Accepted Manuscript

Spectrum of Lung Adenocarcinoma

Barry D. Hutchinson MD , Girish S. Shroff MD ,

Mylene T. Truong MD , Jane P. Ko MD

PII: S0887-2171(18)30125-2
DOI: https://doi.org/10.1053/j.sult.2018.11.009
Reference: YSULT 855

To appear in: Seminars in Ultrasound CT and MRI

Please cite this article as: Barry D. Hutchinson MD , Girish S. Shroff MD , Mylene T. Truong MD ,
Jane P. Ko MD , Spectrum of Lung Adenocarcinoma, Seminars in Ultrasound CT and MRI (2018),
doi: https://doi.org/10.1053/j.sult.2018.11.009

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service
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 ACCEPTED MANUSCRIPT

Spectrum of Lung Adenocarcinoma

Barry D. Hutchinson, MD,* Girish S. Shroff, MD,† Mylene T. Truong, MD,† Jane P. Ko, MD *

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 Department of Radiology, NYU Langone Medical Center, NYU School of Medicine, New York, NY.

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† Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center,

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Houston, TX.

Corresponding author:
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Barry D. Hutchinson, MD, Department of Radiology, NYU Langone Medical Center, 660 First Ave, New
York, NY, 10016.
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E-mail: [email protected]
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Abbreviations

WHO World Health Organization

SCC Squamous Cell Carcinoma

IASLC International Association for the Study of Lung Cancer

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ATS American Thoracic Society

ERS European Respiratory Society

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pGGN Pure Ground-Glass Nodule

PSN

I-ELCAP
Part-Solid Nodule

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International Early Lung Cancer Action Program
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HRCT High Resolution Computed Tomography

GGO Ground-Glass Opacity

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MRP Multiplanar Reformations

AAH Atypical Adenomatous Hyperplasia

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INV Invasive Adenocarcinoma

AIS Adenocarcinoma in Situ

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MIA Minimally Invasive Adenocarcinoma

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IMA Invasive Mucinous Adenocarcinoma

STAS Spread Through Air Spaces

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LPA Lepidic Predominant Adenocarcinoma

KRAS Kirsten Rat Sarcoma Viral Oncogene

EGFR Epidermal growth factor receptor

TKI Tyrosine Kinase Inhibitor

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ALK Anaplastic Lymphoma Kinase

ROS1 Encoding Tyrosine-Protein Kinase ROS

MET Mesenchymal-Epidermal Transition Oncogene

BRAF v-Raf Murine Sarcoma Viral Oncogene

PD-L1/P-1 Programmed Death-Ligand 1/Programmed Cell Death Protein 1

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NSCLC Non-Small Cell Lung Carcinoma

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TNM Tumor, Node and Metastasis

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SCIS Squamous Cell Carcinoma in Situ

LCSG The Lung Cancer Study Group

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Abstract

Lung cancer remains the most common cause of cancer death in the United States of America and

worldwide despite continued advances in lung cancer screening as well as surgical, medical and

radiation oncological treatments.1 Adenocarcinoma is the most common histological subtype of primary

lung cancer,2 accounting for greater than 40% of cases,3 and its relative frequency is increasing.4 The

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most recent World Health Organization (WHO) Classification of Tumors5 published in 2015 heralded a

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different approach to lung adenocarcinoma relative to previous editions.6 Various histological subtypes

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of adenocarcinoma are now organized into a spectrum ranging from indolent preinvasive lesions to

aggressive forms of invasive adenocarcinoma with a poor prognosis.2,6 Increasing emphasis has been

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placed on the integration of molecular and genetic analysis of adenocarcinomas into the diagnosis and

treatment of lung adenocarcinoma owing to the proliferation of novel targeted therapies.6 A correlation
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between imaging findings in lung adenocarcinoma and histologic features/prognosis has been

demonstrated by numerous studies.7-9 An understanding of the pathology, diagnosis and management

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of the spectrum of lung adenocarcinoma is more important than ever, considering the central role of the
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radiologist. The aim of this review is to describe the subtypes of the lung adenocarcinoma spectrum in

terms of histological and imaging features, their pattern of growth on imaging, management, staging
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and evolving knowledge of tumor genetics.

