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Impact of routine sputum cytology in a population at high risk for bronchial carcinoma
Abstract
SETTING:
Sub-Saharan Africa carries a high burden of lung cancer, with limited access to specialised health care.
OBJECTIVE:
To investigate the diagnostic value of sputum cytology and its potential in reducing the need for invasive diagnostic procedures in a high-risk population.
DESIGN:
We collected spontaneously expectorated sputum from 108 patients referred for a diagnostic procedure for suspected lung cancer between June 2010 and June 2012, and examined the diagnostic yield of sputum cytology for malignant cells as well as factors predicting a positive result.
RESULTS:
Bronchial carcinoma was diagnosed in 90 patients (83.3%), of whom 35 (38.9%) had sputum cytology positive for malignant cells with 100% diagnostic accuracy. Positive sputum cytology was significantly associated with endobronchial tumour and obstruction seen during bronchoscopy (OR 4.69 and OR 8.89, respectively), and with a histology of squamous cell carcinoma (OR 1.9). All but one patient with positive sputum were inoperable (97.1%), and we estimated that up to a third of all invasive procedures could be avoided if sputum cytology was used for triage.
CONCLUSION:
Sputum cytology had a high yield and accuracy in this high-risk group. Its routine use in selected patients is likely to result in reduced costs and less patient risk and discomfort.
... Traditional cytologic methods on sputum or bronchial wash specimens have been shown to be relatively insensitive, with only 40% to 60% of patients with cancer having positive results and the majority of those being from endobronchial squamous carcinomas. [5][6][7] One bright spot related to the cytology examination is the relatively high positive predictive value of this procedure, which is reported to generally be >98%, meaning that a positive test is a reliable indicator of disease. 7 The Centers for Medicare and Medicaid Services recently approved reimbursement coverage for low-dose computed tomography (LDCT) for lung cancer screening in patients considered to be at highest risk, 8 and the US Preventive Services Task Force and several other professional and advocacy organizations have made recommendations for screening in high-risk populations. ...
... [5][6][7] One bright spot related to the cytology examination is the relatively high positive predictive value of this procedure, which is reported to generally be >98%, meaning that a positive test is a reliable indicator of disease. 7 The Centers for Medicare and Medicaid Services recently approved reimbursement coverage for low-dose computed tomography (LDCT) for lung cancer screening in patients considered to be at highest risk, 8 and the US Preventive Services Task Force and several other professional and advocacy organizations have made recommendations for screening in high-risk populations. 9,10 Results of the National Lung Screening Trial demonstrated that the use of LDCT can decrease the mortality from lung cancer by 20% compared with conventional chest x-ray. ...
... In the past, traditional cytologic examination of sputum has failed to provide the sensitivity necessary for lung cancer screening. [5][6][7] However, conventional cytologic analysis of sputum has failed to be effective primarily because of the difficulty in identifying the relatively rare cancerous or dysplastic cells that are well known to be present in these specimens if painstaking analysis is performed. 16 Cancer cells that are identifiable via standard microscopic evaluation may be irretrievably rare and/or degenerated, and confounded in a background of far more numerous benign epithelial and inflammatory cells, leading to false-negative screening errors. ...
The LuCED Lung Test comprises an automated 3-dimensional morphologic analysis of epithelial cells in sputum. For each cell, 594 morphology-based features are measured to drive algorithmic classifiers that quantitatively assess whether neoplastic cells are present. The current interim clinical study involves sputum samples from patients with known benign and malignant outcomes to assess the feasibility of LuCED as an adjunctive test after suspicious low-dose computed tomography (LDCT) results or as an independent screening test for lung cancer.
Sputum samples were fixed, enriched for epithelial cells, and analyzed with a 3-dimensional cell scanner called Cell-CT. Candidate abnormal cells were identified by the classifiers for manual review. The sensitivity, specificity, and negative and positive predictive values were calculated for the detection of neoplastic cases.
A total of 91 sputum samples from patients with confirmed lung cancer (49 patients) and patients with no known malignancy (42 patients) were evaluated. After cytology review, sensitivity in the positive group was 91.8%, and specificity was 95.2%. Specificity was not 100% because there were 2 cases in which abnormal cells were identified by the Cell-CT that were confirmed as such at the time of manual cytology review. However, at the time of last follow-up, malignancy had not been detected in these 2 cases. Modeling in a population with a 1% prevalence of lung cancer, the positive and negative predictive values would be 95.4% and 99.9%, respectively.
