Diagnostic Alignment to Optimize Inter-rater Reliability Among Lung Transplant Pathologists.

BACKGROUND: Poor agreement among lung transplant pathologists has been reported in the assessment of rejection. In addition to acute rejection (AR) and lymphocytic bronchiolitis (LB), acute lung injury (ALI) and organizing pneumonia (OP) were recently identified as histopathologic risk factors for chronic lung allograft dysfunction (CLAD). Therefore, maximizing inter-rater reliability (IRR) for identifying these histopathologic risk factors is important to guide individual patient care and to support incorporating them in inclusion criteria for clinical trials in lung transplantation. METHODS: Nine pathologists across eight North American lung transplant centers were surveyed for practices in the assessment of lung transplant transbronchial biopsies. We conducted seven diagnostic alignment sessions with pathologists discussing histomorphologic features of CLAD high-risk histopathology. Then, each pathologist blindly scored 75 digitized slides. Fleiss' kappa, accounting for agreement across numerous observers, was used to determine IRR across all raters for presence of any high-risk finding and each individual entity. RESULTS: IRR (95% confidence intervals) and % agreement for any high-risk finding (AR, LB, ALI and/or OP) and each individual finding is as follows: Any Finding, k = 0.578 (0.487, 0.668), 78.9%; AR, k = 0.582 (0.481, 0.651), 79.1%; LB, k = 0.683 (0.585, 0.764), 83.5%; ALI, k = 0.418 (0.312, 0.494), 70.9%; OP, k = 0.621 (0.560, 0.714), 81.0%. CONCLUSIONS: After pre-study diagnostic alignment sessions, a multi-center group of lung transplant pathologists seeking to identify histopathology high-risk for CLAD achieved good IRR.

A framework for exclusion of alternative diagnoses in sarcoidosis.

Sarcoidosis is a multisystem granulomatous syndrome that arises from a persistent immune response to a triggering antigen(s). There is no "gold standard" test or algorithm for the diagnosis of sarcoidosis, making the diagnosis one of exclusion. The presentation of the disease varies substantially between individuals, in both the number of organs involved, and the manifestations seen in individual organs. These qualities dictate that health care providers diagnosing sarcoidosis must consider a wide range of possible alternative diagnoses, from across a range of presentations and medical specialties (infectious, inflammatory, cardiac, neurologic). Current guideline-based diagnosis of sarcoidosis recommends fulfillment of three criteria: 1) compatible clinical presentation and/or imaging 2) demonstration of granulomatous inflammation by biopsy (when possible) and, 3) exclusion of alternative causes, but do not provide guidance on standardized strategies for exclusion of alternative diagnoses. In this review, we provide a summary of the most common differential diagnoses for sarcoidosis involvement of lung, eye, skin, central nervous system, heart, liver, and kidney. We then propose a framework for testing to exclude alternative diagnoses based on pretest probability of sarcoidosis, defined as high (typical findings with sarcoidosis involvement confirmed in another organ), moderate (typical findings in a single organ), or low (atypical/findings suggesting of an alternative diagnosis). This work highlights the need for informed and careful exclusion of alternative diagnoses in sarcoidosis.

Intermittent Ex Vivo Lung Perfusion in a Porcine Model for Prolonged Lung Preservation.