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Lung Adenocarcinoma
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In the 20th century, squamous cell carcinoma (SCC) was the most common histological subtype of

primary lung cancer in men accounting for nearly half of all cases in the 1970’s.3 Since the 1980’s, the

relative frequency of SCC has declined with adenocarcinoma becoming the most common subtype by

1998-2002.4 This shift has been attributed to a number of factors including: a) the production of filtered
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cigarettes with lower tar content allowing deeper inhalation and more peripheral distribution of

cigarette smoke, b) increasing air pollution and c) earlier cessation of smoking. Improved attitudes

towards the risks of cigarette smoking have increased the proportion of adenocarcinomas relative to

other histologic subtypes of lung cancer, given SCC and small cell carcinoma have a more positive linear

relationship with smoke inhalation than adenocarcinoma.4,10 Overall rates of lung cancer in men,

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including adenocarcinoma, have been declining since the 1980’s for these reasons.3 Adenocarcinoma

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has always been the most common subtype of primary lung cancer in women, thought to be due to later

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adoption of smoking by women.3,4 In contrast to men, the overall incidence of lung cancer and relative

frequency of adenocarcinoma have continued to rise in women until recently when decline has been

seen in some populations.3,4

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Understanding of adenocarcinoma progression was reported by Noguchi et al., who described 6 stages

of tumor development in a seminal study on the growth pattern of small peripheral lung
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adenocarcinomas and its correlation with prognosis.11 The first 3 (Types A-C) were characterized by
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lepidic growth, i.e. replacement of Clara cells and type II pneumocytes that usually line the alveolar walls

with neoplastic cells, progressing to more solid growth with progressive levels of fibrosis, alveolar
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collapse, and dedifferentiation.11 A lepidic growth pattern in resected specimens correlated with a

better prognosis than the latter fibrosing pattern.11 This work served as the basis of a new classification
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of primary lung adenocarcinoma issued by the International Association for the Study of Lung Cancer

(IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS)12 and was later
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adopted by the WHO.5 This system is based on the accumulated knowledge pertaining to molecular

features of adenocarcinoma and the stepwise continuum of lung adenocarcinoma tumorigenesis

characterized by the progression from preinvasive, to minimally invasive, and ultimately to overtly
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invasive pulmonary adenocarcinoma with a lepidic pattern.12,13 (Figure 1). This classification integrated

radiology/pathology correlation knowledge from studies.12,14

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Figure 1

Preinvasive
Lesions

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Minimally
Invasive
Lesions
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Invasive
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Lesions
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FIGURE 1

Flow chart depicting the spectrum of pulmonary adenocarcinoma from preinvasive to invasive lesions.

Technique and Terms

Pulmonary nodules, defined as rounded lung parenchymal opacities measuring less than 30 mm, can be

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divided into solid and subsolid nodules.15 Solid nodules completely obscure the lung parenchyma.16

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Subsolid nodules comprise a) pure ground-glass nodules (pGGNs), which are focal areas of increased

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lung attenuation within which the margins of any normal structures, such as vessels and airways remain

outlined16 and b) part-solid nodules (PSNs) which are nodules containing both solid and ground-glass

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components (Figures 2 and 3).12,15,16 Pulmonary masses measure 30 mm or greater and may also have

solid or subsolid attenuation. 15

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Subsolid nodules are less common than solid nodules. Subsolid nodules were seen in 9.2% of the 57,946

patients enrolled in the International Early Lung Cancer Action Program (I-ELCAP), whereas solid
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pulmonary nodules were seen in 30.2% of the same cohort.17 When persistent, subsolid nodules have a
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high association with malignancy, particularly the adenocarcinoma spectrum. In the I-ELCAP cohort, 34%

of sampled persistent subsolid nodules were malignant, versus 7% of persistent solid pulmonary nodules
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in the same study.18

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Ground-glass opacity (GGO) seen on CT corresponds histologically to partial filling of airspaces;

interstitial thickening due to fluid, cells, or fibrosis; partial collapse of alveoli; increased capillary blood
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volume; or a combination of these. The common factor is partial replacement of lung air.14 When seen

in the context of the adenocarcinoma spectrum, GGO has been shown to correspond to lepidic tumor

growth, while invasive solid tumor appears as a solid nodular opacity on CT.2,9,14,19-21

For evaluating lung nodules on CT scans of the thorax, a standard imaging protocol is recommended.

