Direct MRI-guided In-Bore Targeted Biopsy of the Prostate: A Step-by-Step How To and Lessons Learned.

Multiparametric MRI-the most accurate imaging technique for detection of prostate cancer-has transformed the landscape of prostate cancer diagnosis by enabling targeted biopsies. In a targeted biopsy, tissue samples are obtained from suspicious regions identified at prebiopsy diagnostic MRI. The authors briefly compare the different strategies available for targeting an MRI-visible suspicious lesion, followed by a step-by-step description of the direct MRI-guided in-bore approach and an illustrated review of its application in challenging clinical scenarios. In this technique, direct visualization of the needle, needle guide, and needle trajectory during the procedure provides a precise and versatile strategy to accurately sample suspicious lesions, improving detection of clinically significant cancers. Published under a CC BY 4.0 license Test Your Knowledge questions for this article are available in the supplemental material.

Outcome and Immune Correlates of a Phase II Trial of High-Dose Interleukin-2 and Stereotactic Ablative Radiotherapy for Metastatic Renal Cell Carcinoma.

PURPOSE: This phase II clinical trial evaluated whether the addition of stereotactic ablative radiotherapy (SAbR), which may promote tumor antigen presentation, improves the overall response rate (ORR) to high-dose IL2 (HD IL2) in metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Patients with pathologic evidence of clear cell renal cell carcinoma (RCC) and radiographic evidence of metastasis were enrolled in this single-arm trial and were treated with SAbR, followed by HD IL2. ORR was assessed based on nonirradiated metastases. Secondary endpoints included overall survival (OS), progression-free survival (PFS), toxicity, and treatment-related tumor-specific immune response. Correlative studies involved whole-exome and transcriptome sequencing, T-cell receptor sequencing, cytokine analysis, and mass cytometry on patient samples. RESULTS: Thirty ethnically diverse mRCC patients were enrolled. A median of two metastases were treated with SAbR. Among 25 patients evaluable by RECIST v1.1, ORR was 16% with 8% complete responses. Median OS was 37 months. Treatment-related adverse events (AE) included 22 grade ≥3 events that were not dissimilar from HD IL2 alone. There were no grade 5 AEs. A correlation was observed between SAbR to lung metastases and improved PFS (P = 0.0165). Clinical benefit correlated with frameshift mutational load, mast cell tumor infiltration, decreased circulating tumor-associated T-cell clones, and T-cell clonal expansion. Higher regulatory/CD8+ T-cell ratios at baseline in the tumor and periphery correlated with no clinical benefit. CONCLUSIONS: Adding SAbR did not improve the response rate to HD IL2 in patients with mRCC in this study. Tissue analyses suggest a possible correlation between frameshift mutation load as well as tumor immune infiltrates and clinical outcomes.

Gleason Grade Group Concordance between Preoperative Targeted Biopsy and Radical Prostatectomy Histopathologic Analysis: A Comparison Between In-Bore MRI-guided and MRI-Transrectal US Fusion Prostate Biopsies.

Purpose: To determine and compare rates of grade group (GG) discrepancies between different targeted biopsy techniques (in-bore vs fusion) after propensity score weighting using whole-mount radical prostatectomy (RP) histopathologic analysis as the reference standard. Materials and Methods: This retrospective study evaluated men who underwent targeted (fusion or in-bore) biopsy between April 2017 and January 2019 followed by prostatectomy. The primary endpoint of the study was a change in GG from biopsy to RP at a patient level. For downgrade and upgrade analysis, men with biopsy GG1 (downgrade not possible) and GG5 (upgrade not possible) were excluded, respectively. GG upgrade, downgrade, and concordance rates of each targeting approach were compared using propensity score weighting and logistic regression with inverse probability of treatment weighting. Significance level was set at .05. Index lesion GG on RP specimen served as the reference standard. Results: A total of 191 men (90 in the in-bore [mean age, 63 years ± 7 (standard deviation)] and 101 in the fusion biopsy group [mean age, 65 years ± 7]) were eligible and included. Fewer GG upgrades were noted in the in-bore biopsy group (14%; 12 of 85) compared with the fusion plus systematic biopsy group (30%; 28 of 93) (P = .012). The incidence of GG downgrade in the in-bore group (25%; 21 of 84) was higher than in the fusion group (17%; 16 of 93); however, the difference was not statistically significant (P = .2). Of the 77 men misclassified by both biopsy techniques, the majority (56%, n = 43) had a change in GG of 2 to 3 or 3 to 2. Conclusion: Superior sampling accuracy with MRI-guided in-bore biopsies offers a lower incidence of GG upgrades compared with MRI-transrectal US fusion biopsies upon RP.Keywords: Biopsy/Needle Aspiration, MR-Imaging, Oncology, Pathology, Prostate Supplemental material is available for this article.© RSNA, 2021.