BACKGROUND: Ex vivo lung perfusion expands the lung transplant donor pool and extends preservation time beyond cold static preservation. We hypothesized that repeated regular ex vivo lung perfusion would better maintain lung grafts. METHODS: Ten pig lungs were randomized into 2 groups. The control underwent 16 h of cold ischemic time and 2 h of cellular ex vivo lung perfusion. The intermittent ex vivo lung perfusion group underwent cold ischemic time for 4 h, ex vivo lung perfusion (first) for 2 h, cold ischemic time for 10 h, and 2 h of ex vivo lung perfusion (second). Lungs were assessed, and transplant suitability was determined after 2 h of ex vivo lung perfusion. RESULTS: The second ex vivo lung perfusion was significantly associated with better oxygenation, limited extravascular water, higher adenosine triphosphate, reduced intraalveolar edema, and well-preserved mitochondria compared with the control, despite proinflammatory cytokine elevation. No significant difference was observed in the first and second perfusion regarding oxygenation and adenosine triphosphate, whereas the second was associated with lower dynamic compliance and higher extravascular lung water than the first. Transplant suitability was 100% for the first and 60% for the second ex vivo lung perfusion, and 0% for the control. CONCLUSIONS: The second ex vivo lung perfusion had a slight deterioration in graft function compared to the first. Intermittent ex vivo lung perfusion created a better condition for lung grafts than cold static preservation, despite cytokine elevation. These results suggested that intermittent ex vivo lung perfusion may help prolong lung preservation.

Clinically Occult Diffuse Pleural Mesothelioma in Patients Presenting With Spontaneous Pneumothorax.

OBJECTIVES: To report histologic features of unsuspected diffuse pleural mesothelioma (DPM) in surgical specimens for pneumothorax and demonstrate how ancillary markers support a diagnosis of malignancy in this context. We explored whether pneumothorax may be a clinical manifestation of mesothelioma in situ (MIS). METHODS: A single-institution database search identified patients who underwent surgical resection for spontaneous pneumothorax (n = 229) and/or were diagnosed with DPM (n = 88) from 2000 to 2020. RESULTS: Spontaneous pneumothorax without clinical, radiologic, or intraoperative suspicion of mesothelioma was the initial presentation in 2 (2.3%) of 88 patients diagnosed with DPM. This represented 0.9% (2/229) of all patients undergoing surgical management of pneumothorax but accounted for a larger proportion of older patients (12.5% older than 70 years). Immunohistochemistry for BAP-1 and/or MTAP confirmed the diagnosis of DPM in 2 cases. Mesothelioma in situ was identified retrospectively by immunohistochemistry in 1 case of spontaneous pneumothorax from a 77-year-old man who developed invasive DPM 25 months later. No additional cases of MIS were identified in 19 surgical lung resections for spontaneous pneumothorax. CONCLUSIONS: Histologic examination of bleb resections with ancillary testing for cases with ambiguous features is essential for detection of early DPM. It is uncertain whether spontaneous pneumothorax may represent a clinical manifestation of MIS.

Pathology Education Powered by Virtual and Digital Transformation: Now and the Future.

CONTEXT.­: Myriad forces are changing teaching and learning strategies throughout all stages and types of pathology education. Pathology educators and learners face the challenge of adapting to and adopting new methods and tools. The digital pathology transformation and the associated educational ecosystem are major factors in this setting of change. OBJECTIVE.­: To identify and collect resources, tools, and examples of educational innovations involving digital pathology that are valuable to pathology learners and teachers at each phase of professional development. DATA SOURCES.­: Sources were a literature review and the personal experience of authors and educators. CONCLUSIONS.­: High-quality digital pathology tools and resources have permeated all the major niches within anatomic pathology and are increasingly well applied to clinical pathology for learners at all levels. Coupled with other virtual tools, the training landscape in pathology is highly enriched and much more accessible than in the past. Digital pathology is well suited to the demands of peer-to-peer education, such as in the introduction of new testing, grading, or other standardized practices. We found that digital pathology was well adapted to apply our current understanding of optimal teaching strategies and was effective at the undergraduate, graduate, postgraduate, and peer-to-peer levels. We curated and tabulated many existing resources within some segments of pathology. We identified several best practices for each training or educational stage based on current materials and proposed high-priority areas for potential future development.

Prognostic implications of and clinical risk factors for acute lung injury and organizing pneumonia after lung transplantation: Data from a multicenter prospective cohort study.