Images should be reconstructed with contiguous thin sections (usually 1 mm) and with coronal and
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sagittal multiplanar reformations (MPRs) to enable accurate characterization of small pulmonary

nodules.22 The routine use of intravenous contrast media has not been recommended for the

characterization of pulmonary nodules23 but may be useful in assessing mediastinal structures.20 Use of

a similar technique, particularly section thickness and reconstruction kernel,22 minimizes variability in

measurement and assessment of nodule morphology on follow-up imaging.

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In 2017, the Fleischner Society issued guidelines directed towards standardizing measurement of

incidental pulmonary nodules.24 Measurement of nodule diameter with electronic calipers is currently

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the most widely used approach.24 For small (3 to 10 mm) nodules, measurement should be the average

of long and short-axis diameters, rounded to the nearest whole millimeter, which are acquired typically

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in the axial plane on thin section images using lung windows and a high spatial frequency (sharp) filter.24
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The long-axis diameter can be measured in the coronal or sagittal plane if the nodule is largest in these

dimensions, although this should be specified in the report.22 The long-axis diameter of the nodule
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should be determined first, and then the short axis is to be measured perpendicular to the long axis.24

For larger nodules (> 10 mm) and masses, both long and short axis measurements should be recorded
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and can be measured on thicker reconstructions (Figure 3).24

Measurement of nodule volume by using software that detects nodule boundaries has shown to reduce
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inter-observer variability when compared with standard bidimensional diameter measurement.25 This
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can serve as a more sensitive test for growth in both solid and subsolid nodules.24 Investigational

computer software has also been developed to assist in segmentation of PSNs into fractions of solid and
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ground-glass components.21,26 This method has been shown to have a correlate with the quantity of

invasive component at histology21 and to help stratify between preinvasive and invasive lesions.21,26

Agreement between experienced readers on whether a nodule is a dense pGGN or PSN has been shown

to be low.27 Furthermore, due to the progression from lepidic to solid components, adenocarcinoma
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spectrum lesions can grow by increasing in size and/or attenuation and even by contracting/decreasing

in size.9,28 For this reason, quantitative measures such as nodule mass that incorporate density and

volume (volume x CT number), as proposed by de Hoop and colleagues, may detect earlier growth of

subsolid nodules with improved interobserver agreement.28 Other morphological features frequently

described with adenocarcinoma spectrum lesions are bubble lucencies (small spots of round or ovoid air

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attenuation present within a subsolid nodule, Figure 4) and pleural indentation/retraction. 29-31

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Figure 2

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Pulmonary
Nodule
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Subsolid
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Solid Nodule
Nodule
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Pure
Ground- Part-Solid
Glass Nodule
(PSN)
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Nodule
(pGGN)

Figure 2
Nomenclature of pulmonary nodules by CT appearance.
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Figure 3

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74 year-old woman with a history of multiple adenocarcinomas spectrum lesions as well as metastatic colon
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cancer. Solid (anterior right upper lobe, calipers), PSN (posterior right upper lobe, arrow) and pGGN are all present
(Left lower lobe superior segment, calipers). Note, the solid nodule should be recorded as 12 x 10 mm but the
pGGN has an average diameter of 8 mm
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Figure 4

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82 year-old woman with part-solid nodule in the left lower lobe that is composed of mainly soft tissue attenuation.
This demonstrates both bubble lucencies. This was diagnosed to be a micropapillary predominant adenocarcinoma
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by resection.
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Atypical Adenomatous Hyperplasia (AAH)

Atypical adenomatous hyperplasia (AAH) is a small focus of non-invasive proliferation of type II

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pneumocytes with mild to moderate cellular atypia, which line pre-existing alveolar walls and

sometimes respiratory bronchioles (lepidic growth). 12,13 The term field ‘cancerization’ describes changes
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occurring on the surface of tissues that are exposed to carcinogens for an extended period of time.32
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AAH is frequently found in the vicinity of invasive adenocarcinoma (INV)33 (Figure 5A) which is thought

to be an indication of field cancerization, i.e. lung tissue is at risk of developing adenocarcinoma because
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it possesses genetic features that make the tissue vulnerable to the development of AAH, which is often

followed INV.13 This observation, along with the isolation of specific genetic abnormalities in areas of

