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Table 2 Clinical and radiological variables included in the models described according to Fleischner Guidelines 2017

From: Solitary pulmonary nodule malignancy predictive models applicable to routine clinical practice: a systematic review

Models (year) Clinical characteristics Radiological characteristics Variables not included in Fleischner guidelines Independent predictors of malignancy of SPN in the prediction models
AGE (mean age) Sex/race Smoking history (pack/years) Family history of lung cancer/history of cancer (%) Exposure to asbestos, uranium, radon or second-hand smoke Emphysema/fibrosis/apical scarring/perifissural nodules/multiplicity Nodule size (diameter mm) Growth ratea Morphology/consistency Location
M. Jacob et al. (2020) [26] 64.7 ± 12.3 years (≥ 70 years)
Benign nodules: 35.4%
Malignant nodules: 64.6%
Male or Female/NR NR NR/current extra-pulmonary cancer history:
13.9%
NR NR/Multiple nodules:
Benign nodules: 59.1%
Malignant nodules: 40.9%
≤ 30 mm NR Margins (Smooth, Lobulated, Spiculated)
Calcification
Cavitation Sphericity/Solid and subsolid nodules
Central localization Pleural contact, Air bronchogram, Pulmonary cancer history, Previous TB, Accidental finding, smoking Status. Age Category, Gender, smoking Status, current Extra pulmonary cancer history, Air bronchogram, nodule size.
Chen W et al. (2020) [22] 51.2 ± 10.9 years
Benign nodules: 52.9 ± 10.6 years
Malignant nodules: 50.6 ± 11.0 years
Male or Female/NR Exposure to smoking > 6 months, including second-hand smoke
Benign nodules: 16.1%
Malignant nodules: 5.6%
NR (See “smoking history”) NR/
Incisure surrounding nodules:
Benign nodules: 16.1%
Malignant nodules: 2.5%
Multiple nodules:
Benign nodules: 76.8%
Malignant nodules: 87.5%
≤ 10 mm NR Spiculation, Cavitation sign, Calcification/Solid and subsolid nodules Left
Right
Upper
Middle
Lower
Vascular penetration sign, Pleural adhesions, Long axis, Short axis, Ratio of short-axis to long-axis of the nodule, Nodule density (HU), Lung nodule density (in HU), vascular penetration sign, nodule type, Incisure surrounding nodules
Wu Z et al. (2020) [23] Benign nodules: 51.9 ± 11.8 years
Malignant nodules: 59.6 ± 9.5 years
Male or Female/NR (yes/no)
Benign nodules: 33% (yes)
Malignant nodules: 51%(yes)
NR NR NR < 30 mm NR Smooth margin
Calcification
Nodule density (Patch, Glass, Dense, Cavity, Soft tissue)
Clear border
/NR
Upper lobe
Other lobes
During of smoking Drinking, Superficial lymphadenopathy, Pleural effusion, Profession, others (RCDW, WBC, PLT, Percentage of lymphocyte, monocyte, and basophil, Albumin, globulin, Fibrinogen) Age, gender, smoking history, drinking history, smooth margin, calcification, clear border
Chen et al. (2019) [17] Benign nodules: 50.35 ± 10.65 years
Malignant nodules: 54.92 ± 9.59 years (range 25-75 years)
Male or Female/NR (yes/no)
Benign nodules: 34.05% (yes)
Malignant nodules: 33.18% (yes)
Benign nodules: 13.98%
Malignant nodules: 16.82%/History of extrathoracic malignant neoplasm (>5 years ago): 4.32%
NR Emphysema/NR 8–20 mm NR Marginal Spiculation/Solid nodules ·Upper lobe Pleural Indentation, BMI, Chronic interstitial or obstructive lung disease, significant enhancement, biomarkers (CEA, CA125, CA199, CA724, NSE, SCC, Ferritin) Age, marginal spiculation, significant enhancement, and pleural indentation