We determined prognostic implications of acute lung injury (ALI) and organizing pneumonia (OP), including timing relative to transplantation, in a multicenter lung recipient cohort. We sought to understand clinical risks that contribute to development of ALI/OP. We analyzed prospective, histologic diagnoses of ALI and OP in 4786 lung biopsies from 803 adult lung recipients. Univariable Cox regression was used to evaluate the impact of early (≤90 days) or late (>90 days) posttransplant ALI or OP on risk for chronic lung allograft dysfunction (CLAD) or death/retransplantation. These analyses demonstrated late ALI/OP conferred a two- to threefold increase in the hazards of CLAD or death/retransplantation; there was no association between early ALI/OP and these outcomes. To determine risk factors for late ALI/OP, we used univariable Cox models considering donor/recipient characteristics and posttransplant events as candidate risks. Grade 3 primary graft dysfunction, higher degree of donor/recipient human leukocyte antigen mismatch, bacterial or viral respiratory infection, and an early ALI/OP event were significantly associated with increased late ALI/OP risk. These data from a contemporary, multicenter cohort underscore the prognostic implications of ALI/OP on lung recipient outcomes, clarify the importance of the timing of these events, and identify clinical risks to target for ALI/OP prevention.

Prone ex vivo lung perfusion protects human lungs from reperfusion injury.

BACKGROUND: We previously reported beneficial effects of prone positioning during ex vivo lung perfusion (EVLP) using porcine lungs. In this study, we sought to determine if prone positioning during EVLP was beneficial in human donor lungs rejected for clinical use. METHODS: Human double lung blocs were randomized to prone EVLP (n = 5) or supine EVLP (n = 5). Following 16 h of cold storage at 4°C and 2 h of cellular EVLP in either the prone or supine position. Lung function, compliance, and weight were evaluated and transplant suitability determined after 2 h of EVLP. RESULTS: Human lungs treated with prone EVLP had significantly higher partial pressure of oxygen/fraction of inspired oxygen (P/F) ratio [348 (291-402) vs. 199 (191-257) mm Hg, p = 0.022] and significantly lower lung weight [926(864-1078) vs. 1277(1029-1483) g, p = 0.037] after EVLP. 3/5 cases in the prone group were judged suitable for transplant after EVLP, while 0/5 cases in the supine group were suitable. When function of upper vs. lower lobes was evaluated, prone EVLP lungs showed similar P/F ratios and inflammatory cytokine levels in lower vs. upper lobes. In contrast, supine EVLP lungs showed significantly lower P/F ratios [68(59-150) vs. 467(407-515) mm Hg, p = 0.012] and higher tissue tumor necrosis factor alpha levels [100.5 (46.9-108.3) vs. 39.9 (17.0-61.0) ng/ml, p = 0.036] in lower vs. upper lobes. CONCLUSIONS: Prone lung positioning during EVLP may optimize the outcome of EVLP in human donor lungs, possibly by improving lower lobe function.

Usual Interstitial Pneumonia is the Most Common Finding in Surgical Lung Biopsies from Patients with Persistent Interstitial Lung Disease Following Infection with SARS-CoV-2.

