Larsen, Brandon T.

Context.— Studies of lungs in patients with COVID-19 have focused on early findings. Objective.— To systematically study histopathologic and imaging features and presence of SARS-CoV-2 RNA in lung tissue from patients in later stages of COVID-19. Design.— Autopsies, explants, surgical lung biopsies, transbronchial biopsies, cryobiopsies, and needle biopsies from patients with COVID-19 whose onset of symptoms/confirmed diagnosis was more than 28 days before the procedure were studied. Available images were reviewed. Reverse transcription droplet digital polymerase chain reaction for SARS-CoV-2 RNA was performed on lung tissue. Results.— Of 44 specimens (43 patients; median age, 59.3 years; 26 [60.5%] male) features of acute lung injury (ALI) were seen in 39 (88.6%), predominantly organizing pneumonia and diffuse alveolar damage, up to 298 days after onset of COVID-19. Fibrotic changes were found in 33 specimens (75%), most commonly fibrotic diffuse alveolar damage (n = 22) and cicatricial organizing pneumonia (n = 12). Time between acquiring COVID-19 and specimen was shorter in patients with diffuse ALI (median, 61.5 days) compared with patients with focal (140 days) or no ALI (130 days) (P = .009). Sixteen (of 20; 80%) SARS-CoV-2 reverse transcription droplet digital polymerase chain reaction tests were positive, up to 174 days after COVID-19 onset. Time between COVID-19 onset and most recent computed tomography in patients with consolidation on imaging was shorter (median, 43.0 days) versus in patients without consolidation (87.5 days; P = .02). Reticulations were associated with longer time to computed tomography after COVID-19 onset (median, 82 versus 23.5 days; P = .006). Conclusions.— ALI and SARS-CoV-2 RNA can be detected in patients with COVID-19 for many months. ALI may evolve into fibrotic interstitial lung disease.

AbstractNoonan syndrome (NS) is an autosomal dominant condition with variable expressivity most commonly due to a germline pathogenic variant in PTPN11, which encodes the protein tyrosine phosphatase SHP‐2. Gain‐of‐function variants in PTPN11 are known to promote oncogenic behavior in affected tissues. We report the clinical description of a young adult male presenting with relapsing ganglioneuromas, dysmorphic features, cardiac abnormalities, and multiple lentigines, strongly suspicious for NS. Solid tumor testing identified the recurrent pathogenic c.922G>A (p.Asn308Asp) in PTPN11. Proband and parental blood sampling testing confirmed c.922G>A as a de novo germline alteration. Comprehensive literature review of solid tumors specifically associated to PTPN11, indicates that this is the first documentation of ganglioneuroma and its clinical recurrence after resection in conjunction with a genetically confirmed NS diagnosis. The findings in our patient further extend the list of neuroblastic and neural crest‐derived neoplasms associated with this condition.

Hepatic artery stenosis after liver transplant is often treated with endovascular stent placement. Our institution has adopted use of drug-eluting stents, particularly in small-caliber arteries. We aimed to compare patency rates of drug-eluting stents vs. traditional bare-metal stents. This was a single-institution, retrospective study of liver transplant hepatic artery stenosis treated with stents. Primary patency was defined as time from stent placement to resistive index on Doppler ultrasonography (<0.5), hepatic artery thrombosis, or any intervention including surgery. Fifty-two patients were treated with stents (31 men; mean age, 57 years): 15, drug-eluting stents; 37, bare-metal stents. Mean arterial diameters were 4.1 mm and 5.1 mm, respectively. Technical success was 100% (52/52). At 6 months, 1, 2, and 3 years, primary patency for drug-eluting stents was 80%, 71%, 71%, and 71%; bare-metal stents: 76%, 65%, 53%, and 46% (p = 0.41). Primary patency for small-caliber arteries (3.5–4.5 mm) with drug-eluting stents was 93%, 75%, 75%, and 75%; bare-metal stents: 60%, 60%, 50%, and 38% (p = 0.19). Overall survival was 100%, 100%, 94%, and 91%. Graft survival was 100%, 98%, 96%, and 90%. Stenting for hepatic artery stenosis was safe and effective. While not statistically significant, patency improved with drug-eluting stents compared with bare-metal stents, especially in arteries < 4.5 mm in diameter. Drug-eluting stents can be considered for liver transplant hepatic artery stenosis, particularly in small-caliber arteries.

Light chain deposition disease, characterized by nonamyloidogenic deposits of immunoglobulin light chains, is rare in the lung and possibly underdiagnosed due to low clinical suspicion and lack of readily accessible tests. We encountered a case of pulmonary light chain deposition disease (PLCDD) in which light chain deposits appeared crimson red with a Masson trichrome (MT) stain and salmon pink with a sulfated Alcian blue (SAB) stain. This prompted us to characterize a series of PLCDD cases and assess the utility of MT and SAB stains to distinguish them from amyloidosis. From the pathology archives of 2 institutions spanning 10 years, we identified 11 cases of PLCDD, including 7 diagnosed as such and 4 determined retrospectively. The deposits in all cases of PLCDD stained crimson red with MT and salmon pink with SAB, while the cases of pulmonary amyloid (n=10) stained blue-gray and blue-green, respectively. The immunoglobulin light chain nature of the deposits was confirmed in 10 of 11 cases by either immunofluorescence microscopy (n=5) or mass spectrometry (n=5). Transmission electron microscopy revealed osmiophilic, electron-dense deposits in all cases analyzed (n=3). An extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type was diagnosed in 10 cases and 1 represented a plasma cell neoplasm. Our study highlights the importance of considering PLCDD in the differential diagnosis of amyloid-like deposits in the lung and the value of performing MT and SAB stains to distinguish between PLCDD and amyloidosis.