Rare prostate cancer mimic on multiparametric MRI: Cowper's gland hyperplasia.

Multiparametric MRI and targeted biopsies of the prostate have been increasingly utilized in men with elevated PSA. It is important to recognize potential mimics of prostate cancer on MRI and on biopsy specimens. Familiarity with the location, imaging and histological appearance of Cowper's glands will prevent misdiagnosis and help avoid unnecessary biopsies. We present a case of Cowper's gland hyperplasia with a review of its imaging and histopathologic characteristics.

Impact of the Number of Cores on the Prostate Cancer Detection Rate in Men Undergoing in-Bore Magnetic Resonance Imaging-Guided Targeted Biopsies.

OBJECTIVE: To determine the incremental detection rate of clinically significant prostate cancer (csPCa) provided by sequential cores during in-bore magnetic resonance imaging (MRI)-guided prostate biopsies. METHODS: Single-center, retrospective interpretation of prospectively acquired data in men without previous diagnosis of csPCa who underwent in-bore MRI-guided prostate biopsy between May 2017 and December 2019. Endpoints included detection of csPCa (grade group [GG] ≥ 2) and rate of GG upgrade provided by additional cores. Descriptive statistics presented as mean and standard deviation for the continuous variables, and frequency and percentage for the categorical variables. RESULTS: Four hundred and forty-three men with 747 lesions met eligibility criteria. Clinically significant prostate cancer was detected in 43.1% (322/747) of the biopsied lesions and GG 2 PCa or greater was identified by the first core in 78.3% (252/322) of them. On a per-core basis, cores 2, 3, 4, and 5 found new csPCa in 6% (42/744), 4% (26/719), 1% (2/137), and 0% (0/11) of the cases. Core biopsy 2, 3, 4, and 5 resulted in GG upgrade in 12% (91/744), 7% (49/719), 7% (9/137), and 0% (0/11) of the lesions, respectively. Each additional core was associated with a mean increase of 5 minutes in the duration of the biopsy. CONCLUSIONS: In men undergoing in-bore MRI-guided prostate biopsies, 3 targeted cores per lesion provide an optimal trade-off between detection of clinically significant tumors and biopsy duration.

Turbo Spin-Echo Diffusion-Weighted Imaging in Prostate Magnetic Resonance Imaging of Men With Pelvic Hardware.

We evaluated an alternative diffusion-weighted imaging (DWI) acquisition for prostate magnetic resonance imaging of men with pelvic hardware, using radial k-space sampling (MultiVane [MV]), short-tau inversion-recovery (STIR) fat suppression, and split acquisition of turbo spin-echo signals. The optimized STIR-MV-DWI reduced metal-associated artifacts and image distortion, and aided in visualization of the prostate and lesions. The STIR-MV-DWI can be a valuable adjunct in prostate magnetic resonance imaging of men with pelvic hardware, among whom the conventional echo-planar DWI is compromised.

Prevalence and clinical significance of discordant LI-RADS® observations on multiphase contrast-enhanced MRI in patients with cirrhosis.

PURPOSE: To determine the prevalence and clinical significance of discordant LI-RADS® (Liver Imaging Reporting and Data System) liver observations on multiphase contrast-enhanced (MCE) magnetic resonance imaging (MRI) in patients with cirrhosis. METHODS: This cross-sectional study included 93 cirrhosis patients who underwent 1.5 or 3 T MCE MRI for evaluation of hepatocellular carcinoma (HCC). Two abdominal radiologists independently reviewed T1-, T2-, diffusion-weighted unenhanced images as well as MCE T1-weighted fat-suppressed images and reported liver observations using LI-RADS®. Concordance were recorded for detection (co-detected by both radiologists or not), size category (< 10; 10-19; ≥ 20 mm), and LI-RADS® category assignment as reportable (LR-3/4/5/M) and actionable (LR-4/5/M). The overall concordance (i.e., concordant in detection, size, and LR-category) was calculated with 95% confidence interval [CI], and separately for detection, size, and LR-category. Clinical significance of discordance was assessed as impact on follow-up imaging, referral for biopsy, liver transplant eligibility, or treatment modality. RESULTS: Reportable and actionable observations were overall concordant between two radiologists only in 32.3% [24.6, 41.0] and 40.1% [29.5, 51.5] of cases, respectively. Poor overall concordance was related to detection concordance of 52.0% [44.3, 59.5] and 62.5% [52.3, 71.8], as well as LR-category concordance of 73.7% [61.6, 83.1] and 70.9% [57.3, 81.6], for reportable and actionable observations, respectively. Discordant LI-RADS® observations would have impacted clinical management in 30 subjects (43.5%), most (66.7%) of whom were due to discordant detection. CONCLUSION: Discordant MRI LI-RADS® observations are common in patients with cirrhosis and may have potential implications for patient management.

