > 0.1 kPa L(-1) s: 2.94(1.94-4.46), p < 0.001. CONCLUSION: Spirometry or IOS measurements were equally useful as potential markers of asthma control in persistent asthmatic patients.