Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies that arise from neuroendocrine cells throughout the body, most commonly originating from the lungs and gastrointestinal ...tract. Lung NETs can be classified as well differentiated (low-grade typical carcinoids TCs and intermediate-grade atypical carcinoids ACs) and poorly differentiated (high-grade large cell neuroendocrine carcinoma or SCLC). The incidence of these tumors is increasing, but disease awareness remains low among thoracic specialists, who are often involved in the diagnosis and early treatment for these patients. An accurate and timely diagnosis can ensure the implementation of appropriate treatment and have a substantial impact on prognosis. However, lung NET classification and diagnosis, particularly for TCs/ACs, are complicated by several factors, including a variable natural history and nonspecific symptoms. Surgery remains the only curative option for TCs/ACs, but there is a lack of consensus between lung NET management guidelines regarding optimal treatment approaches in the unresectable/metastatic setting on account of the limited availability of high-level clinical evidence. As a result, a multidisciplinary approach to management of lung NETs is required to ensure a consistent and optimal level of care. RADIANT-4 is the first phase III trial involving a large subpopulation of patients with advanced well-differentiated lung NETs to report reductions in the risk for disease progression and death with everolimus over placebo. This led to the recent U.S. approval of everolimus—the first agent approved for advanced lung TCs/ACs. To further improve evidence-based care, additional randomized controlled trials in patients with lung carcinoids are needed.
Although Ki-67 labeling index (Ki-67%) is not a diagnostic or grading criterion in the World Health Organization classification of pulmonary carcinoid tumor, oncologists often request this test. A ...survey was administered at a North American Society for Neuroendocrine Tumors meeting to understand how Ki-67% is used in oncologic practices. A systematic literature review was performed to gather best evidence regarding the use of Ki-67%. Consecutive pulmonary carcinoids were stratified into pulmonary typical carcinoids with Ki-67% <5% (group A, n = 187), typical carcinoids with Ki-67% ≥5% (group B, n = 38) and atypical carcinoids irrespective of Ki-67% (group C, n = 31). Overall survival, progression-free survival, recurrence proportions and time to recurrence were compared, by group, using the log-rank test, chi-square statistics and ANOVA, respectively. Our survey confirmed that Ki-67% is frequently used by specialists caring for these patients. Ki-67% of 1–7% significantly correlated with overall survival in the literature but we found no information about Ki-67% cut-off values that would accurately distinguish pulmonary typical from atypical carcinoids or estimate the prognosis of patients stratified by World Health Organization diagnosis and Ki-67% cut-off. Overall survival was significantly different in our 3 patient groups (p < 0.001), with survival probabilities decreasing from groups A to C. Progression-free survival was significantly longer in group A than B (p < 0.007). Our results support the concept that by combining World Health Organization diagnosis and Ki-67%, pulmonary carcinoids can be stratified into 3 grades: G1 (typical carcinoids with Ki-67% <5), G2 (typical carcinoids with Ki-67% ≥5%) and G3 (atypical carcinoids) with different prognoses.
- Tumor spread through alveolar spaces (STAS) has been correlated with unfavorable prognosis in lung adenocarcinomas treated with sublobar resection, but it is unknown whether STAS can be reliably ...identified in frozen section (FS) to help stratify patients for lobectomy or sublobar resection.
- To evaluate STAS in FS.
- Tumor spread through alveolar spaces was evaluated in hematoxylin-eosin-stained FS, FS control slides, and all additional slides with lung tissue adjacent to tumor (AdLT) from 48 pT1-2 adenocarcinomas operated on using video-assisted thoracotomy (n = 25) or open thoracotomy (n = 23). The samples included lobectomies (n = 27) and sublobar resections (n = 21). The STAS incidences were compared by FS versus FS control versus AdLT, video-assisted thoracotomy versus open thoracotomy, and lobectomy versus sublobar resection. Sensitivity, specificity, and positive and negative predictive values of STAS
findings were calculated. The literature was queried for best evidence regarding incidence and predictive value of STAS in FS.
- Tumor spread through alveolar spaces positivity was identified in 46 of 48 cases (95.8%), including 23 FS (47.9%), 32 FS control (66.7%), and 43 AdLT (89.6%). The STAS incidence was significantly higher in AdLT than in FS or FS control. Only 2 of the 25 cases that were STAS
in FS were true negatives. Frozen section sensitivity to detect STAS positivity was 50%, with a 100% positive predictive value and 8% negative predictive value. Systematic literature review identified no evidence regarding STAS identification in FS.
