The 2022 Banff Meeting Lung Report.

The Lung Session of the 2022 16th Banff Foundation for Allograft Pathology Conference-held in Banff, Alberta-focused on non-rejection lung allograft pathology and novel technologies for the detection of allograft injury. A multidisciplinary panel reviewed the state-of-the-art of current histopathologic entities, serologic studies, and molecular practices, as well as novel applications of digital pathology with artificial intelligence, gene expression analysis, and quantitative image analysis of chest computerized tomography. Current states of need as well as prospective integration of the aforementioned tools and technologies for complete assessment of allograft injury and its impact on lung transplant outcomes were discussed. Key conclusions from the discussion were: (1) recognition of limitations in current standard of care assessment of lung allograft dysfunction; (2) agreement on the need for a consensus regarding the standardized approach to the collection and assessment of pathologic data, inclusive of all lesions associated with graft outcome (eg, non-rejection pathology); and (3) optimism regarding promising novel diagnostic modalities, especially minimally invasive, which should be integrated into large, prospective multicenter studies to further evaluate their utility in clinical practice for directing personalized therapies to improve graft outcomes.

The over diagnosis of diffuse mesothelioma: An analysis of 311 cases with recommendations for the avoidance of pitfalls.

BACKGROUND: The diagnosis of mesothelioma may be challenging. We investigated a large database of cases in order to determine the frequency with which a diagnosis of mesothelioma was made incorrectly and the most frequent causes of error. DESIGN: A database including more than 4000 consultation cases of histologically confirmed mesothelioma was examined to identify cases in which mesothelioma was diagnosed by at least one pathologist when the available information pointed towards a different diagnosis. RESULTS: There were 311 cases misdiagnosed as mesothelioma. The most common category was metastatic carcinoma to the pleura or peritoneum (129 cases: 73 lung carcinomas, 15 renal cell carcinomas). The next most common category was primary lung cancer (111 cases: 55 sarcomatoid carcinoma, 56 pseudomesotheliomatous carcinoma). The third most common category was primary malignancies arising from or near the serosal membranes (33 cases). The fourth most common category was fibrous pleurisy (38 cases). The most common errors were failure to consider important radiographic information regarding the gross distribution of tumor, lack of awareness or consideration of another malignancy, overreliance on certain immunohistochemical results, and failure to perform certain diagnostic histochemical, immunohistochemical, or ultrastructural studies. CONCLUSIONS: There are a number of diagnostic pitfalls that can lead to the over diagnosis of mesothelioma. Careful attention to clinical and radiographic information as well as performance of appropriate ancillary tests can help to prevent such misdiagnoses. Detailed examples will be presented to assist in the avoidance of these pitfalls with emphasis on the most commonly observed errors.

Chronological trends in the causation of malignant mesothelioma: Fiber burden analysis of 619 cases over four decades.

Malignant mesothelioma is a relatively rare malignancy with a strong association with prior asbestos exposure. A percentage of cases is not related to asbestos, and fiber analysis of lung tissue is a useful methodology for identifying idiopathic or spontaneous cases. We have performed fiber analyses in more than 600 cases of mesothelioma over the past four decades and were interested in looking for trends in terms of fiber types and concentrations as well as percentages of cases not related to asbestos. Demographic information was also considered including patient age, gender, and tumor location (pleural vs. peritoneal). The histologic pattern of the tumor and the presence or absence of pleural plaques or asbestosis were noted. Fiber analysis was performed in 619 cases, using the sodium hypochlorite technique for digestion of lung tissue samples. Asbestos bodies were counted by light microscopy (LM) and coated and uncoated fibers by scanning electron microscopy (EM). The results were stratified over four decades. Trends that were observed included increasing patient age, increasing percentage of women, increasing percentage of peritoneal cases, and increasing percentage of epithelial histological type. There was a decreasing trend in the percentage of patients with concomitant asbestosis (p < 0.001). The percentage of cases with an elevated lung asbestos content decreased from 90.5% in the 1980s to 54.1% in the 2010s (p < 0.001). This trend also held when the analysis was limited to 490 cases of pleural mesothelioma in men (91.8% in the 1980s vs. 65.1% in the 2010s). There was a decrease in the median asbestos body count by LM from 1390 asbestos bodies per gram of wet lung in the 1980s to 38 AB/gm in the 2010s. Similar trends were observed for each of the asbestos fiber types as detected by EM. We conclude that there has been a progressive decrease in lung fiber content of mesothelioma patients during the past four decades, with an increasing percentage of cases not related to asbestos and an increase in median patient age.

Essential role of PR-domain protein MDS1-EVI1 in MLL-AF9 leukemia.

A subgroup of leukemogenic mixed-lineage leukemia (MLL) fusion proteins (MFPs) including MLL-AF9 activates the Mecom locus and exhibits extremely poor clinical prognosis. Mecom encodes EVI1 and MDS1-EVI1 (ME) proteins via alternative transcription start sites; these differ by the presence of a PRDI-BF1-RIZ1 (PR) domain with histone methyltransferase activity in the ME isoform. Using an ME-deficient mouse, we show that ME is required for MLL-AF9-induced transformation both in vitro and in vivo. And, although Nup98-HOXA9, MEIS1-HOXA9, and E2A-Hlf could transform ME-deficient cells, both MLL-AF9 and MLL-ENL were ineffective, indicating that the ME requirement is specific to MLL fusion leukemia. Further, we show that the PR domain is essential for MFP-induced transformation. These studies clearly indicate an essential role of PR-domain protein ME in MFP leukemia, suggesting that ME may be a novel target for therapeutic intervention for this group of leukemias.