BACKGROUND: There is increasing interest in persistent interstitial lung disease (ILD) following resolution of acute COVID-19. No studies have yet reported findings in surgical lung biopsies (SLB) from this patient population. METHODS: Our Michigan Medicine pathology database was queried for SLB reviewed between January 2020 and April 2021 from patients with persistent ILD following recovery from acute COVID-19. Slides for our retrospective observational study were independently reviewed by two thoracic pathologists, who were blinded to patient clinical data, radiographic findings, and previous pathologic diagnosis. FINDINGS: Eighteen cases met inclusion criteria. Of these, nine had usual interstitial pneumonia (UIP). These included two patients with superimposed acute lung injury (ALI). Five cases showed a spectrum of ALI that ranged from persistent diffuse alveolar damage to organizing pneumonia. Four patients had desquamative interstitial pneumonia (1), acute and organizing bronchopneumonia (1), or no diagnostic abnormality (2). Compared to patients without UIP, those with UIP tended to be older and have pre-existing lung disease prior to COVID-19. In patients with UIP, pre-SLB chest computed tomography changes included groundglass with interstitial thickening or peripheral reticulations with bronchiectasis; no UIP patients had groundglass only. The most common radiographic finding in patients without UIP was groundglass opacities only. INTERPRETATION: UIP was the most common pathologic finding in patients undergoing evaluation for post-COVID-19 ILD. Our preliminary data suggests that CT changes described as interstitial thickening, peripheral reticulations, and/or bronchiectasis may be helpful in identifying patients with underlying fibrotic chronic interstitial pneumonia for which UIP is the chief concern. FUNDING: No intramural or extramural funding sources supported this work.

A 30-Year-Old Immune Deficient Woman With Persistent Cough and Shortness of Breath.

CASE PRESENTATION: A 30-year-old woman was referred with increasing shortness of breath and cough in the setting of GATA2 deficiency. She initially presented 9 years previously with recurrent episodes of pneumonia and sinusitis. Genetic testing revealed a heterozygous GATA2 mutation (c.988C>T). She has since had multiple infections that have included necrotizing fasciitis of the right thumb, recurrent pilonidal infections (which required 23 procedures), esophageal candidiasis, and human papillomavirus-positive high-grade squamous intraepithelial lesion of the cervix. Serial bone marrow biopsy specimens showed persistent hypocellularity (20% to 60%) with intermittent erythroid atypia and variable detection of trisomy 8, which were concerning for evolving myelodysplastic syndrome. One year before the current admission, she was diagnosed with disseminated Mycobacterium avium complex and was treated with rifabutin, ethambutol, and azithromycin. She was taking voriconazole, acyclovir, and trimethoprim-sulfamethoxazole prophylaxis.

Transcription factor FOXF1 identifies compartmentally distinct mesenchymal cells with a role in lung allograft fibrogenesis.

In this study, we demonstrate that forkhead box F1 (FOXF1), a mesenchymal transcriptional factor essential for lung development, was retained in a topographically distinct mesenchymal stromal cell population along the bronchovascular space in an adult lung and identify this distinct subset of collagen-expressing cells as key players in lung allograft remodeling and fibrosis. Using Foxf1-tdTomato BAC (Foxf1-tdTomato) and Foxf1-tdTomato Col1a1-GFP mice, we show that Lin-Foxf1+ cells encompassed the stem cell antigen 1+CD34+ (Sca1+CD34+) subset of collagen 1-expressing mesenchymal cells (MCs) with a capacity to generate CFU and lung epithelial organoids. Histologically, FOXF1-expressing MCs formed a 3D network along the conducting airways; FOXF1 was noted to be conspicuously absent in MCs in the alveolar compartment. Bulk and single-cell RNA-Seq confirmed distinct transcriptional signatures of Foxf1+ and Foxf1- MCs, with Foxf1-expressing cells delineated by their high expression of the transcription factor glioma-associated oncogene 1 (Gli1) and low expression of integrin α8 (Itga), versus other collagen-expressing MCs. FOXF1+Gli1+ MCs showed proximity to Sonic hedgehog-expressing (Shh-expressing) bronchial epithelium, and mesenchymal expression of Foxf1 and Gli1 was found to be dependent on paracrine Shh signaling in epithelial organoids. Using a murine lung transplant model, we show dysregulation of epithelial-mesenchymal SHH/GLI1/FOXF1 crosstalk and expansion of this specific peribronchial MC population in chronically rejecting fibrotic lung allografts.

Significance of Lung Weight in Cellular Ex Vivo Lung Perfusion.