HIF-2 Complex Dissociation, Target Inhibition, and Acquired Resistance with PT2385, a First-in-Class HIF-2 Inhibitor, in Patients with Clear Cell Renal Cell Carcinoma.

PURPOSE: The heterodimeric transcription factor HIF-2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC). Although considered undruggable, structural analyses at the University of Texas Southwestern Medical Center (UTSW, Dallas, TX) identified a vulnerability in the α subunit, which heterodimerizes with HIF1ß, ultimately leading to the development of PT2385, a first-in-class inhibitor. PT2385 was safe and active in a first-in-human phase I clinical trial of patients with extensively pretreated ccRCC at UTSW and elsewhere. There were no dose-limiting toxicities, and disease control ≥4 months was achieved in 42% of patients. PATIENTS AND METHODS: We conducted a prospective companion substudy involving a subset of patients enrolled in the phase I clinical trial at UTSW (n = 10), who were treated at the phase II dose or above, involving multiparametric MRI, blood draws, and serial biopsies for biochemical, whole exome, and RNA-sequencing studies. RESULTS: PT2385 inhibited HIF-2 in nontumor tissues, as determined by a reduction in erythropoietin levels (a pharmacodynamic marker), in all but one patient, who had the lowest drug concentrations. PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression. In contrast, HIF-1 complexes were unaffected. Prolonged PT2385 treatment resulted in the acquisition of resistance, and we identified a gatekeeper mutation (G323E) in HIF2α, which interferes with drug binding and precluded HIF-2 complex dissociation. In addition, we identified an acquired TP53 mutation elsewhere, suggesting a possible alternate mechanism of resistance. CONCLUSIONS: These findings demonstrate a core dependency on HIF-2 in metastatic ccRCC and establish PT2385 as a highly specific HIF-2 inhibitor in humans. New approaches will be required to target mutant HIF-2 beyond PT2385 or the closely related PT2977 (MK-6482).

Current Challenges in Diagnosis and Assessment of the Response of Locally Advanced and Metastatic Renal Cell Carcinoma.

Locally advanced and metastatic renal cell carcinoma (RCC) present a specific set of challenges to the radiologist. The detection of metastatic disease is confounded by the ability of RCC to metastasize to virtually any part of the human body long after surgical resection of the primary tumor. This includes sites not commonly included in routine surveillance, which come to light after the patient becomes symptomatic. In the assessment of treatment response, the phenomenon of tumor heterogeneity, where clone selection through systemic therapy drives the growth of potentially more aggressive phenotypes, can result in oligoprogression despite overall disease control. Finally, advances in therapy have resulted in the development of immuno-oncologic agents that may result in changes that are not adequately evaluated with conventional size-based response criteria and may even be misinterpreted as progression. This article reviews the common challenges a radiologist may encounter in the evaluation of patients with locally advanced and metastatic RCC. ©RSNA, 2019.

Role of Virtual Biopsy in the Management of Renal Masses.

OBJECTIVE. Renal masses comprise a heterogeneous group of pathologic conditions, including benign and indolent diseases and aggressive malignancies, complicating management. In this article, we explore the emerging role of imaging to provide a comprehensive noninvasive characterization of a renal mass-so-called "virtual biopsy"-and its potential use in the management of patients with renal tumors. CONCLUSION. Percutaneous renal mass biopsy (RMB) remains a valuable method to provide a presurgical histopathologic diagnosis of renal masses, but it is an invasive procedure and is not always feasible. Accumulating data support the use of imaging features to predict histopathology of renal masses. Imaging may help address some of the inherent limitations of RMB, and in certain settings, a multimodal clinical approach may allow decreasing the need for RMB.

Diagnostic Performance of Prospectively Assigned Likert Scale Scores to Determine Extraprostatic Extension and Seminal Vesicle Invasion With Multiparametric MRI of the Prostate.