Context.— Idiopathic pulmonary fibrosis is a clinical syndrome characterized by the presence of usual interstitial pneumonia (UIP) radiologically and pathologically. Per consensus criteria adopted in 2011, diagnosis of idiopathic pulmonary fibrosis no longer requires a biopsy in an appropriate context if UIP is seen on imaging. As a result, lung biopsies are now typically reserved for patients having indeterminate clinical or imaging findings or suspicion for alternative diagnoses, but the impact of updated guidelines on pathology practice remains unclear. Objective.— To determine the frequency of histologic UIP before and after 2011. Design.— Surgical lung biopsies from adults were studied within two 4-year periods: July 1, 2006 through June 30, 2010 and January 1, 2012 through December 31, 2015. Pathology slides were reviewed in a fashion blinded to clinical information and were classified using current guidelines. Results.— Biopsies from 177 and 86 patients (mean [SD] age, 62 [12] and 59 [14] years; 50.3% [89 of 177] and 48.8% [42 of 86] men) before and after 2011, respectively, were reviewed. Probable UIP or UIP was less-frequently encountered after 2011 in all patients with fibrosis (9 of 54 [16.7%] versus 41 of 119 [34.5%] before 2011, P = .02) and also in patients 50 years old and older (8 of 46 [17.4%] versus 39 of 109 [35.8%] before 2011, P = .02), with a concomitant rise in cases indeterminate for UIP or showing alternative diagnoses. Conclusions.— Histology for UIP is less frequently encountered in our contemporary practice compared with the historic era. The pretest probability of a non-UIP diagnosis is now high, even in elderly patients, underscoring the need for pathologists to be familiar with the histologic features of alternative diagnoses.

Only 50% to 70% of patients with mesothelioma report asbestos exposure. Other exposures (eg, radiation) play a role in some cases, but some patients have no obvious cause. We describe a series of patients with long-standing indwelling intra-abdominal shunt catheters who developed malignant peritoneal mesothelioma, suggesting a novel association. We identified 7 patients who had shunts and subsequently developed mesothelioma (5 women; median age: 31 y, range: 18 to 45 y). Clinical history and pathology materials were reviewed, and RNA sequencing was performed. Clinical presentations varied; 6 patients had hydrocephalus and a ventriculoperitoneal shunt, and 1 patient had portal hypertension and a portoatrial shunt. The median duration of shunt therapy in 5 cases was 29 years (range: 12 to 35 y); the remaining 2 patients also had shunts for many years, but specific details were unavailable. Two patients had radiotherapy for malignancies in childhood. One had an alleged exposure to asbestos and 1 had prior exposure to talc. The rest had no known risk factors. Histologically, all tumors were purely epithelioid. Treatments included surgical debulking, chemotherapy, and palliative care. All 7 died of disease (median survival: 7 mo, range: 1 to 18 mo). Molecular testing showed loss of NF2 and CDKN2A/B and a BAP1 mutation in 1 case, and no genomic alterations associated with mesothelioma in 2 cases. Peritoneal mesothelioma may represent a complication of long-standing indwelling shunt catheters. The mechanism is unknown, but chronic peritoneal irritation may play a role. Albeit rare, mesothelioma should be considered in patients with a shunt who present with new ascites.

Context.— Accurate diagnosis of idiopathic pulmonary fibrosis (IPF) requires multidisciplinary diagnosis that includes clinical, radiologic, and often pathologic assessment. In 2018, the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and the Latin American Thoracic Society (ATS/ERS/JRS/ALAT) and the Fleischner Society each published guidelines for the diagnosis of IPF, which include criteria for 4 categories of confidence of a histologic usual interstitial pneumonia (UIP) pattern. Objective.— To (1) identify the role of the guidelines in pathologic assessment of UIP; (2) analyze the 4 guideline categories, including potential areas of difficulty; and (3) determine steps the Pulmonary Pathology Society and the greater pulmonary pathology community can take to improve current guideline criteria and histopathologic diagnosis of interstitial lung disease. Data Sources.— Data were derived from the guidelines, published literature, and clinical experience. Conclusions.— Both guidelines provide pathologists with a tool to relay to the clinician the likelihood that a biopsy represents UIP, and serve as an adjunct, not a replacement, for traditional histologic diagnosis. There are multiple challenges with implementing the guidelines, including (1) lack of clarity on the quantity and quality of histologic findings required, (2) lack of recognition that histologic features cannot be assessed independently, and (3) lack of guidance on how pathologists should incorporate clinical and radiographic information. Current criteria for “probable UIP” and “indeterminate for UIP” hinder accurate reflection of the likelihood of IPF. These challenges highlight the need for further morphologic-based investigations in the field of pulmonary pathology.