LuCED testing is highly sensitive and specific for the detection of lung cancer and has potential value as an adjunctive test after suspicious LDCT findings or as a primary screening test in which LuCED-positive cases would be triaged to diagnostic CT. Further prospective studies currently are underway to evaluate its full usefulness. Cancer (Cancer Cytopathol) 2015. © 2015 American Cancer Society.
© 2015 American Cancer Society.
... A mirror fragment was fixed in formalin, embedded in paraffin, and stained with hematoxylin and eosin for histological evaluation, in order to guarantee the tumor representation. Two investigators (MPR and VLC) reviewed and verified the histological diagnosis in non-small-cell LC to be SqCC, AD, and LCC, classified according to the recently published classification for LC (31), and selected a sample of the paraffinembedded tumor for immunohistochemical scoring and analyses of the cell-specific localization by immunofluorescence and confocal microscopy. ...
... According to the literature, sputum cytology sensitivity ranges from 42% to 97% and specificity ranges from 68 to 100% (40). Our findings contrast with a recent study published by Van Rensburg et al. (31) in which the sputum cytology in a high-risk population revealed a sensitivity of 38.9% to detect malignant cells and 100% accuracy. Comparing our findings to the literature, we presume that the sensitivities between 60% and 66% that we found can be within the same limits of variation as cytology sputum. ...
Hyaluronan (HA) shows promise for detecting cancerous change in pleural effusion and urine. However, there is uncertainty about the localization of HA in tumor tissue and its relationship with different histological types and other components of the extracellular matrix, such as angiogenesis. We evaluated the association between HA and degree of malignancy through expression in lung tumor tissue and sputum. Tumoral tissue had significantly increased HA compared to normal tissue. Strong HA staining intensity associated with cancer cells was significant in squamous cell carcinoma compared to adenocarcinoma and large cell carcinoma. A significant direct association was found between tumors with a high percentage of HA and MVD (microvessel density) in tumoral stroma. Similarly significant was the direct association between N1 tumors and high levels of HA in cancer cells. Cox multivariate analysis showed significant association between better survival and low HA. HA increased in sputum from lung cancer patients compared to cancer-free and healthy volunteers and a significant correlation was found between HA in sputum and HA in cancer tissue. Localization of HA in tumor tissue was related to malignancy and reflected in sputum, making this an emerging factor for an important diagnostic procedure in patients suspected to have lung cancer. Further study in additional patients in a randomized prospective trial is required to finalize these results and to validate our quantitative assessment of HA, as well as to couple it to gold standard sputum cytology.
2We found that adenocarcinoma is now the most common histological subtype of primary lung cancer diagnosed in the Western Cape and that almost 90% of all patients with non-small cell lung cancer have advanced local or metastatic disease at the time of diagnosis. ‘Lung cancer’ denotes cancer arising in the airways and pulmonary parenchyma. Its histopathological designation is based on the World Health Organization classification system, with 4 cell types responsible for most deaths: adenocarcinoma (including bronchoalveolar carcinoma), squamous cell carcinoma, large cell (undifferentiated) carcinoma and small cell carcinoma. 3 Carcinoid tumours and other rare cell types complete the list of cell types. An interesting phenomenon in the developed world over the last two decades has been the relative increase in the diagnosis of adenocarcinoma which has replaced squamous cell carcinoma as the most frequent histological subtype. 4 Many explanations for this well-documented phenomenon have been suggested. There are few current South African data regarding the relative incidence of the various cell types. The latest National Cancer Registry (NCR) report is from 2001, and contains no data on the relative incidence of the lung cancer cell types. 5 Moreover, published and unpublished data from the 1980s suggested that more than 50 - 60% of all lung cancers were squamous cell carcinomas. 6
The incidence of adenocarcinoma is increasing, particularly among females. We sought to assess the role of tobacco consumption in clinical presentation according to sex.
In this retrospective study, 848 patients diagnosed between 1997 and 2006 at Grenoble University Hospital (Grenoble, France) were stratified into four groups according to smoking habits.
Differences between sexes and two contrasting female profiles emerged. Female current smokers were younger than female never-smokers (median 51 versus 69 yrs; p<0.001), more often had surgery (62.7% versus 39%; p=0.01) and had a median (95% CI) estimated survival of 26.2 (18.1–49.2) versus 15.1 (12.8–22.2) months (p=0.002). Both groups had similar survival when taking treatment into account. Among males, smoking did not influence presentation. Male current smokers were older than female current smokers (median 59 yrs; p<0.001) and fewer had surgery (48.8%; p=0.015), although the percentage of stage IIIb–IV disease was similar (53% and 46%; nonsignificant) and they had a poorer estimated survival of 14.3 (13.0–18.5) months (p=0.0024). Males smoked more than females (median 41 versus 30 pack-yrs; p<0.001). Quitting smoking delayed age at diagnosis by 11 yrs for females (p=0.0035) and 8 yrs for males (p<0.001).