OBJECTIVE: The objective of this study was to determine the diagnostic performance of a prospectively assigned 5-point Likert scale for determination of extraprostatic extension (EPE) and seminal vesicle invasion (SVI). MATERIALS AND METHODS: This study was a single-center, retrospective analysis of prospectively collected data including all men with abnormal 3-T multiparametric MRI and subsequent radical prostatectomy between November 1, 2016, and September 30, 2017. Scores from a 5-point subjective Likert scale (1 = highly unlikely, 5 = highly likely) for the likelihood of EPE and SVI were prospectively assigned during clinical MRI interpretation. EPE and SVI status at whole-mount prostatectomy specimen served as the standard of reference. RESULTS: Among the 89 eligible men, whole-mount histopathology revealed organ-confined prostate cancer, EPE, and SVI in 49% (44/89), 46% (41/89), and 18% (16/89) of patients, respectively. Of the pathologically proven cases of EPE, 18% (2/11), 17% (4/24), 65% (17/26), 46% (6/13) and 80% (12/15) were assigned Likert scores of 1-5, respectively. Of the pathologically proven cases of SVI, 5% (3/58), 11% (2/18), 66% (2/3), 66% (2/3) and 100% (7/7) were assigned Likert scores of 1-5, respectively. The positive predictive values for scores of 4 or 5 were 64% for EPE and 90% for SVI. The negative predictive values for scores of 1 or 2 were 87% for EPE and 93% for SVI. Likert scores for EPE (odds ratio, 2.1; 95% CI, 1.3-3.4) and for SVI (odds ratio, 4.7; 95% CI, 2.3-9.6) were both associated with EPE and SVI on multivariate analysis. CONCLUSION: A 5-point Likert scale can effectively convey the degree of suspicion of EPE and SVI on multiparametric MRI of the prostate, facilitating informed decision-making.

Case 258: Granulomatous Prostatitis.

History A 68-year-old man with a remote history of a previously resected high-grade urothelial carcinoma in the renal pelvis was being observed and was undergoing urologic treatment for recurrent low-grade urothelial carcinoma of the bladder. During his most recent evaluation, he reported no specific symptoms and denied experiencing hematuria, dysuria, or abdominal pain. At routine surveillance MRI of the abdomen and pelvis (images not shown), a lesion was noted in the peripheral zone of the prostate gland. The prostate-specific antigen level was elevated (7.51 ng/mL [normal range, 0.00-4.00 ng/mL]). The patient had no family history of prostate cancer and had never undergone prostate biopsy. MRI of the prostate with an endorectal coil was subsequently performed.

Reproducibility of Index Lesion Size and Mean Apparent Diffusion Coefficient Values Measured by Prostate Multiparametric MRI: Correlation With Whole-Mount Sectioning of Specimens.

OBJECTIVE: The purpose of this study is to determine the intra- and interreader agreement for index lesion size and mean apparent diffusion coefficient (ADC) value measurements performed by five readers using whole-mount histopathologic specimens processed with a patient-specific, MRI-based, 3D-printed mold as the standard of reference. MATERIALS AND METHODS: All men who underwent multiparametric MRI of the prostate performed using a 3-T scanner with endorectal and phased-array surface coils, followed by prostatectomy conducted between November 2015 and July 2016 at our institution, were identified. MRI examinations were independently reviewed by five readers with varying degrees of experience, two of whom had essentially no experience in prostate MRI interpretation before the study, to assess index lesion size and ADC values. A linear mixed model-based intraclass correlation was used to assess intra- and interreader reader agreement for lesion size and ADC measurements and agreement for size measurements between pathologic analysis and readers. RESULTS: A total of 80 men met the study eligibility criteria. Overall inter- and intrareader agreement for ADC measurements was excellent, with interclass correlation coefficient (ICC) values of 0.84 and 0.90, respectively; both inter- and intrareader agreement between experienced readers (0.82 and 0.92, respectively) and inexperienced readers (0.86 and 0.87, respectively) were excellent as well. The agreement between mean lesion size on imaging and histopathologic analysis ranged from poor (0.32) to good (0.66), with overall agreement considered fair (0.49). CONCLUSION: Readers with varying degrees of experience achieved good-to-excellent agreement for index lesion size and ADC values on multiparametric MRI of men with prostate cancer. This degree of reproducibility may improve preoperative risk stratification, informed decision making, and treatment planning for men with known or suspected prostate cancer.