Pulmonary Granular Cell Tumors: A Study of 4 Cases Including a Malignant Phenotype.

Granular cell tumors are lesions of Schwannian phenotype that most frequently arise in the skin, breast, and tongue. Pulmonary granular cell tumors (pGCTs) are exceedingly rare and only a handful of cases worldwide have been reported as malignant. We report here a series of 4 pGCTs, including an extremely rare case of a malignant pGCT which underwent next-generation sequencing to identify a novel pathogenic mutation. We are the first to report any prognostic data and response to treatment. Consistent with granular cell tumors of other primary sites, the majority of pGCTs (75%) were deemed histologically and biological benign without metastasis or recurrence after resection (mean follow-up, 750 d). pGCTs occurred predominantly in women (75%) with a mean age of 57 years (range, 49 to 66 y) and variable smoking history. Notably, 2 women also developed an associated lung carcinoma (adenocarcinoma and small cell carcinoma). We also report here an exceedingly rare case of a 51-year-old nonsmoker woman diagnosed with a malignant pGCT. She presented with a 6.4×6.1×4.4 cm infrahilar left lower lobe mass with extrinsic compression and obstruction of the left mainstem on enhanced computed tomography. Pathology of the resection specimen confirmed a pGCT composed of sheets of tumor cells with pleural, pericardial, and diaphragmatic metastases. Molecular analysis by next-generation sequencing failed to yield any driver mutations common to primary lung adenocarcinomas. Only 2 previous malignant pGCTs have been reported; our case revealed a novel pathologic ATM mutation.

Thrombus on the inflow cannula of the HeartWare HVAD: an update.

BACKGROUND: The HeartWare HVAD (Medtronic, Minneapolis, MN) is a continuous-flow left ventricular assist device (LVAD) approved by the FDA in 2012 as a bridge to transplant in patients with end-stage left ventricular heart failure. The current inflow cannula has a smooth outer surface near the inflow edge and a sintered collar of titanium microspheres near the pump. A previous case series of HVAD patients bridged to transplant revealed thrombus on the outer surface of the inflow cannula in 8 of 8 patients, predominantly at the smooth-sintered interface, that was associated with a clinical stroke rate of 12.5%. DESIGN: Cases of HVAD devices removed at the time of heart transplant were identified in the surgical pathology database. The gross and microscopic findings were reviewed along with clinical data. RESULTS: A total of 22 patients with 24 HVAD implants diagnosed with dilated cardiomyopathy (13 patients), ischemic heart disease (4 patients), lymphocytic myocarditis (2 patients), hypertrophic cardiomyopathy (2 patients), and congenital valvular disease (1 patient) were included. Two patients received two HVADs to provide biventricular support. All patients received post-implantation anti-coagulation with an INR goal of 2 to 3. Gross pathologic examination revealed thrombi on the outer aspect of the HVAD inflow cannula in 23 of 24 devices (96%). The inflow cannula of the one device that did not develop thrombus was positioned such that the smooth-sintered interface was buried in the ventricular myocardium and not in contact with blood in the ventricular chamber. Complications during the period of device support included 9 thromboembolic events (41%) including 6 ischemic strokes (27%), 2 intracoronary thromboembolic events and 1 splenic infarct. Patients suffered strokes 4 to 174 days (mean 82) after HVAD placement and had thrombus on the inflow cannula ranging in size from 0.1-2.5 cm (axial), 0.4-4.5 cm (circumferential) and 0.1-0.5 cm (thickness). Histologic evaluation revealed bland, partially organized thrombi without evidence of infection. Other complications included driveline infections (9%), non-driveline related bacteremia (9%) and hemorrhage (5%). CONCLUSIONS: We report here an extension of our original study to a total of 22 patients with 24 HVAD implants who were all successfully bridged to transplant. We validate the very high prevalence of thrombus around the HVAD inflow cannula, associated with a clinical thromboembolic event in over a third of the patients, the majority of which were strokes. The nidus for thrombus formation appears to be the smooth-sintered interface of the HVAD inflow cannula.

Natural history of cranial fibrous dysplasia revealed during long-term follow-up: Case report and literature review.

BACKGROUND: Fibrous dysplasia (FD) is a rare developmental disease characterized by the replacement of bone marrow with proliferating fibro-osseous tissue. There exist three forms of FD-monostotic, polyostotic, and that associated with McCune-Albright syndrome. The disease can present in different locations and with a variety of symptoms. One of the more common locations of FD occurrence is the craniofacial region. Treatment of asymptomatic FD often involves conservative management with serial imaging. Medical management with bisphosphonates is an option, though long-term efficacy data are lacking. Surgical resection is usually reserved for very large or symptomatic lesions. CASE DESCRIPTION: We discuss the most unusual case of a 52-year-old male found to have a left pterional mass while being worked up for sinus headaches. The patient elected to follow this lesion conservatively, and imaging several years later showed obvious growth which accelerated in the last 4 years during an 18-year observational period. He ultimately underwent successful resection of an extradural and intradural FD. CONCLUSIONS: The significant growth potential of these lesions was revealed in this patient, in whom conservative management had been adopted. Despite optimal surgical resection and outcome in this case, the importance of surveillance imaging and perhaps earlier intervention cannot be underestimated when managing cranial FD.