Our results support the hypothesis that carcinogenesis differs between males and females, and between female smokers and never-smokers.
Tuberculous pleuritis remains the commonest cause of exudative effusions in areas with a high prevalence of tuberculosis and histological and/or microbiological confirmation on pleural tissue is the gold standard for its diagnosis. Uncertainty remains regarding the choice of closed pleural biopsy needles.
This prospective study compared ultrasound-assisted Abrams and Tru-Cut needle biopsies with regard to their diagnostic yield for pleural tuberculosis.
89 patients (54 men) of mean ± SD age 38.7 ± 16.7 years with pleural effusions and a clinical suspicion of tuberculosis were enrolled in the study. Transthoracic ultrasound was performed on all patients, who were then randomly assigned to undergo ≥ 4 Abrams needle biopsies followed by ≥ 4 Tru-Cut needle biopsies or vice versa. Medical thoracoscopy was performed on cases with non-diagnostic closed biopsies. Histological and/or microbiological proof of tuberculosis on any pleural specimen was considered the gold standard for pleural tuberculosis.
Pleural tuberculosis was diagnosed in 66 patients, alternative diagnoses were established in 20 patients and 3 remained undiagnosed. Pleural biopsy specimens obtained with Abrams needles contained pleural tissue in 81 patients (91.0%) and were diagnostic for tuberculosis in 54 patients (sensitivity 81.8%), whereas Tru-Cut needle biopsy specimens only contained pleural tissue in 70 patients (78.7%, p=0.015) and were diagnostic in 43 patients (sensitivity 65.2%, p=0.022).
Ultrasound-assisted pleural biopsies performed with an Abrams needle are more likely to contain pleura and have a significantly higher diagnostic sensitivity for pleural tuberculosis.
Rapid on-site evaluation has been proposed as a method to improve the yield of transbronchial needle aspiration.
This study investigated whether on-site analysis facilitates routine diagnostic bronchoscopy in terms of sampling, yield and cost.
Patients with lesions accessible for transbronchial needle aspiration on computed tomography were investigated. A cytopathologist screened the needle aspirates on site for the presence of diagnostic material. The bronchoscopic sampling process was adjusted according to the results. In 90 consecutive patients with neoplastic disease (n=70; 78%), non-neoplastic disease (n=16; 18%) or undiagnosed lesions (n=4; 4%) we aspirated 162 lung tumours or lymph node sites (mediastinal: 7%; tracheobronchial: 68%; other: 25%). In 90 consecutive patients with neoplastic disease (n=70; 78%), non-neoplastic disease (n=16; 18%) or undiagnosed lesions (n=4; 4%) we aspirated 162 lung lesions (paratracheal tumours or lymph nodes: 7%; tracheobronchial lymph nodes: 68%; other: 25%).
The diagnostic yield of needle aspiration was 77 and 25% in patients with neoplastic and non-neoplastic lesions, respectively. Sampling could be terminated in 64% of patients after needle aspiration had been performed as the only diagnostic modality, and on-site analysis identified diagnostic material from the first site aspirated in 50% of patients. Only in 2 patients (2%) diagnostic aspirates were not recognized on site. On-site analysis was cost effective due to savings for disposable diagnostic tools, which exceeded the extra expense for the on-site cytology service provided.
Rapid on-site analysis of transbronchial aspirates is a highly useful, accurate and cost-effective addition to routine diagnostic bronchoscopy.
There is a paucity of prospective data on flexible bronchoscopy with rapid on-site evaluation (ROSE) in the setting of superior vena cava (SVC) syndrome. The aims of this prospective study were to assess the diagnostic yield and safety of these investigations and specifically to evaluate the role of ROSE in limiting the need for tissue biopsies. Over a 5-year period 48 patients (57.4 ± 9.7 years) with SVC syndrome secondary to intrathoracic tumors underwent flexible bronchoscopy with TBNA and ROSE. Endobronchial Forceps biopsy was reserved for visible endobronchial tumors with no on-site confirmation of diagnostic material. ROSE confirmed diagnostic material in 41 cases (85.4%), and in only one of the remaining cases did the addition of a forceps biopsy increase the diagnostic yield (overall diagnostic yield of 87.5%). No serious complications were noted. The final diagnoses made included nonsmall lung cancer (n = 27), small cell lung cancer (n = 16), and metastatic carcinoma (n = 3). Two undiagnosed cases died of suspected advanced neoplasms (unknown primary tumors). We conclude that TBNA has a high diagnostic yield and is safe in the setting of SVC syndrome. With the addition of ROSE, tissue biopsy is required in the minority of cases. Diagn. Cytopathol. 2011. © 2011 Wiley Periodicals, Inc.
