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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