AAH that are also frequently found in INVs, suggests a carcinogenic sequence pathway.11,13,33 Observed

progression of AAH to INV is very uncommon however.22,34 AAH, like all members of the
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adenocarcinoma spectrum, are usually peripheral lesions.12 AAH is seen more commonly in patients with

multiple synchronous primary INVs than in those with a single lesion.33

Being the earliest member of the adenocarcinoma histopathologic spectrum, AAH is the earliest

adenocarcinoma spectrum lesion detectable by thin-section CT.12 AAH is not always visible on CT but

when seen, it is characterized by purely lepidic growth and appears as a pGGN having the lowest density

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of ground-glass lesions of the adenocarcinoma spectrum.14 AAH lesions are usually well-circumscribed

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with smooth round margins20,29 (Figure 5B) AAH is often bilateral and usually located in the upper

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lobes.33 While it is described as typically measuring less than 5 mm at histology,12 the lesions can

measure greater than 5 mm on CT. In a study comparing imaging and histologic findings of 60 pGGNs by

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Si et al, the mean diameter of AAH lesions (17/60) was 7.6 ± 2.5 mm.29 None of these lesions
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demonstrated spiculation or pleural indentation.
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Adenocarcinoma in Situ (AIS)

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Adenocarcinoma in situ (AIS) was adopted by the WHO for the first time in the 2015 classification of lung

tumors.5 Like AAH, AIS demonstrates purely lepidic growth of neoplastic type II pneumocytes or Clara
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cells along intact septae and lacks stromal, vascular, and pleural invasion.12 AAH and AIS are a

morphologic continuum with AIS demonstrating more cellular and structural atypia than AAH, but their
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histologic distinction can be challenging.13 While AIS can be mucinous, virtually all cases are non-
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mucinous.12 The diagnosis of AIS can only be made in a completely resected specimen that enables

exclusion of any invasive foci in the entire lesion.6

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AIS is larger than AAH histologically, usually measuring between 5 mm and 3 cm,12 although mean

diameter of AIS on CT (9.0 ± 3.2 mm) has not been shown to be statistically significantly different from

AAH.29 Like AAH, AIS usually appears as a pGGN on CT,12,14,29 but the attenuation of the ground-glass is

often higher than that of AAH, likely due to differences in the amount of cellular components in the

alveolar airspaces or the thickness of alveolar walls (Figure 6).14 Non-mucinous AIS can demonstrate a

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small solid component, owing to collapse of alveolar walls or a benign scar,14,35 but as a general rule,

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non-mucinous AIS should not have a solid component greater than 0.5 cm on imaging.35 AIS, like AAH, is

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more frequently non-smoothly-marginated in contour than MIA and INV.36 Lesion size is the only

significant discriminator between preinvasive lesions and INVs with a pGGN morphology.36 Using a cut-

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off value of 10 mm in pGGNs is shown by one investigation to have a specificity of 100%. This means

that a size smaller than 10-mm favors preinvasive lesions rather than INVs.36
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Figure 5A
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56 year-old man who underwent right upper lobectomy for a part-solid nodule (calipers) which was an acinar-
predominant invasive adenocarcinoma at histology. A pure ground-glass nodule adjacent to it (arrow) was found
to be atypical adenomatous hyperplasia.
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Figure 5B

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Multiple similar pure ground-glass nodules (arrows) in the right lung apex were also found to be atypical
adenomatous hyperplasia at histology.
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Minimally Invasive Adenocarcinoma (MIA)

Minimally Invasive Adenocarcinoma (MIA), like AIS, is comprised of predominantly lepidic tumor growth,
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measures 3 cm or less, and has a 100% 5 year survival when fully resected.11,12,37,38 However, it is

distinguished from AIS by the presence of a focus or foci of invasive adenocarcinoma measuring less
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than 5 mm.5 Histologic invasion is defined as tumor cellular arrangement in acinar or papillary tubular
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structures or solid nests in a fibroblastic stroma, often accompanied by collagenization.14,39