Transbronchial needle aspiration (TBNA) via flexible bronchoscopy is a well-established sampling modality for lung masses. The procedure is useful in the diagnosis of neoplastic and non-neoplastic lesions as well as for staging of bronchogenic carcinoma. Rapid on-site evaluation (ROSE) adds value as it has the advantage of triaging material during the procedure so avoiding a battery of investigations. Frequently used rapid stains are the modified Wright-Giemsa water-based stain (WG-ROSE) and the alcohol-based modified Papanicolaou stain (Pap-ROSE). Final review of laboratory-based Giemsa and Pap stains supplemented by ancillary investigations is essential for quality assurance. To investigate whether and how ROSE influenced the quantity and quality of the material submitted to the laboratory we randomized 126 patients to WG-ROSE, requiring only one pathologist on-site, or combined WG- and Pap-ROSE, requiring an additional person on-site to assist with staining. In those patients with positive TBNA we graded the laboratory-based slides of the first pass containing diagnostic material into insufficient, suspicious, adequate and excellent. The first diagnostic pass was found after 3.06 ± 1.94 (SD) passes and 3.13 ± 2.16 passes with WG-ROSE and combined ROSE (P = 0.87), respectively. Following WG-ROSE and combined ROSE 69% and 71.1% (P = 0.509) of slides were diagnostic (adequate or excellent) on laboratory-based Giemsa stains, and 93.3% and 100% (P = 0.134) were scored adequate or excellent on laboratory-based Pap stains. We concluded that the less costly and labour intensive WG-ROSE procedure is adequate for TBNA. This has cost implications especially in resource poor settings.
The diagnostic accuracy of sputum cytology for the diagnosis of bronchial carcinoma using paraffin-embedded, serially sectioned and hematoxylin and eosin-stained specimens was tested in 4,297 sputum samples from 1,889 patients, 219 of whom had bronchial carcinoma. The diagnostic sensitivity depended mainly on the number of investigated samples and was 85.4% with three sufficient sputa. The sensitivity was not influenced by the histologic types, location or TNM stage of the tumor. The specificity of the method was 99.5%. In three cases localization of sputum cytologically diagnosed bronchial carcinomas was not possible immediately (occult carcinomas, pTx); in two of these cases the bronchial carcinomas were located during follow-up. The third patient died without verification of the cytologic diagnosis. According to our results, sputum cytology on serial sections is a valuable instrument for mass screening of high-risk groups for the early detection of bronchial carcinoma. Lower sensitivities of sputum cytology in mass screening programs for the early diagnosis of lung cancer are discussed critically.
Cigarette smoking is the major contributor to chronic bronchial irritation, and tobacco smoke is the most common bronchial carcinogen. A newly developed quantitative sputum cytology test was applied to three-day-pooled, spontaneously produced sputa collected from 349 cigarette smokers and 93 patients who had never smoked; the samples were processed by the Saccomanno technique. In addition to identifying malignant and precancerous cells in sputum, this test identifies eight morphologic parameters of bronchial irritation. Cross-sectional analysis of the cytologic data indicated that, within a 99% confidence interval, cigarette smokers had statistically significantly higher levels of all eight components, producing a unique profile. Discriminant analysis revealed that pigmentation of macrophages, alveolar macrophages and mucous spirals (in that order) were the leading components differentiating smokers from nonsmokers. This new quantitative sputum cytology test correlates with the model of lung carcinogenesis. The detection of proliferative cellular alterations, such as benign and early atypical metaplasia, represent the detection of chronic persistent irritation, which is considered to be a reversible change. The ability to monitor individual responses to toxic inhalants (before the development of irreversible disease) by utilizing a noninvasive test represents a unique opportunity to impact the historic course of lung carcinogenesis.
To assess the potential health and cost effects of initial testing with sputum cytology to diagnose lung cancer.
Cost-effectiveness analysis.