Wang et al. (2018) [28] Benign nodules: 56.19 ± 10.82 years Malignant nodules: 64.22 ± 9.36 years Male or
Female/NR
(yes/no)
Benign nodules: 11% (yes)
Malignant nodules: 36% (yes)
NR/ History of cancer: benign nodules: 2%, malignant nodules: 11%. NR NR 6–30 mm NR Border
Lobulation Vascular convergence Pleural retraction Cavity
Spiculation Calcification Vacuole Calcification, Spiculation, /
Solid and subsolid nodules
RUL
RML
RLL LUL
LLL
Time since quitting, Family cancer history, CT value, SUVmax Age, lobulation, vascular convergence, pleural retraction, SUVmax
Yang et al. (2017) [29] 55.41 ± 11.94 years (Range, 17–87 years)
Benign nodules: 49.01 ± 11.88 years
Malignant nodules: 58.22 ± 10.83 years
Male or Female/NR Benign nodules: 41.03 ± 36.58 pack/years Malignant nodules: 36.09 ± 63.51 pack/years Indeterminate nodules: 32.39 ± 20.50 pack/years NR/Previous medical history of malignancy lung disease: 5% NR NR 4–30 mm NR Thin cavitation Thickened cavitation Lobulation
Lobulation + spiculation
Others:
Spiculated protuberances
Irregular edge
Smooth edge
Density
Necrosis/ Solid and subsolid nodules
Upper lobe
Middle lobe
Lower lobe
Previous medical history, extrathoracic disease/ lung Disease excluding malignancy Gender, age, smoking history, previous extrathoracic disease, previous chronic lung disease except cancer, malignancy history, diameter, lobulation, spiculation, lobulation and spiculation, irregular edges, calcification
She et al. (2017) [24] 58.87 ± 10.74 years Male or Female/NR NR NR/History of cancer: 5.2% NR Peripheral emphysema/NR 5–30 mm NR Calcification, Spiculation, Cavitation/Solid nodules ·Left lung
·Upper lobe
Family history of cancer, biomarkers (CEA, SCCA) Pleural indentation Diameter, cancer history, age, spiculation, pleural indentation, calcification, CEA
Van Gómez López et al. (2015) [16] Benign nodules: 58.0±9.1 years Malignant nodules: 64.2±11.1 years Male or Female/NR (yes/no)
Benign nodules: 27.3% (yes) Malignant nodules: 63.6% (yes)
NR NR NR < 30 mm NR NR/NR NR SUVmax, age
Zhang et al. (2015) [25] 55.1±10.7 years Male or Female/ Benign nodules: 162.0±47.8 NR/Previous cancer NR NR ≤ 30 mm NR Calcification
Spiculation
Cavitation
LUL
LLL
RUL
Family history of cancer, biomarkers Age, smoking history, diameter, spiculation, clear
Yang et al. (2017) [29] 55.41 ± 11.94 years (Range, 17–87 years)
Benign nodules: 49.01 ± 11.88 years
Malignant nodules: 58.22 ± 10.83 years
Male or Female/NR Benign nodules: 41.03 ± 36.58 pack/years Malignant nodules: 36.09 ± 63.51 pack/years Indeterminate nodules: 32.39 ± 20.50 pack/years NR/Previous medical history of malignancy lung disease: 5% NR NR 4–30 mm NR Thin cavitation Thickened cavitation Lobulation
Lobulation + spiculation
Others:
Spiculated protuberances
Irregular edge
Smooth edge
Density
Necrosis/ Solid and subsolid nodules
Upper lobe
Middle lobe
Lower lobe
Previous medical history, extrathoracic disease/ lung Disease excluding malignancy Gender, age, smoking history, previous extrathoracic disease, previous chronic lung disease except cancer, malignancy history, diameter, lobulation, spiculation, lobulation and spiculation, irregular edges, calcification
She et al. (2017) [24] 58.87 ± 10.74 years Male or Female/NR NR NR/History of cancer: 5.2% NR Peripheral emphysema/NR 5–30 mm NR Calcification, Spiculation, Cavitation/Solid nodules ·Left lung