- The sensitivity and negative predictive value of FS for STAS detection are unacceptably low. There are insufficient data to support intraoperative detection of STAS as a useful predictive feature to help stratify patients for lobectomy or sublobar resections.
The diagnosis of malignant mesothelioma (MM) is rendered with the aid of immunohistochemistry to demonstrate the presence of "mesothelial," "epithelial," or "sarcomatous" differentiation. Antibody ...panels that have been proposed for the distinction between MM and other neoplasms usually include 2 or more epithelial markers used to exclude the diagnosis of a carcinoma, such as monoclonal and polyclonal carcinoembryonic antigen, Ber-EP4, B72.3, CD15, MOC-31, thyroid transcription factor 1, BG8, and others, and 2 or more mesothelial markers used to confirm the diagnosis of MM, such as cytokeratin 5/6, calretinin, HBME-1, thrombomodulin, WT-1, mesothelin, D2-40, and podoplanin. In general, most antibody panels provide excellent sensitivity and specificity for the differential diagnosis between MM epithelial variant and adenocarcinoma, particularly of lung origin. However, the accuracy of these markers is lower for the diagnosis of sarcomatous MM and for the differential diagnosis between MM and squamous cell carcinoma and carcinomas of renal, ovarian, and other origin.
To identify optimal antibody panels for the diagnosis of MM.
Literature review to determine how many and which mesothelial and epithelial markers need to be included in differential diagnosis antibody panels.
Various antibody panels have been recommended for the diagnosis of MM, with no overall consensus about how many and which markers should be used. A recent study with Bayesian statistics has demonstrated that the use of many markers does not provide higher diagnostic accuracy than the use of selected single antibodies or various combinations of only 2 markers. There is a need for the development of evidence-based or consensus-based guidelines for the diagnosis of MM in different differential diagnosis situations.
Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose.
To provide updated practical guidelines for the pathologic diagnosis of MM.
Pathologists involved in the ...International Mesothelioma Interest Group and others with an interest in the field contributed to this update. Reference material includes peer-reviewed publications and textbooks.
There was consensus opinion regarding (1) distinction of benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiation of epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid mesothelioma, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels used is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Immunohistochemical panels should contain both positive and negative markers. It is recommended that immunohistochemical markers have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic membranous markers). These guidelines are meant to be a practical reference for the pathologist.
Patients with post-acute or long COVID-19 syndrome (PA-COVID) develop persistent symptoms and complications that last beyond 4 weeks of the initial infection. There is limited information regarding ...the pulmonary pathology in PA-COVID patients that require bilateral orthotopic lung transplantation (BOLT). Our experience with 40 lung explants from 20 PA-COVID patients that underwent BOLT is described. Clinico-pathologic findings are correlated with best evidence from literature. The lung parenchyma showed bronchiectasis (n=20) and severe interstitial fibrosis with areas resembling the nonspecific interstitial pneumonia (NSIP) pattern of fibrosis (n=20), interstitial fibrosis NOS (n=20) and fibrotic cysts (n=9). None of the explants exhibited a usual interstitial pneumonia (UIP) pattern of fibrosis. Other parenchymal changes included multinucleated giant cells (n=17), hemosiderosis (n=16), peribronchiolar metaplasia (n=19), obliterative bronchiolitis (n=6) and microscopic honeycombing (n=5). Vascular abnormalities included thrombosis of a lobar artery (n=1) and microscopic thrombi in small vessels (n=7). Systematic literature review identified 7 articles reporting the presence in 12 patients of interstitial fibrosis showing NSIP pattern (n=3), organizing pneumonia/diffuse alveolar damage (DAD) (n=4) and NOS (n=3) patterns. All but one of these studies also reported the presence of multinucleated giant cells and none of the studies reported the presence of severe vascular abnormalities.
PA-COVID patients undergoing BOLT show a pattern of fibrosis that resembles mixed cellular-fibrotic NSIP pattern and generally lack severe vascular complications. As the NSIP pattern of fibrosis is often associated with autoimmune diseases, additional studies are needed to understand the mechanism of disease and learn whether this information can be used for therapeutic purposes.