Surveillance Epidemiology and End Results (SEER) program; cost data from Northern California Kaiser Permanente Hospitals and Universities of Stanford and Iowa; National Center for Health Statistics; and a MEDLINE search.
The use of sputum cytologies preceding other tests (ie, fine-needle aspiration, bronchoscopy, thoracoscopy) in patients with suspected lung cancer.
Mortality associated with testing and initial surgical treatment (eg, performance of thoracoscopy to remove a local-stage, centrally located cancer), cost of testing and initial treatment, life expectancy, lifetime cost of medical care, and cost-effectiveness.
In central lesions, sputum cytology as the first test was the dominant strategy because it both lowers medical-care costs ($2,516 per patient) and lowers the mortality risk (19 deaths in 100,000 patients) of the evaluation without adversely affecting long-term survival. In peripheral lesions, sputum cytology costs less then $25,000 per year of life saved if the pretest probability of cancer exceeds 50%. The estimated annual savings of adopting sputum cytology as the first test for diagnosing lung cancer in the United States is at least $30 million.
Experience in regional centers indicates that sputum cytologic testing is infrequently ordered before implementing invasive diagnostic techniques, even in patients with central lung masses. The study findings suggest that sputum cytology as the first test in suspected lung cancer is likely to be cost saving without adversely affecting patient outcomes.
To determine the test performance characteristics of various modalities for the diagnosis of suspected lung cancer.
A systematic search of MEDLINE, HealthStar, and Cochrane Library databases to July 2001 and print bibliographies was performed to identify studies comparing the results of sputum cytology, bronchoscopy, transthoracic needle aspirate (TTNA), or biopsy with histologic reference standard diagnoses among at least 50 patients with suspected lung cancer.
For sputum cytology, the pooled specificity was 0.99 and the pooled sensitivity was 0.66, but sensitivity was higher for central lesions than for peripheral lesions (0.71 vs 0.49, respectively). Studies on bronchoscopic procedures provided data only on diagnostic yield (sensitivity). The diagnosis of endobronchial disease by bronchoscopy in 30 studies showed the highest sensitivity for endobronchial biopsy (0.74), followed by cytobrushing (0.59) and washing (0.48). The sensitivity for all modalities combined was 0.88. Thirty studies reported on peripheral lesions. Cytobrushing demonstrated the highest sensitivity (0.52), followed by transbronchial biopsy (0.46) and BAL/washing (0.43). The overall sensitivity for all modalities was 0.69. Peripheral lesions < 2 cm or > 2 cm in diameter showed sensitivities of 0.33 and 0.62, respectively. Updating a previous meta-analysis with 19 studies revealed a pooled sensitivity of 0.90 for TTNA. A trend toward lower sensitivity was noted for lesions that were < 2 cm in diameter. The accuracy in differentiating between small cell and non-small cell cytology for the various diagnostic modalities was 0.98, with individual studies ranging from 0.94 to 1.0. The average false-positive and false-negative rates were 0.09 and 0.02, respectively.
The sensitivity of bronchoscopy is high for endobronchial disease and poor for peripheral lesions that are < 2 cm in diameter. The sensitivity of TTNA is excellent for malignant disease. The distinction between small cell lung cancer and non-small cell lung cancer by cytology appears to be accurate.
Tobacco smoking leads to lung cancer. Approximately 10% of patients with lung cancer are life long never-smokers. There are only limited data available on the clinical characteristics and outcomes of lung cancer in never-smokers from the Western hemisphere.
Demographic and survival information was collected on 254 never-smokers with a confirmed pathologic diagnosis of non-small cell lung cancer (NSCLC) by reviewing their medical records and the Social Security database.
The study population consisted of 182 (71.6%) women and 72 (28.3%) men. The median age was 70 years (range: 31-91 years). Adenocarcinoma was the most common histology accounting for 60.8% of all patients, followed by NSCLC not otherwise specified (14.4%), bronchoalveolar carcinoma (13.6%), squamous cell carcinoma (8.8%), and large-cell type (2.4%). Majority of patients presented with stage III or IV disease (62.5%). We compared survival between never-smokers and smokers with NSCLC matched for gender, histology, tumor stage, and years of diagnosis. No significant difference in 5-year survival was seen between never-smokers (27.2%) and smokers with NSCLC (31.3%; p = 0.73).
Two thirds of patients with lung cancer who report no history of tobacco smoking are women. In the matched case-control analysis, we report no significant survival difference between lung cancer in never-smokers and those with history of tobacco smoking and lung cancer.