Roden, Anja C.

Interstitial lung diseases (ILDs) in patients with shortened telomeres have not been well characterized. We describe demographic, radiologic, histopathologic, and molecular features, and p16 expression in patients with telomeres ≤10th percentile (shortened telomeres) and compare them to patients with telomere length >10th percentile. Lung explants, wedge biopsies, and autopsy specimens of patients with telomere testing were reviewed independently by 3 pathologists using defined parameters. High-resolution computed tomography scans were reviewed by 3 radiologists. p16-positive fibroblast foci were quantified. A multidisciplinary diagnosis was recorded. Patients with shortened telomeres (N=26) were morphologically diagnosed as usual interstitial pneumonia (UIP) (N=11, 42.3%), chronic hypersensitivity pneumonitis (N=6, 23.1%), pleuroparenchymal fibroelastosis, fibrotic nonspecific interstitial pneumonia, desquamative interstitial pneumonia (N=1, 3.8%, each), and fibrotic interstitial lung disease (fILD), not otherwise specified (N=6, 23.1%). Patients with telomeres >10th percentile (N=18) showed morphologic features of UIP (N=9, 50%), chronic hypersensitivity pneumonitis (N=3, 16.7%), fibrotic nonspecific interstitial pneumonia (N=2, 11.1%), or fILD, not otherwise specified (N=4, 22.2%). Patients with shortened telomeres had more p16-positive foci (P=0.04). The number of p16-positive foci correlated with outcome (P=0.0067). Thirty-nine percent of patients with shortened telomeres harbored telomere-related gene variants. Among 17 patients with shortened telomeres and high-resolution computed tomography features consistent with or probable UIP, 8 (47.1%) patients showed morphologic features compatible with UIP; multidisciplinary diagnosis most commonly was idiopathic pulmonary fibrosis (N=7, 41.2%) and familial pulmonary fibrosis (N=5, 29%) in these patients. In conclusion, patients with shortened telomeres have a spectrum of fILDs. They often demonstrate atypical and discordant features on pathology and radiology leading to diagnostic challenges.

Abstract Objectives Differentiating malignant pleural mesothelioma from benign reactive mesothelial processes can be quite challenging. Ancillary tests such as BRCA1-associated protein 1 (BAP1) immunohistochemistry and p16 fluorescence in situ hybridization (FISH) are helpful tools to aid in this distinction. Immunohistochemistry for methylthioadenosine phosphorylase (MTAP) has recently been proposed as an effective surrogate marker for p16 FISH and is an attractive alternative test due to shorter turnaround time. There are little data regarding the specificity of MTAP loss for mesothelioma or whether it may be useful to distinguish mesothelioma from the most common entity in the differential diagnosis, sarcomatoid carcinoma. Methods We studied well-characterized cases of sarcomatoid carcinoma (n = 34) and sarcomatoid mesothelioma (n = 62), which were stained for MTAP (clone 2G4) and BAP1 (clone C-4). Results Loss of MTAP expression was observed in 17 (50%) of 34 pulmonary sarcomatoid carcinomas; BAP1 expression was retained in all of the cases in which it was performed (n = 31). MTAP expression was lost in 38 (61%) of 62 sarcomatoid mesotheliomas; BAP1 was lost in 6 (10%) of 62. In the six cases with BAP1 loss, five also had loss of MTAP, while MTAP expression was retained in one. Conclusions Loss of MTAP expression by immunohistochemistry is common in pulmonary sarcomatoid carcinoma, as it is present in half of cases. This rate is similar to what is observed in sarcomatoid mesothelioma (61%). Therefore, this stain is not useful to distinguish between these two malignancies. MTAP loss is more common than BAP1 loss in the setting of sarcomatoid mesothelioma (61% vs 10%, respectively).

Epithelioid hemangioendothelioma (EHE) is a rare vascular neoplasm which typically originates from liver, lung, or bone. Due to the low incidence of disease, the most effective treatment is not easily studied and much of the information known about EHE has been learned through case reports and case series. In this case, we will present an uncommon form of primary soft tissue EHE with local recurrence, bone metastasis, and lymphangitic spread to the lungs leading to respiratory failure. Imaging of the chest was atypical for EHE with intraseptal thickening and hilar lymphadenopathy. Respiratory failure was progressive despite aggressive multimodal treatment. This case highlights an unusually aggressive recurrence and metastasis of primary soft tissue EHE with atypical pulmonary imaging findings.