·Upper lobe
Family history of cancer, biomarkers (CEA, SCCA) Pleural indentation Diameter, cancer history, age, spiculation, pleural indentation, calcification, CEA
Van Gómez López et al. (2015) [16] Benign nodules: 58.0±9.1 years Malignant nodules: 64.2±11.1 years Male or Female/NR (yes/no)
Benign nodules: 27.3% (yes) Malignant nodules: 63.6% (yes)
NR NR NR < 30 mm NR NR/NR NR - SUVmax, age
Zhang et al. (2015) [25] 55.1±10.7 years (Range, 32-80 years)
Benign
nodules: 50.11±10.15 years Malignant nodules: 61.01±11.36 years
Male or Female/NR Benign nodules: 162.0±47.8 pieces-year Malignant nodules: 258.9±71.1pieces-year NR/Previous cancer history: 1.7% NR NR ≤ 30 mm NR Calcification
Spiculation
Cavitation
Lobulation
Others:
Pleural retraction sign
Clear border
Vascular convergence sign/NR
LUL
LLL
RUL
RML
RLL
Family history of cancer, biomarkers (CEA, NSE CYFRA 21-1) Age, smoking history, diameter, spiculation, clear border, CYFRA 21-1
Zheng et al. (2015) [18] Benign nodules: 52.5 ± 12.0
years
Malignant nodules: 58.7 ± 11.4 years
Male or Female/NR Pieces-year ≥ 400 %:
Benign
nodules: 24.45%
Malignant nodules: 19.45%
NR NR NR < 30 mm NR Calcification
Spiculation
Cavitation
Lobulation
Others: satellite lesions/Subsolid nodules
RUL
RML
RLL
LUL
LLL
Haemoglobin, total protein, albumin, ALP, creatinine, LDH, calcium, biomarkers (CEA), family tumour history, BMI, past related diseases, symptoms, FEV1, Pleural tail, central pixel attenuation, enhancement attenuation value, enlarged lymph nodes, pleural effusion Model with Nodules < 50% GGO: age, symptoms, serum total protein, diameter, lobulation, calcification.
Model with Nodules ≥ 50% GGO: sex, FEV1 %, diameter, calcification
Dong et al. (2013) [15] 58.12 years (Range, 32–80 years)
Benign nodules: 50.11±10.15 years Malignant nodules: 61.01±11.36 years
Male or Female/NR 468.15 Pieces-year pieces-year Malignant nodules: 258.9±71.1pieces-year NR/Previous history of history: 1.7% NR NR < 30 mm NR Calcification
Spiculation
Cavitation
Lobulation
Others:
Pleural retraction sign
Clear border
Vascular convergence sign/NR
LUL
LLL
RUL
RML
RLL
Family cancer history, biomarkers (CEA, NSE CYFRA 21-1) Age, smoking history, CEA, CYFRA 21-1, border, CYFRA 21-1
Zheng et al. (2015) [18] Benign nodules: 52.5 ± 12.0
years
Malignant nodules: 58.7 ± 11.4 years
Male or Female/NR Pieces-year ≥400 %:
Benign
nodules: 24.45%
Malignant nodules: 19.45%
NR NR NR < 30 mm NR Calcification
Spiculation
Cavitation
Lobulation
Others: satellite lesions/Subsolid nodules
RUL
RML
RLL
LUL
LLL
Haemoglobin, total protein, albumin, ALP, creatinine, LDH, calcium, biomarkers (CEA), family tumour history, BMI, past related diseases, symptoms, FEV1, Pleural tail, central pixel attenuation, enhancement attenuation value, enlarged lymph nodes, pleural effusion Model with Nodules < 50% GGO: age, symptoms, serum total protein, diameter, lobulation, calcification
Model with Nodules ≥ 50% GGO: sex, FEV1 %, diameter, calcification
Dong et al. (2013) [15] 58.12 years Male or Female/NR 468.15 Pieces-year NR/Previous history of NR NR < 30 mm NR Calcification
Spiculation
Cavitation
LUL
LLL
RUL
Family cancer history, biomarkers Age, smoking history, CEA, CYFRA 21-1,
  Malignant tumour > 1 year ago:3.45%      Lobulation
Others:
Clear border Satellite lesions Pleura retraction sign /NR
RML
RLL