The small focus of invasion in MIAs can be seen on CT as a solid component in a PSN that is

predominantly ground glass attenuation (Figure 6). PSNs with a solid component smaller than 6 mm

have been shown to typically represent either AIS or MIA.22 The solid component in a MIA can appear

larger than 5 mm on CT due to scar, collapse of alveoli, macrophages filling alveolar sacs, and
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intraalveolar hemorrhage.14 Alternatively, foci of invasion of 5 mm or smaller in MIA and even those of

greater than 5 mm in INV commonly manifest as a pGGN on CT because of the limited resolution of thin-

section CT (0.2 – 0.3 mm).14,30 In a large prospective study of subsolid nodules performed by Kakinuma

and colleagues, 977 pGGNs were examined, and 35 of these were resected. The breakdown of these 35

pGGNs was 10 MIA, 21 AIS and 5 AAH.40 MIA has been shown to be significantly larger than AAH and AIS

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when presenting as a pGGN. In a study of 60 pGGNs with histologic correlation, using a diameter of 7.5

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mm as a cutoff, yielded a sensitivity of 100% in distinguishing MIA from the preinvasive lesions.29

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Therefore, the most common presentation of MIA on CT is a pGGN of greater than 10 mm in diameter

without an internal solid component14,30 (Figure 6) but a significant minority appear as a PSN with a

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small solid component (Figure 7).41 Bubble lucency can be seen in MIA41 but has not been shown to

reliably distinguish them from preinvasive lesions.29

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Figure 6
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74 year-old woman with pGGNs measuring 7mm and 11 mm in the lingula. At histology, the smaller lesion was AIS
and the larger MIA.
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Figure 7

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78 year-old man with a part-solid nodule with a 4 mm peripheral solid component and predominant GGO. This was
found to be MIA at histology. Note that the sold component is measured in its longest dimension.

Invasive Adenocarcinoma (INV)

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Unlike AIS and MIA, INVs are strictly non-mucinous and a separate diagnosis from invasive mucinous

adenocarcinoma (IMA). INVs contain a focus of invasion greater than 5 mm in diameter.5 It is important
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to note that the histologic distinction between MIA and early INV is subjective. In a study of 296
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resected pulmonary adenocarcinoma spectrum lesions, there was disagreement between a diagnosis of

MIA and INV in 45 cases (15%).42 Invasive components may be arranged in an acinar, papillary, solid or
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micropapillary histologic patterns, with infiltration of stroma and infiltration of blood vessels or

structures such as the visceral pleura.5 An additional pattern of tumor invasion called “spread through
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air spaces” (STAS) has also recently been described. It is characterized by the spread of lung cancer

tumor cells into air spaces in the lung parenchyma adjacent to the main tumor and has been associated
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with a significantly higher rate of recurrence.43 In the majority of cases of INV, these tumors are

composed of a complex, heterogeneous mixture of histologic subtypes including lepidic

adenocarcinoma.12 Since the 2015 WHO classification of lung tumors, INVs are classified by their

predominant subtype.5 Another change in the latest classification pertains to the reporting, in 5%
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increments, of all adenocarcinoma subtypes present in the lesion,12 for example, a diagnosis of “invasive

Adenocarcinoma 40% Lepidic, 35% Acinar, 25% Papillary” would be rendered. The histologic

heterogeneity of adenocarcinoma is associated with a wide variation in prognosis depending on the

varying amounts of each subtype. Three distinct prognostic groups have emerged in resected Stage 1

INVs: Lepidic predominant adenocarcinoma (LPA), acinar/papillary predominant adenocarcinoma and

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solid/micropapillary predominant adenocarcinoma.8,44

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Intuitively, INV prognosis correlates with the proportion of lepidic component. LPAs with more than 50%

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lepidic component have demonstrated a 0% 5-year recurrence rate,37 and in one large study, the 5-year

survival rate for all LPAs was 90%.8 With poorer prognosis than for LPA, papillary and acinar