The checkpoint protein programmed cell death ligand-1 protein (PD-L1) binds to its receptor (PD-1) activating the PD-L1/PD-1 pathway, an important therapeutic target. There is limited information ...regarding PD-L1 and PD-1 expression in thymic lesions. Sections from nonneoplastic thymi (n = 20), thymomas World Health Organization types A, AB, B1, B2, and B3 (n = 38) and thymic squamous cell carcinoma (n = 8) were stained for PD-L1 (clone SP142; Spring BioScience), PD-1 (MRQ22; Cell Marque), CD4 (clone SPO32; Cell Marque), and CD8 (JCB117; Ventana). Immunoreactivity for each antibody was classified as focal or diffuse and scored as follows: 0, negative; 1%-5%, 1+; 6%-20%, 2+; and >20%, 3+. The proportions of cases expressing PD-L1, PD-1, CD4, and C8 at score ≥1+ were compared by diagnosis, using χ2 statistics. PD-L1 was expressed in 90% of nonneoplastic thymi, 92% of thymomas, and 50% of carcinomas, with significantly higher scores (P < .01) in B2 and B3 thymomas and carcinomas than in AB and B1 thymomas; PD-L1 was diffuse in most B2 and B3 thymomas and focal in carcinomas. PD-1 was focally expressed, and mostly with scores 1+, in 55% of nonneoplastic thymi, 63% of thymomas, and 37.5% of carcinomas. CD4+ and CD8+ cells were diffusely distributed with scores 3+ in all lesions other than B3 thymomas and carcinomas. The latter showed CD4+ cells mostly at the interface between neoplastic cells and stroma. PD-L1 and PD-1 are not expressed in similar locations and cellular proportions in thymic lesions, raising a question as to whether the PD-L1/PD-1 pathway is an actionable therapeutic target in these lesions.
Aims
To gather the best available evidence regarding Ki‐67% values in large‐cell neuroendocrine carcinoma (LCNEC) and determine whether certain cut‐off values could serve as a prognostic feature in ...LCNEC.
Methods and results
Aperio ScanScope AT Turbo, eSlide Manager and ImageScope software (Leica Biosystems) were used to measure Ki‐67% in 77 resected LCNEC diagnosed by World Health Organisation (WHO) criteria. Cases were stratified into six classes by 10% Ki‐67 increments. Using the Kaplan–Meier method, overall (OS) and disease‐free survivals (DFS) were compared by AJCC stage, by six Ki‐67% classes and with Ki‐67% cut‐points ≥20% and ≥40%. Tumours were from 0.9 to 11.5 cm and pathological stages 1–3. The system measured Ki‐67% positivity using 4072–44 533 tumour nuclei per case (mean 16610 ± 8039). Ki‐67% ranged from 1 to 64% (mean = 26%; median = 26%). Only 16 (21%) tumours had Ki‐67% ≥40%. OS ranged from 1 to 298 months (median follow‐up = 25 months). DFS ranged from 1 to 276 months (median follow‐up = 9 months). OS and DFS differed across AJCC stage (overall log‐rank P = 0.038 and P = 0.037). However, neither OS nor DFS significantly correlated with Ki‐67% when six or two classes were used with either ≥20% Ki‐67 or ≥40% Ki‐67 as cut‐point. A literature review identified 14 reports meeting our inclusion criteria with ≥10 LCNEC. Reported Ki‐67% ranged from 2% to 100%. Problems contributing to variability in Ki‐67% measurements are discussed.
Conclusion
Our findings caution against a blanket use of 20%, 40% or other Ki‐67% cut‐points for LCNEC diagnosis or prognostication.
Sialylated HEG1 has been reported as a highly specific and sensitive mesothelioma marker but a comprehensive evaluation of its expression in carcinomas in different organs, various sarcomas and ...reactive mesothelial proliferations has not been reported. The aim of this study was to evaluate the clinical applicability of HEG1 as a marker in the diagnosis of mesothelioma. HEG1 immunoreactivity was evaluated in whole sections of 122 mesotheliomas, 75 pulmonary carcinomas, 55 other carcinomas, 16 mesenchymal tumors, and 24 reactive mesothelial proliferations and in tissue microarrays containing 70 epithelioid (EM), 36 biphasic (BM), and 2 sarcomatoid mesotheliomas (SM). In whole sections and tissue microarrays, respectively, membranous HEG1 was expressed in 93.0% and 85.5% of EM, 81.3% and 69.4% of BM, 0% and 0% of SM. HEG1 was not expressed in pulmonary adenocarcinomas. HEG1 was expressed as cytoplasmic immunoreactivity in pulmonary squamous cell carcinomas (21.7%). Membranous HEG1 staining was seen in ovarian carcinomas (66.7%), thyroid carcinomas (100%), reactive conditions (16.7%), and mesenchymal tumors (18.8%). The sensitivity of membranous HEG1 expression to distinguish EM/BM from all carcinomas was 88.8%. The specificity for the differential diagnosis between EM/BM and all carcinomas and pulmonary carcinomas was 92.3% and 98.7%, respectively.
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