Abstract Objectives Numerous studies on malignant mesothelioma (MM) highlight the prognostic importance of histologic subtype, nuclear grade, and necrosis. This study compares these parameters in paired biopsy and resection specimens of pleural MM. Methods Histologic subtype, percentage of epithelioid morphology, nuclear grade, and the presence or absence of necrosis were compared in 429 paired biopsies and resection specimens of pleural MM from 19 institutions. Results Histologic subtype was concordant in 81% of cases (κ = 0.58). When compared with resection specimens, epithelioid morphology at biopsy had a positive predictive value (PPV) of 78.9% and a negative predictive value (NPV) of 93.5%; sarcomatoid morphology showed high PPV (92.9%) and NPV (99.3%), and biphasic morphology PPV was 89.7% and NPV was 79.7%. Agreement of the percentage of epithelioid morphology was fair (κ = 0.27). Nuclear grade and necrosis were concordant in 75% (κ = 0.59) and 81% (κ = 0.53) of cases, respectively. Nuclear grade showed moderate (κ = 0.53) and substantial (κ = 0.67) agreement from patients with and without neoadjuvant therapy, respectively, and necrosis showed moderate (κ = 0.47 and κ = 0.60) agreement, respectively, in the same subsets of paired specimens. Conclusions Paired biopsy-resection specimens from pleural MM show overall moderate agreement in pathologic parameters. These findings may help guide postbiopsy management and triage of patients with MM.

Context.— Small case series have evaluated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection in formalin-fixed, paraffin-embedded tissue using reverse transcription–polymerase chain reaction, immunohistochemistry (IHC), and/or RNA in situ hybridization (RNAish). Objective.— To compare droplet digital polymerase chain reaction, IHC, and RNAish to detect SARS-CoV-2 in formalin-fixed, paraffin-embedded tissue in a large series of lung specimens from coronavirus disease 2019 (COVID-19) patients. Design.— Droplet digital polymerase chain reaction and RNAish used commercially available probes; IHC used clone 1A9. Twenty-six autopsies of COVID-19 patients with formalin-fixed, paraffin-embedded tissue blocks of 62 lung specimens, 22 heart specimens, 2 brain specimens, and 1 liver, and 1 umbilical cord were included. Control cases included 9 autopsy lungs from patients with other infections/inflammation and virus-infected tissue or cell lines. Results.— Droplet digital polymerase chain reaction had the highest sensitivity for SARS-CoV-2 (96%) when compared with IHC (31%) and RNAish (36%). All 3 tests had a specificity of 100%. Agreement between droplet digital polymerase chain reaction and IHC or RNAish was fair (κ = 0.23 and κ = 0.35, respectively). Agreement between IHC and in situ hybridization was substantial (κ = 0.75). Interobserver reliability was almost perfect for IHC (κ = 0.91) and fair to moderate for RNAish (κ = 0.38–0.59). Lung tissues from patients who died earlier after onset of symptoms revealed higher copy numbers by droplet digital polymerase chain reaction (P = .03, Pearson correlation = −0.65) and were more likely to be positive by RNAish (P = .02) than lungs from patients who died later. We identified SARS-CoV-2 in hyaline membranes, in pneumocytes, and rarely in respiratory epithelium. Droplet digital polymerase chain reaction showed low copy numbers in 7 autopsy hearts from ProteoGenex Inc. All other extrapulmonary tissues were negative. Conclusions.— Droplet digital polymerase chain reaction was the most sensitive and highly specific test to identify SARS-CoV-2 in lung specimens from COVID-19 patients.

