Khoór, András

AbstractRobotic‐assisted bronchoscopy (RAB) improves endoscopic diagnostic yield of solitary pulmonary nodules (SPN). Needle‐based confocal laser endomicroscopy (nCLE) is an emerging technology that allows high‐resolution, in‐vivo, real‐time assessment of living tissues at a cellular and subcellular level. Their combined use has been scarcely reported. We used them simultaneously in three patients with SPNs. For each, the nodule was evaluated with nCLE and sampled for pathology, followed by mediastinal staging. Median age was 77 years (67% male). Median nodule minimum size was 1.8 cm and maximum was 2.1 cm. nCLE detected abnormal patterns suggestive of malignancy for all nodules and pathology confirmed primary lung adenocarcinomas in two patients and lung primary squamous cell carcinoma in the other. The combined use of RAB with nCLE may potentially enhance the differentiation of malignant cells in real‐time and increase sample adequacy, accuracy, and diagnostic yield when biopsying a suspicious pulmonary lesion.

The use of lymphoid interstitial pneumonia (LIP) as a diagnostic term has changed considerably since its introduction. Utilizing a multi-institutional collection of 201 cases from the last 20 years that demonstrate features associated with the LIP rubric, we compared cases meeting strict histologic criteria of LIP per American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus (“pathologic LIP”; n=62) with cystic cases fulfilling radiologic ATS/ERS criteria (“radiologic LIP”; n=33) and with other diffuse benign lymphoid proliferations. “Pathologic LIP” was associated with immune dysregulation including autoimmune disorders and immune deficiency, whereas “radiologic LIP” was only seen with autoimmune disorders. No case of idiopathic LIP was found. On histology, “pathologic LIP” represented a subgroup of 70% (62/88) of cases with the distinctive pattern of diffuse expansile lymphoid infiltrates. In contrast, “radiologic LIP” demonstrated a broad spectrum of inflammatory patterns, airway-centered inflammation being most common (52%; 17/33). Only 5 cases with radiologic cysts also met consensus ATS/ERS criteria for “pathologic LIP.” Overall, broad overlap was observed with the remaining study cases that failed to meet consensus criteria for “radiologic LIP” and/or “pathologic LIP.” These data raise concerns about the practical use of the term LIP as currently defined. What radiologists and pathologist encounter as LIP differs remarkably, but neither “radiologic LIP” nor “pathologic LIP” present with sufficiently distinct findings to delineate such cases from other patterns of diffuse benign lymphoid proliferations. As a result of this study, we believe LIP should be abandoned as a pathologic and radiologic diagnosis.

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.

Abstract Context. —Brain metastases of adenocarcinoma of unknown primary pose a diagnostic dilemma to the surgical pathologist. Although the most common source in these cases is the lung, determining a primary source is difficult on routinely stained slides. Immunohistochemical stain panels including differential cytokeratins, hormone receptors, and breast-specific proteins are commonly used in these cases. Recently, attention has turned to tissue-specific transcription factors, such as thyroid transcription factor 1 (TTF-1) and Cdx2, in the appraisal of metastatic adenocarcinomas. Objective. —To characterize the previously unpublished immunohistochemical expression of the relatively new tissue-specific transcription factor Cdx2 in metastatic adenocarcinomas to the brain. Design. —We reviewed the surgical pathology files of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla, and retrieved 38 consecutive cases of metastatic adenocarcinoma (22 pulmonary, 10 breast, 6 gastrointestinal [2 esophagus/gastroesophageal junction, 4 colorectal]) to the brain with confirmation of the primary site by chart review and histologic evaluation. Sections were immunohistochemically stained with antibodies to TTF-1, Cdx2, and cytokeratins 7 and 20 by standard methods. Results. —Specificities and positive predictive values for Cdx2 and TTF-1 equaled 100% for metastatic gastrointestinal and pulmonary adenocarcinomas, respectively. The negative predictive value of Cdx2 was also very high at 97%. Conclusions. —Cdx2 is a specific and valuable tool for the surgical pathologist when faced with the common problem of metastatic adenocarcinoma of unknown primary. In conjunction with TTF-1, cytokeratin 7, and cytokeratin 20, Cdx2 can accurately differentiate the most common sources of metastatic adenocarcinoma to the brain.