BACKGROUND: Currently, pulmonary edema is evaluated via surgical inspection and palpation in donor lungs, and there is no quantitative standard diagnostic tool for evaluating pulmonary edema in donor procurement and ex vivo lung perfusion (EVLP). The purpose of this study was to investigate the significance of lung weight at the donor hospital and lung weight during EVLP as a complementary parameter of transplant suitability in EVLP. MATERIALS AND METHODS: Twenty-one of rejected human lungs were perfused in cellular EVLP. Transplant suitability was evaluated at 2 h as per standard criteria of Lund-protocol EVLP. RESULTS: Lung weight at donor hospital was significantly correlated with PaO2/FiO2 (P/F) ratio in EVLP (r = -0.44). There was a significant difference in lung weight at donor hospital between suitable cases (n = 13) and nonsuitable cases (n = 8). Light lung group (lung weight at donor hospital < 1280 g; n = 17) was suitable for transplant in 76%, whereas none of heavy lung group (lung weight at donor hospital ≥ 1280 g; n = 4) was suitable (P < 0.05). Lung weight at 2 h and lung weight change during EVLP were significantly associated with P/F ratio at 2 h and transplant suitability (P < 0.05, each). CONCLUSIONS: Our findings demonstrate that lung weight at donor hospital, lung weight change, and lung weight at 2 h of EVLP might be a predictor of P/F ratio and transplant suitability in cellular EVLP.

Humoral immune responses mediate the development of a restrictive phenotype of chronic lung allograft dysfunction.

Understanding the distinct pathogenic mechanisms that culminate in allograft fibrosis and chronic graft failure is key in improving outcomes after solid organ transplantation. Here, we describe an F1 → parent orthotopic lung transplant model of restrictive allograft syndrome (RAS), a particularly fulminant form of chronic lung allograft dysfunction (CLAD), and identify a requisite pathogenic role for humoral immune responses in development of RAS. B6D2F1/J (H2-b/d) donor lungs transplanted into the parent C57BL/6J (H2-b) recipients demonstrated a spectrum of histopathologic changes, ranging from lymphocytic infiltration, fibrinous exudates, and endothelialitis to peribronchial and pleuroparenchymal fibrosis, similar to those noted in the human RAS lungs. Gene expression profiling revealed differential humoral immune cell activation as a key feature of the RAS murine model, with significant B cell and plasma cell infiltration noted in the RAS lung allografts. B6D2F1/J lung allografts transplanted into µMt-/- (mature B cell deficient) or activation-induced cytidine deaminase (AID)/secretory µ-chain (µs) double-KO (AID-/-µs-/-) C57BL/6J mice demonstrated significantly decreased allograft fibrosis, indicating a key role for antibody secretion by B cells in mediating RAS pathology. Our study suggests that skewing of immune responses determines the diverse allograft remodeling patterns and highlights the need to develop targeted therapies for specific CLAD phenotypes.

Hyperinflation With Pulmonary Dysfunction in Donor Lungs With Smoking History During Lung Perfusion.

BACKGROUND: Donor lungs with smoking history are perfused in ex vivo lung perfusion (EVLP) to expand donor lung pool. However, the impact of hyperinflation of perfused lungs in EVLP remains unknown. The aim of this study was to investigate the significance of hyperinflation, using an ex vivo measurement delta VT, during EVLP in smoker's lungs. MATERIALS AND METHODS: Seventeen rejected donor lungs with smoking history of median 10 pack-years were perfused for 2 h in cellular EVLP. Hyperinflation was evaluated by measuring delta VT = inspiratory - expiratory tidal volume (VT) difference at 1 h. All lungs were divided into two groups; negative delta VT (n = 11, no air-trapping pattern) and positive delta VT (n = 6, air-trapping pattern). Transplant suitability was judged at 2 h. By using lung tissue, linear intercept analysis was performed to evaluate the degree of hyperinflation. RESULTS: The positive delta VT group had significantly lower transplant suitability than the negative delta VT group (16 versus 81%, P = 0.035). The positive delta VT group was significantly associated with lower partial pressure of oxygen/fraction of inspired oxygen ratio ratio (278 versus 356 mm Hg, P = 0.049), higher static compliance (119 versus 98 mL/cm H2O, P = 0.050), higher lung weight ratio (1.10 versus 0.96, P = 0.014), and higher linear intercept ratio (1.52 versus 0.93, P = 0.005) than the negative delta VT group. CONCLUSIONS: Positive delta VT appears as an ex vivo marker of ventilator-associated lung hyperinflation of smoker's lungs during EVLP.