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predominant adenocarcinoma has a 5-year disease-free survival of 83 and 84%8, respectively, and the
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overall survival for both is 70%.44,45 Solid and micropapillary predominant adenocarcinomas have the

worst prognosis with a 5 year disease free survival of 70 and 67%,8 respectively, and an overall survival
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rate of 55% for both.45 The significant clinical impact of these latter subtypes was underscored by recent

studies which have shown that the presence of minor components of micropapillary and/or solid
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subtypes of lung adenocarcinoma correlate with lymph node metastasis and poor prognosis (Figure 4).46

Like their histology and prognosis, imaging findings of INV at CT are highly variable, typically a part-solid
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nodule or completely solid nodule/mass although can be a pGGN (Figure 8). Like all of the
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adenocarcinoma spectrum lesions described, INVs are most commonly peripheral in location.12 INVs are

often accompanied by additional earlier adenocarcinoma spectrum lesions including AAH, AIS and MIA
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(Figure 5A).47 When appearing as a pGGN, nodule size has been shown to be a significant discriminator

between INV and AIS/MIA. In a study of 46 resected pGGNs, a cutoff of 16.4 mm was shown to reliably

discriminate INV from AIS/MIA.30 In another study of 83 resected pGGNs, the mean nodule diameter of

the 17 patients (20.5%) diagnosed with INV was 19mm, significantly larger than that of the 66 cases of

AIS/MIA (79.5%) which averaged 12mm in diameter.48 The pGGN size has also been shown to correlate
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significantly with size and number of histologically invasive foci.49 Density/mass of a pGGN has been

reported as reliable discriminators of INV from AIS/MIA in several studies.30,50

As described, the presence of small solid components do not necessarily indicate the presence of

invasive foci. However the presence of solid components measuring greater than 5 mm in a PSN has

been shown to correlate with a substantial likelihood of local invasion and as a method to distinguish

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INV from AIS/MIA.22 In the large study by Kakinuma et al, the mean maximal diameter of the solid

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component in the mediastinal window was 3.3 mm for MIAs and 5.5 mm for invasive adenocarcinomas;

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this difference in the mean diameter of the solid component was statistically significant.40 The relative

proportions of solid to ground-glass components in a PSN, when measured with investigational

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segmentation software, have been shown to not only distinguish INV from AIS/MIA but also LPA from
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other more invasive forms of INV. The mean percentage solid volume of non-lepidic INVs was 35.4%,

higher than the 14.5% for LPA and 8.2% for AIS/MIA.26 Lastly pleural retraction is more commonly seen
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in INV than AIS/MIA and other non-malignant lesions,50 seen in 76.5% of cases of INVs in one study vs

15.2% for non-INVs.48

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Figure 8
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72-year-old woman with pGGN measuring 19 mm in the right upper lobe. This was LPA with an invasive focus of
papillary adenocarcinoma at histology.
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Variants of Invasive Adenocarcinoma

Variants of invasive adenocarcinoma include IMA as well as colloid, fetal, and enteric subtypes.12 IMA
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was formally classified as separate from non-mucinous INV in the most recent adenocarcinoma

classification5 due to their major clinical, radiological, pathologic , genetic, and staging differences.12 IMA
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tumor cells are goblet or columnar cells and contain intracytoplasmic mucin.12 Biopsy can be non-

diagnostic, as the alveolar spaces at the tumor periphery can be filled entirely with mucin and therefore
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no cells.51 A lepidic growth pattern with microscopic skip lesions is a characteristic of IMAs, which may
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show the same heterogeneous mixture of lepidic, acinar, papillary, micropapillary, and solid growth

patterns as INVs.51 IMAs also have distinct molecular make-ups. Kirsten rat sarcoma viral oncogene
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(KRAS) driver mutations are seen in up to 86%.51 Conversely, epidermal growth factor receptor (EGFR)

mutations are very rare.12 At imaging, IMAs can present with multi-centric opacities in one lobe or

multiple lesions in one or both lungs. IMAs may appear as solid, subsolid nodules, or as air space

opacity, and they can mimic pneumonia (pneumonic-type adenocarcinomas, Figure 9).51,52 IMAs have

been associated with a high recurrence rate8 which has been hypothesized to be due to tumor cells
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travelling through the abundant mucin in a pattern similar to STAS.51 The “ CT angiogram” sign, which is

the ability to see normal pulmonary vasculature within parenchymal consolidations (Figure 10) was

initially thought to be specific for IMA,53 but subsequent studies found it unhelpful in distinguishing IMA

from other causes of airspace opacities including infectious pneumonia, post-obstructive pneumonitis,

passive atelectasis and pulmonary lymphoma.54

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Colloid adenocarcinomas (which also contain abundant amounts of mucin), fetal and enteric subtypes of

invasive adenocarcinoma are rare and do not have well described distinguishing imaging features.12

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Figure 9
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36-year-old woman with IMA appearing as airspace opacity, both GGO and consolidation.