Safety and efficacy of concurrent immune checkpoint inhibitors and hypofractionated body radiotherapy.

Integration of hypofractionated body radiotherapy (H-RT) into immune checkpoint inhibitor (ICI) therapy may be a promising strategy to improve the outcomes of ICIs, although sufficient data is lacking regarding the safety and efficacy of this regimen. We, hereby, reviewed the safety and efficacy of this combination in 59 patients treated with H-RT during or within 8 weeks of ICI infusion and compared results with historical reports of ICI treatment alone. Most patients had RCC or melanoma. Median follow-up was 11 months. Most patients received either Nivolumab alone or with Ipilimumab; 83% received stereotactic RT and 17% received conformal H-RT. Any grade adverse events (AEs) were reported in 46 patients, and grade 3-4 in 12 patients without any treatment-related grade 5 toxicity. The most common grade 3 AEs were fatigue and pneumonitis. Grade 3-4 toxicities were higher with ICI combination and with simultaneous ICIs. Overall, most any-grade or grade ≥3 AE rates did not differ significantly from historically reported rates with single-agent or multi-agent ICIs. Toxicity did not correlate with H-RT site, dose, fraction number, tumor type, or ICI and H-RT sequencing. Median progression-free survival was 6.5 months. Objective response rate (ORR) was 26%; 10% had complete response (CR). Median duration of response was 9.4 ± 4.6 months. H-RT of lung lesions was more likely to achieve CR than other sites. H-RT of bone lesions had a lower ORR than non-bone H-RT. In conclusion, combining body H-RT with ICIs is safe and promising. Prospective validation is warranted.

Diagnostic Performance and Interreader Agreement of a Standardized MR Imaging Approach in the Prediction of Small Renal Mass Histology.

Purpose To assess the diagnostic performance and interreader agreement of a standardized diagnostic algorithm in determining the histologic type of small (≤4 cm) renal masses (SRMs) with multiparametric magnetic resonance (MR) imaging. Materials and Methods This single-center retrospective HIPAA-compliant institutional review board-approved study included 103 patients with 109 SRMs resected between December 2011 and July 2015. The requirement for informed consent was waived. Presurgical renal MR images were reviewed by seven radiologists with diverse experience. Eleven MR imaging features were assessed, and a standardized diagnostic algorithm was used to determine the most likely histologic diagnosis, which was compared with histopathology results after surgery. Interreader variability was tested with the Cohen κ statistic. Regression models using MR imaging features were used to predict the histopathologic diagnosis with 5% significance level. Results Clear cell renal cell carcinoma (RCC) and papillary RCC were diagnosed, with sensitivities of 85% (47 of 55) and 80% (20 of 25), respectively, and specificities of 76% (41 of 54) and 94% (79 of 84), respectively. Interreader agreement was moderate to substantial (clear cell RCC, κ = 0.58; papillary RCC, κ = 0.73). Signal intensity (SI) of the lesion on T2-weighted MR images and degree of contrast enhancement (CE) during the corticomedullary phase were independent predictors of clear cell RCC (SI odds ratio [OR]: 3.19; 95% confidence interval [CI]: 1.4, 7.1; P = .003; CE OR, 4.45; 95% CI: 1.8, 10.8; P < .001) and papillary RCC (CE OR, 0.053; 95% CI: 0.02, 0.2; P < .001), and both had substantial interreader agreement (SI, κ = 0.69; CE, κ = 0.71). Poorer performance was observed for chromophobe histology, oncocytomas, and minimal fat angiomyolipomas, (sensitivity range, 14%-67%; specificity range, 97%-99%), with fair to moderate interreader agreement (κ range = 0.23-0.43). Segmental enhancement inversion was an independent predictor of oncocytomas (OR, 16.21; 95% CI: 1.0, 275.4; P = .049), with moderate interreader agreement (κ = 0.49). Conclusion The proposed standardized MR imaging-based diagnostic algorithm had diagnostic accuracy of 81% (88 of 109) and 91% (99 of 109) in the diagnosis of clear cell RCC and papillary RCC, respectively, while achieving moderate to substantial interreader agreement among seven radiologists. © RSNA, 2018 Online supplemental material is available for this article.

Imaging and Screening of Kidney Cancer.