Diffuse alveolar damage (DAD) resulting from coronavirus disease 2019 Infection is Morphologically Indistinguishable from Other Causes of DAD.

AIMS: Diffuse alveolar damage (DAD) is a ubiquitous finding in inpatient coronavirus disease 2019 (COVID-19)-related deaths, but recent reports have also described additional atypical findings, including vascular changes. An aim of this study was to assess lung autopsy findings in COVID-19 inpatients, and in untreated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive individuals who died in the community, in order to understand the relative impact of medical intervention on lung histology. Additionally, we aimed to investigate whether COVID-19 represents a unique histological variant of DAD by comparing the pathological findings with those of uninfected control patients. METHODS AND RESULTS: Lung sections from autopsy cases were reviewed by three pulmonary pathologists, including two who were blinded to patient cohort. The cohorts included four COVID-19 inpatients, four cases with postmortem SARS-CoV-2 diagnoses who died in the community, and eight SARS-CoV-2-negative control cases. DAD was present in all but one SARS-CoV-2-positive patient, who was asymptomatic and died in the community. Although SARS-CoV-2-positive patients were noted to have more focal perivascular inflammation/endothelialitis than control patients, there were no significant differences in the presence of hyaline membranes, fibrin thrombi, airspace organisation, and 'acute fibrinous and organising pneumonia'-like intra-alveolar fibrin deposition between the cohorts. Fibrinoid vessel wall necrosis, haemorrhage and capillaritis were not features of COVID-19-related DAD. CONCLUSIONS: DAD is the primary histological manifestation of severe lung disease in COVID-19 patients who die both in hospital and in the community, suggesting no contribution of hyperoxaemic mechanical ventilation to the histological changes. There are no distinctive morphological features with which to confidently differentiate COVID-19-related DAD from DAD due to other causes.

Effectiveness of a Leadership Development Course for Chief Residents: A Longitudinal Evaluation.

BACKGROUND: Nonclinical skills (eg, self-regulation, team leadership, conflict resolution) are essential for success as a chief resident (CR). The literature on programs teaching these skills reports few if any effectiveness outcomes. OBJECTIVE: We reported the outcomes of a leadership course for CRs using participants' self-reported outcomes and assessments from their program directors (PDs). METHODS: A 2-day curriculum focused on emotional intelligence competencies, including self-awareness, self-management, social awareness, and relationship management. We used a logic model to align 2017-2018 curriculum with targeted outcomes. Questionnaires before and after the course assessed short-term and intermediate outcomes for the participants and PD interviews evaluated observed changes in CRs' performance attributable to the course. RESULTS: A total of 74 residents participated in the course, and 65% and 59% responded to the post-course and follow-up questionnaires, respectively. Over 95% of respondents indicated developing leadership knowledge and skills and connecting with new CRs in the post-course questionnaire. During follow-up, CRs reported applying concepts learned during chief residency, using tools to address conflict, engaging in quality and patient safety projects, and continuing to interact with other participants. The relationships between reported outcomes and participants' gender/prior leadership training were not significant (P > .05), with small to medium effect sizes (0.01-0.32). All 14 PDs offered positive appraisal of the CRs, but we could not specifically attribute this growth to the course. CONCLUSIONS: Participation in this CR leadership development course was associated with enhancement and application of leadership competencies in immediate and intermediate time frames.