Figure 10

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68 year-old woman with IMA. Right lower lobar consolidation demonstrates the “CT angiogram sign” with
enhancing vessels seen in the consolidation.
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Genomics

While smoking is the main risk factor for lung cancer, up to 25% of lung cancer patients are never-

smokers; this is especially evident in women with adenocarcinoma.32 In these patients, other risk factors

including genetic alterations play a major role. Genetic alterations are necessary for all oncogenesis.

These alterations may be inherited or acquired through errors in copying DNA, also known as “somatic

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genomic alterations”.32 Those somatic genomic alterations that are causing carcinogenesis are known as

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“driver” alterations, whereas those that are not, are called “passenger” alterations.32 Recent progress in

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gene sequencing technologies has led to the identification of several driver genes which play a

significant role in lung carcinogenesis.55 Of note, many of these genetic alterations are seen in AAH, AIS,

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and MIA and support the hypothesis of a stepwise continuum for lung adenocarcinoma.13 Molecular-
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targeted therapies against driver gene aberrations have dramatically changed the treatment strategies

for malignant tumors and are considered first-line agents when these drivers are identified.55
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The EGFR gene encodes proteins that belong to the cell-surface tyrosine kinase receptor family. In 2004,

EGFR mutations were described which lead to activation of oncogenic signaling pathways.10 EGFR is
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mutated in 10–16% of cases of lung adenocarcinoma and is more prevalent in Asian populations and

non-smoking women, present in up to 60%.32 A majority of EGFR mutations sensitize tumors to first
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generation tyrosine kinase inhibitors (TKI) erlotinib and gefitinib.10 Gene rearrangements involving
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anaplastic lymphoma kinase (ALK) and encoding tyrosine-protein kinase ros (ROS1), as well as mutations

of mesenchymal-epidermal transition oncogene (MET), are susceptible to the TKI Crizotinib.10,32,55 These
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are rare but exclusively found in lung adenocarcinoma and enriched in young female light smokers.10

Genetic alterations in KRAS (the earliest described lung cancer driver), v-Raf murine sarcoma viral

oncogene (BRAF), and others are potential targets for targeted molecular therapy and are currently

being investigated.55 Currently, it is recommended that all patients with advanced lung

adenocarcinoma should undergo testing for EGFR mutations , ALK6 and ROS1 rearrangements
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irrespective of smoking history.10 Further molecular testing can also be performed in individual cases,

for example young non-smokers with lung adenocarcinoma.10

Another type of targeted therapy called immunotherapy blocks immune checkpoints such as

programmed death-ligand 1/programmed cell death protein 1 (PD-L1/PD-1).10 Checkpoint inhibitors

limit the body’s immune system to avoid excessive tissue damage from T cells.32 PD-1 is an inhibitory

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receptor expressed on activated T cells. PD-L1 that is overexpressed by tumors binds PD-1 preventing an

inflammatory response and thereby protecting the tumor from the immune system.32 PD-L1/PD-1

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inhibitor drugs target this pathway. Three of these medications have been approved for the treatment

of advanced-stages of non-small cell lung carcinoma (NSCLC): Nivolumab, pembrolizumab and

atezolizumab.32 US
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Radiogenomics is a trend in clinical research which aims to correlate the imaging appearance of tumors

with molecular markers with the goal of identifying targeted therapies without the need for invasive
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samples, but the field is still in its early stages.20

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Progression through the Adenocarcinoma Spectrum