Abstract Objectives To evaluate SATB2 expression and prognostic implications in a large cohort of thoracic neuroendocrine tumors. Methods Surgical pathology files (1995-2017) and an institutional thymic epithelial tumor database (2010-2020) were searched for resected neuroendocrine tumors. Cases were stained with SATB2 (clone EP281). Percent SATB2-positive tumor cells and expression intensity were scored. Results In the lung, SATB2 was expressed in 5% or more of tumor cells in 29 (74.4%) of 39 small cell carcinomas and 9 (22.5%) of 40 atypical and 26 (40.6%) of 64 typical carcinoid tumors. SATB2 percent tumor cell expression and intensity were higher in small cell carcinomas than in carcinoid tumors (both P < .001, respectively). After adjusting for tumor subtype, SATB2 expression did not correlate with outcome. In the thymus, four (100%) of four atypical carcinoid tumors and one large cell neuroendocrine carcinoma but no small cell carcinoma (n = 2) expressed SATB2 in 5% or more of tumor cells. Conclusions SATB2 (clone EP281) is expressed in a large subset of pulmonary and thymic neuroendocrine tumors and therefore does not appear to be a useful marker to identify the origin of neuroendocrine tumors. Validation studies are needed, specifically including thymic neuroendocrine tumors, as the expression pattern might be different in those tumors.

Abstract Context. —In comparison to αβ T cells, little is known about the immunophenotype of healthy peripheral blood γδ T cells or about conditions associated with expansion of this usually minor T-cell subset. Objective. —To study the immunophenotype of increased nonneoplastic peripheral blood γδ T cells and to determine clinical conditions associated with this laboratory finding. Design. —Flow cytometric T-cell phenotyping studies performed on 352 consecutive peripheral blood specimens were reviewed, and 62 cases (18%) in which γδ T cells comprised either more than 5% of the total lymphocytes or had an absolute count of more than 200 cells per μL or both, were studied further. Clinical data were available from 36 cases. Results. —The γδ T cells often had an immunophenotype distinct from the αβ T cells, with differences in CD5 expression as the most common (n = 17), followed by differences in CD3 (n = 6) and CD7 (n = 3). CD16 coexpression by the γδ T cells was also frequent (n = 20). In 28 (78%) of 36 cases, there were one or more associated conditions: infection/inflammatory disease (n = 18), autoimmune disease (n = 9), lymphoproliferative disorder (n = 6), and splenectomy (n = 3). Conclusions. —Circulating γδ T cells are immunophenotypically distinct from αβ T cells, and mild increases in these cells are not uncommon and may be associated with immune system activation and splenectomy. Recognition of this phenomenon is important because reactive γδ T cells can exhibit distinctive immunophenotypic features that are also encountered in neoplastic conditions, such as T-cell large granular lymphocytic leukemia.