(NSE, CEA, CYFRA 21-1, CA125, SCC), histological diagnosis malignant family history of cancer, diameter, lobulation, calcification, spiculation, clear border, satellite lesions
Li et al. (2012) [19] 57.1 years
Benign nodules: 48.0 ± 14.6 years
Malignant nodules: 61.2 ± 13.1 years
Male or Female/NR Benign nodules: 169.8 ± 328.3 pieces-year Malignant nodules: 260.6 ± 410.3 pieces-year NR/Previous cancer history > 5 years ago: 2.25% NR NR < 30 mm NR Calcification
Spiculation
Cavitation
Lobulation Others:
Pleural retraction sign
Clear border
Vascular convergence/NR
Upper lobe
Non-upper lobe
Left
Right
Family history of cancer Age, diameter, spiculation, family cancer history, calcification, clear border
Yonemori et al. (2007) [20] 62 years
Benign nodules: 58 years
Malignant
nodules: 64 years
Male or Female/ NR Benign nodules: 19 pack-years
Malignant nodules: 24 pack-years
NR/Other cancer
> 5 years ago: 2.21%
NR NR < 30 mm NR Calcification
Spiculation
Cavitation
Lobulation
Others:
CT bronchus sign/NR
LUL
Lingular segment
LLL
RUL
RML
RLL
Right
WCC, serum CRP, biomarkers (CEA) Calcification, spiculation, Bronchus sign, CEA, CRP
Gould et al. (2007) [27] 65.9 ± 10.7 years
Benign nodules: 62 years
Malignant nodules: 68 years
Male or Female/NR Benign nodules: 46 pack-years Malignant nodules: 63 pack-years NR/History of other cancers: 9.06% NR NR 7–30 mm NR “definitely malignant”b/NR Upper lobe /right lung Number of years since quitting smoking, time since diagnosis of lung/other cancer Years since quitting smoking, smoking history, age, diameter
Swensen et al. (1997) [21] Benign nodules: 60 years (range, 15-82 years)
Malignant nodules: 65 years (range, 35-87 years)
Male or Female/NR Benign nodules: 24 pack-years Malignant nodules: 45 pack-years Indeterminate nodules: 32 pack-years Of extrathoracic malignancy: 2.86% 6 subjects with SPN had been exposed to asbestos NR 4–30 mm NR Calcification, Spiculation, Cavitation, Lobulation Others: Entirely smooth, Spiculated or shaggy/NR ·Central/peripheral
·Upper lobe ·Location lobe:
RUL RML
RLL
LUL
LLL
Lingula
Pleural tail, Air bronchogram, residence > 192 km from clinic Age, history of smoking, Remote history (>5 years) of extrathoracic cancer, diameter, spiculation, upper lobe
  1. Notes: a100-400 days for volume doubling time (solid nodules); 3–5 years (subsolid nodules). b“Definitely malignant” is described in Gould et al. article as: ‘readers of chest radiographs were asked to provide a radiographic diagnosis on a 5-point Likert scale that ranged between “definitely benign” and “definitely malignant.” We therefore used a radiographic diagnosis of “definitely malignant” as a proxy for spiculation
  2. Abbreviations :LLL, left lower lobe; RUL, right upper lobe; RML, right middle lobe; RLL, right lower lobe; LUL, left upper lobe; GGO, ground-glass opacity; BMI, body mass index; LDH, lactate dehydrogenase; ALP, alkaline phosphatase; NSE, neuron-specific enolase; CEA, carcinoembryonic antigen; CYFRA 21-1, cytokeratin 19-fragment marker; SCC, squamous cell carcinoma; CA125, carbohydrate antigen 125; CA199, carbohydrate antigen 199; CA724, carbohydrate antigen 724; FEV1, forced expiratory volume 1; WCC, leukocytes; CRP, RCDW, red cell distribution width; WBC, white blood cell; PLT, platelet counts; SUVmax, the maximum of standardized uptake value; CRP, C-reactive protein; HU, Hounsfield units; TB, tuberculosis; NR, not reported