Renal cell carcinoma (RCC) exhibits a diverse and heterogeneous disease spectrum, but insight into its molecular biology has provided an improved understanding of potential risk factors, oncologic behavior, and imaging features. Computed tomography (CT) and MR imaging may allow the identification and preoperative subtyping of RCC and assessment of a response to various therapies. Active surveillance is a viable management option in some patients and has provided further insight into the natural history of RCC, including the favorable prognosis of cystic neoplasms. This article reviews CT and MR imaging in RCC and the role of screening in selected high-risk populations.

Role of Multiparametric MR Imaging in Malignancies of the Urogenital Tract.

Multiparametric MR imaging (mpMRI) combine different sequences that, properly tailored, can provide qualitative and quantitative information about the tumor microenvironment beyond traditional tumor size measures and/or morphologic assessments. This article focuses on mpMRI in the evaluation of urogenital tract malignancies by first reviewing technical aspects and then discussing its potential clinical role. This includes insight into histologic subtyping and grading of renal cell carcinoma and assessment of tumor response to targeted therapies. The clinical utility of mpMRI in the staging and grading of ureteral and bladder tumors is presented. Finally, the evolving role of mpMRI in prostate cancer is discussed.

Quantification of regional interstitial lung disease from CT-derived fractional tissue volume: a lung tissue research consortium study.

RATIONALE AND OBJECTIVES: Evaluation of chest computed tomography (CT) is usually qualitative or semiquantitative, resulting in subjective descriptions often by different observers over time and imprecise determinations of disease severity within distorted lobes. There is a need for standardized imaging biomarkers to quantify regional disease, maximize diagnostic yield, and facilitate multicenter comparisons. We applied lobe-based voxelwise image analysis to derive regional air (Vair) and tissue (Vtissue) volumes and fractional tissue volume (FTV = tissue/[tissue+air] volume) as internally standardized parameter for assessing interstitial lung disease (ILD). MATERIALS AND METHODS: High-resolution CT was obtained at supine and prone end-inspiration and supine end-expiration in 29 patients with ILD and 20 normal subjects. Lobar Vair, Vtissue, and FTV were expressed along standard coordinate axes. RESULTS: In normal subjects from end-inspiration to end-expiration, total Vair declined ~43%, FTV increased ~80%, but Vtissue remained unchanged. With increasing ILD, Vair declined and Vtissue rose in all lobes; FTV increased with a peripheral-to-central progression inversely correlated to spirometry and lung diffusing capacity (r(2) = 0.57-0.75, prone end-inspiration). Inter- and intralobar coefficients of variation of FTV increased 84-148% in mild-to-moderate ILD, indicating greater spatial heterogeneity, then normalized in severe ILD. Analysis of discontinuous images incurs <3% error compared to consecutive images. CONCLUSIONS: These regional attenuation-based biomarkers could quantify heterogeneous parenchymal disease in distorted lobes, detect mild ILD involvement in all lobes and describe the pattern of disease progression. The next step would be to study a larger series, examine reproducibility and follow longitudinal changes in correlation with clinical and functional indices.

Subclinical lung disease, macrocytosis, and premature graying in kindreds with telomerase (TERT) mutations.

BACKGROUND: Mutations in the human gene encoding the protein component of telomerase (TERT) are the most common genetic defect in patients with familial idiopathic pulmonary fibrosis (IPF). The subclinical phenotypes of asymptomatic members of these families have not been evaluated with respect to TERT mutation status or telomere length. METHODS: We measured a variety of pulmonary, blood, skin, and bone parameters for 20 subjects with heterozygous TERT mutations (carriers) and 20 family members who had not inherited a TERT mutation (noncarriers) to identify the spectrum of phenotypes associated with mutations in this gene. The two groups were matched for sex, age, and cigarette smoking. Three TERT mutation carriers had IPF (IPF carriers). The rest of the carriers were apparently healthy (asymptomatic carriers) and were compared with the noncarriers. RESULTS: Asymptomatic carriers exhibited significantly lower diffusing capacity of lung for carbon monoxide (Dlco), impaired recruitment of Dlco with exercise, radiographic signs of lung fibrosis, and increased fractional lung tissue volume quantified by high-resolution chest CT scan than noncarriers. RBC and platelet counts were significantly lower, and the mean corpuscular volume and mean corpuscular hemoglobin concentration were significantly higher in carriers than in noncarriers. Carriers reported significantly earlier graying of hair than noncarriers. TERT mutation status is more accurately predicted by short telomere lengths than any of these measured phenotypes. CONCLUSIONS: TERT mutation carriers exhibit early preclinical signs of lung fibrosis, bone marrow dysfunction, and premature graying. These clinical features and short telomere lengths characterize patients with germline TERT mutations.