Abstract OBJECTIVES Neuroendocrine thymic tumours (NETTs) are a distinct subgroup of rare malignancies. An international, multicentre retrospective analysis was used to study the clinicopathological features, current pattern of diagnosis, treatment and outcomes of patients with NETT. METHODS One hundred and forty-six NETT treated from 1989 to 2016 at 21 centres in China, Europe and North America were retrospectively collected and reclassified according to the World Health Organization histological type and International Thymic Malignancy Interest Group (ITMIG)/International Association for Studies in Lung Cancer (IASLC)/Union for International Cancer Control (UICC) staging. Clinicopathological features, diagnostic and therapeutic approaches and outcomes were investigated. Results in the earlier and latter halves of the study period were also compared. RESULTS The pretreatment work-up relied exclusively on computed tomography in 85.6% (125/146) of cases. Most patients had advanced disease, with 32.2% (47/146) having lymph node involvement. Higher-grade histological type was associated with more advanced disease (P < 0.05). Induction therapies and surgical procedures were used more often in the latter half of the study. However, the complete resection rate remained unchanged, being 71.5% (98/137) in the whole group. Complete resection was associated with significantly longer 5-year overall survival (77.2% vs 51.2%; P < 0.001) than incomplete or no resection. Significant survival differences were seen with the T, N and M categories of ITMIG/IASLC/UICC staging. Poorly differentiated carcinoma, ITMIG/IASLC/UICC stage IIIa or above and incomplete or no resection were independent risk factors for worse survival. No survival difference was noted between the earlier and the latter halves of the study (58.2% vs 71.9%; P = 0.299). CONCLUSIONS Current management similar to that for thymomas is unsatisfactory in providing disease control or long-term survival for patients with NETT. Specific diagnostic tools and novel therapeutic agents are needed to improve management outcomes of this disease.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its resultant clinical presentation, coronavirus disease 2019 (COVID-19), is an emergent cause of mortality worldwide. Cardiac complications secondary to this infection are common; however, the underlying mechanisms of such remain unclear. A detailed cardiac evaluation of a series of individuals with COVID-19 undergoing postmortem evaluation is provided, with 4 aims: (1) describe the pathological spectrum of the myocardium; (2) compare with an alternate viral illness; (3) investigate angiotensin-converting enzyme 2 expression; and (4) provide the first description of the cardiac findings in patients with cleared infection. Methods: Study cases were identified from institutional files and included COVID-19 (n=15: 12 active, 3 cleared), influenza A/B (n=6), and nonvirally mediated deaths (n=6). Salient information was abstracted from the medical record. Light microscopic findings were recorded. An angiotensin-converting enzyme 2 immunohistochemical H-score was compared across cases. Viral detection encompassed SARS-CoV-2 immunohistochemistry, ultrastructural examination, and droplet digital polymerase chain reaction. Results: Male sex was more common in the COVID-19 group ( P =0.05). Nonocclusive fibrin microthrombi (without ischemic injury) were identified in 16 cases (12 COVID-19, 2 influenza, and 2 controls) and were more common in the active COVID-19 cohort ( P =0.006). Four active COVID-19 cases showed focal myocarditis, whereas 1 case of cleared COVID-19 showed extensive disease. Arteriolar angiotensin-converting enzyme 2 endothelial expression was lower in COVID-19 cases than in controls ( P =0.004). Angiotensin-converting enzyme 2 myocardial expression did not differ by disease category, sex, age, or number of patient comorbidities ( P =0.69, P =1.00, P =0.46, P =0.65, respectively). SARS-CoV-2 immunohistochemistry showed nonspecific staining, whereas ultrastructural examination and droplet digital polymerase chain reaction were negative for viral presence. Four patients (26.7%) with COVID-19 had underlying cardiac amyloidosis. Cases with cleared infection had variable presentations. Conclusions: This detailed histopathologic, immunohistochemical, ultrastructural, and molecular cardiac series showed no definitive evidence of direct myocardial infection. COVID-19 cases frequently have cardiac fibrin microthrombi, without universal acute ischemic injury. Moreover, myocarditis is present in 33.3% of patients with active and cleared COVID-19 but is usually limited in extent. Histological features of resolved infection are variable. Cardiac amyloidosis may be an additional risk factor for severe disease.

Abstract Objectives To describe the histologic features that are helpful in the diagnosis of the rare bronchiolar adenomas/ciliated muconodular papillary tumors (BAs/CMPTs) during intraoperative consultation. Methods Multi-institutional retrospective review of frozen sections of 18 BAs/CMPTs. Results In 14 of 18 cases, BA/CMPT was the primary reason for sublobar lung resection, and in 4 cases, BA/CMPT was an incidental finding intraoperatively for resections performed for carcinoma in other lobes. There were 11 proximal-type/classic BAs/CMPTs and 7 distal-type/nonclassic BAs/CMPTs. Only 3 (16.7%) of 18 were correctly diagnosed at the time of frozen section, all of which were proximal type/classic. The remainder were diagnosed as adenocarcinoma (n = 7); invasive mucinous adenocarcinoma (n = 1); non–small cell lung carcinoma (n = 1); cystic mucinous neoplasm, favor adenocarcinoma (either mucinous or colloid type) (n = 1); favor adenocarcinoma, cannot exclude CMPT (n = 1); atypical proliferation (n = 2); mucinous epithelial proliferation (n = 1); and mucous gland adenoma (n = 1). Conclusions BA/CMPT can potentially be misdiagnosed as carcinoma during intraoperative consultation. On retrospective review of the frozen sections, the presence of the following may help to avoid misdiagnosis: a mixture of bland ciliated columnar cells, mucinous cells, and, most important, a basal cell layer, as well as a lack of necrosis, significant atypia, and mitoses.