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare inflammatory condition that mostly affects lungs in smokers. On imaging, it usually presents as multiple, upper lobe predominant, solid, and cavitary nodules, but presentation as solitary pulmonary nodule (SPN) is rare. We describe a case of SPN seen on low-dose lung cancer screening CT (LDCT) that was FDG avid on PET/CT. Given concern for malignancy, lobectomy was planned if intraoperative frozen section was consistent with malignancy. Lobectomy was performed based on frozen section; however, on formal pathology review, the nodule was ultimately found to be PLCH. This case illustrates an atypical presentation of PLCH as a solitary nodule. Furthermore, it helps demonstrate how rare etiologies (like PLCH) may be more frequently encountered and should be considered in the differential diagnosis for solitary lung nodules, especially in the era of lung cancer screening.

mTOR activation has been observed in rhabdomyosarcoma (RMS); however, mTOR complex (mTORC) 1 inhibition has had limited success thus far. mTOR activation alters the metabolic pathways, which is linked to survival and metastasis. These pathways have not been thoroughly analyzed in RMSs. We performed immunohistochemistry on 65 samples to analyze the expression of mTOR complexes (pmTOR, pS6, Rictor), and several metabolic enzymes (phosphofructokinase, lactate dehydrogenase-A, β-F1-ATPase, glucose-6-phosphate dehydrogenase, glutaminase). RICTOR amplification, as a potential mechanism of Rictor overexpression, was analyzed by FISH and digital droplet PCR. In total, 64% of the studied primary samples showed mTOR activity with an mTORC2 dominance (82%). Chemotherapy did not cause any relevant change in mTOR activity. Elevated mTOR activity was associated with a worse prognosis in relapsed cases. RICTOR amplification was not confirmed in any of the cases. Our findings suggest the importance of the Warburg effect and the pentose-phosphate pathway beside a glutamine demand in RMS cells. The expression pattern of the studied mTOR markers can explain the inefficacy of mTORC1 inhibitor therapy. Therefore, we suggest performing a detailed investigation of the mTOR profile before administering mTORC1 inhibitor therapy. Furthermore, our findings highlight that targeting the metabolic plasticity could be an alternative therapeutic approach.

Metastases to the brain may be the first presentation of systemic malignancy in 3–10% of new patients and thus pose a diagnostic challenge. While lung is the most common source, other frequent sites of origin include the GI tract and breast. The histologic appearance of metastatic adenocarcinoma often does not lend itself to identification of the primary source. In many cases immunohistochemical studies (IHC) to define these lesions may provide a reliable result, thus limiting the time and expense incurred by various clinical investigations. We have examined the IHC expression of cytokeratins 7 and 20, thyroid transcription factor ‐1 (TTF‐1) and the relatively new tissue specific transcription factor CDX2 in metastatic adenocarcinomas to the brain. 38 consecutive cases of metastatic adenocarcinoma (22 pulmonary, 10 breast, 6 gastrointestinal (2 esophagus/GE junction, 4 colorectal) to the brain were retrieved through a search of the surgical pathology files of the H. Lee Moffitt Cancer Center, Tampa, Florida. Confirmation of the primary site was obtained by chart review and histologic evaluation. Sections were immunohistochemically reacted with antibodies to TTF‐1, CDX2, and Cytokeratins 7 and 20 (CK7 and CK20) by standard methods. Specificities and positive predictive values for CDX2 and TTF‐1 equaled 100% for metastatic gastrointestinal and pulmonary adenocarcinomas, respectively. The negative predictive value of CDX2 was also very high at 97%. Our studies confirm that in conjunction with TTF‐1, CK7 and CK20, CDX2 can accurately differentiate the most common sources of metastatic adenocarcinoma from an unknown primary site to the brain.

COPA syndrome is a newly discovered, rare genetic autoimmune disorder, which can affect the lungs, joints, and kidneys. It is difficult to recognize, and the survival benefit of lung transplantation for these patients is not yet known. We present a case of a 24-year-old woman who received bilateral lung transplant for COPA syndrome. At 15 months posttransplant, her pulmonary function is stable with no episodes of acute cellular- or antibody-mediated rejection and no evidence of disease recurrence.