A 46-Year-Old Woman With a Mediastinal Mass.

CASE PRESENTATION: A 46-year-old otherwise healthy woman visited the ED twice over a period of 4 days for chest discomfort, midback pain, and dyspnea. The pain was localized, constant, nonpleuritic in nature, moderate in severity, and was not relieved by over-the-counter medications.

Cellular Ex Vivo Lung Perfusion Beyond 1 Hour May Improve Marginal Donor Lung Assessment.

BACKGROUND: Ex vivo lung perfusion (EVLP) permits extended evaluation of donor lungs for transplant. However, the optimal EVLP duration of Lund protocol is unclear. Using human lungs rejected for clinical transplant, we sought to compare the results of 1 versus 2 h of EVLP using the Lund protocol. METHODS: Twenty-five pairs of human lungs rejected for clinical transplant were perfused with the Lund EVLP protocol. Blood gas analysis, lung compliance, bronchoscopy assessment, and perfusate cytokine analysis were performed at both 1 and 2 h. Recruitment was performed at both time points. Donor lung transplant suitability was determined at both time points. RESULTS: All cases were divided into four groups based on transplant suitability assessment at 1 h and 2 h of EVLP. In group A (n = 10), lungs were judged suitable for transplant at both 1 and 2 h of EVLP. In group B (n = 6), lungs were suitable at 1 h but nonsuitable at 2 h. In group C (n = 2), lungs were nonsuitable at 1 h but suitable at 2 h. Finally, in group D (n = 7), lungs were nonsuitable for transplant at both time points. In both groups B and C (n = 8), the transplant suitability assessment changed between 1 and 2 h of EVLP. CONCLUSIONS: In human lungs rejected for transplant, transplant suitability differed at 1 versus 2 h of EVLP in 32% of lungs studied. Evaluation of lungs with Lund protocol EVLP beyond 1 h may improve donor organ assessment.

The Role of Histologic Grading and Ki-67 Index in Predicting Outcomes in Pulmonary Carcinoid Tumors.

Pulmonary carcinoid tumors are relatively uncommon and have an indolent clinical course. The role of histologic grading and cell proliferation as measured by a Ki-67 index in predicting long-term recurrence in carcinoid tumors of the lung is not defined. We report the largest single-institution study of carcinoid tumors and correlate histologic grade and Ki-67 index with clinical outcome. We reviewed all surgical lung resection cases from 1995 to 2016 with a diagnosis of primary carcinoid tumor. We collected clinicopathologic parameters, including tumor size, nodal status, histologic pattern, presence of lymphovascular invasion, mitotic count, %Ki-67 positive cells (Ki-67 index) using a digital algorithm, time to tumor recurrence, and staged these tumors based on the 8th edition of TNM Staging. The final cohort consists of 176 carcinoid tumor cases with complete data: 165 (94%) were typical carcinoids and 11 (6%) were atypical carcinoids. The Ki-67 index is significantly increased in atypical versus typical carcinoids and in higher stage disease. Only the Ki-67 index and not the histologic patterns or lymphovascular invasion status was a significant predictor of tumor recurrence on multivariate analysis among all pulmonary carcinoid tumors and within typical carcinoid tumors alone. A Ki-67 index cutoff of 5% offered the optimal combination of sensitivity and specificity in predicting long-term recurrence based on the receiver operating characteristic curve. In addition, stratifying pulmonary carcinoid tumors based on a 3-tier histologic grading system (grade 1: typical carcinoids with Ki-67 index ≤5%, grade 2: typical carcinoids with Ki-67 index >5%, and grade 3: atypical carcinoids regardless of Ki-67 index) significantly correlated with likelihood of tumor recurrence. Finally, we propose an integrated staging system unique to pulmonary carcinoid tumors by keeping the original TNM stage for grade 1 tumors, but upstaging grade 2 tumors to stage II, and grade 3 tumors to stage III.