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Adenocarcinoma spectrum lesions, particularly when presenting as pGGNs on CT, are frequently slow-
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growing56 with volume-doubling times between 265 and 887 days.34 Follow-up imaging over a prolonged

time-frame22 and surgical treatment of a potentially indolent disease have raised the question of
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overdiagnosis.57 However, a subset of adenocarcinoma spectrum lesions that demonstrate early imaging

appearances that is similar to indolent lesions will progress more rapidly and be associated with a worse

prognosis.8
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The imaging characteristics that predict the likelihood of growth in a suspected adenocarcinoma lesion

are namely size and solid components.58 The pGGNs measuring 5 mm or less, often thought to

represent small foci of AAH, have a very low likelihood of growth.22 In a study of 438 solitary pGGNs

measuring 5 mm, 10% grew and 1% developed into MIA or INV over a mean follow-up of 3.6 years.34 The

Fleischner society do not recommend routine follow-up imaging for solitary pGGNs or PSNs measuring

T
less than 6 mm.22 PSNs with a solid component of 5 mm or less have been found to have a probability of

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growth of 17% and 48% at 2 and 5 years, respectively. While lesions in this group that grow are likely to

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be MIA or INV, no survival disadvantage has been demonstrated with a "follow-up until interval growth"

approach. A study compared outcomes in patients with PSNs containing a solid component of 5 mm or

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less who had immediate resection versus those who had resection after a period of imaging

surveillance during which the nodule grew. No significant difference in the recurrence-free survival
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and overall survival was identified,58 and this study also found that pGGN nodule size of > 10 mm and

PSN size of > 8mm were associated with a higher likelihood of growth.58 PSNs with a solid component
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greater than 5 mm have the highest likelihood of growth.22

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Staging and Tumor Measurement

Recently, the IASLC made a number of proposals for changes to T categories in subsolid nodules for the
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8th edition of the Tumor, Node and Metastasis TNM Classification of Lung Cancer, partly to address
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several new entities described in the most recent WHO classification of adenocarcinoma.59 Proposals are

as follows. The T descriptor of Tis (AIS) for AIS should be used to distinguish it from TIS (SCIS), now that
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lung in situ carcinoma can be either AIS or squamous cell carcinoma in situ (SCIS).59 In addition, MIA of

the lung should be classified as T1mi. Use of the size of the invasive component to determine the T

descriptor size is recommended.59 While the Fleischner Society recommends using an average

diameter,24 for T staging purposes, the TNM system uses the single largest dimension measured on thin

CT sections and multiplanar reconstructions. For pathologic TNM assessment, although three-
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dimensional measurements are frequently recorded in pathology reports, the single maximum

diameter is traditionally (Figure 7). For a PSN, the solid component, if > 3mm, should also be

recorded.59 As CT features are not definitive for diagnosis or measurement of a tumor, the suspected

diagnosis and clinical staging should be regarded as a preliminary assessment that is subject to revision

after pathologic evaluation.59

T
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Mucinous adenocarcinomas (including mucinous AIS, MIA, IMA and colloid adenocarcinoma) are

addressed separately, as they often appear as pneumonic-type adenocarcinomas with multilobar

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involvement and poorly-demarcated borders.35 New proposals recommend using standard size

measurements if there is one site of pulmonary involvement in a single lobe. Lesions are considered T3,

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if the disease is difficult to measure but confined to a single lobe, and T4, if multiple lobes of the same
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lung are involved, and M1a, if involving both lungs.35,59

Surgery
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Lobectomy and mediastinal node dissection has been considered the gold standard for the treatment of
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all stage 1A for NSCLC as a result of the only randomized controlled trial performed by The Lung Cancer

Study Group (LCSG) in 1995 comparing lobectomy and limited resection (wedge resection or anatomical
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segmentectomy) in patients with T1N0 NSCLC. They found a significantly reduced 5-year survival rate

(56% vs 73%), a lower freedom from recurrence rate (62% vs 78%), and three-fold increase in local
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recurrence rates (5.4% vs 1.9%) in the limited resection arm.60,61 Limited resections have the advantage

of preservation of lung function in patients with poor pulmonary function tests and synchronous or
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metachronous adenocarcinoma spectrum lesions.61 Recently, there has been a trend towards sublobar

resections based on improved techniques, better understanding of tumor biology and retrospective

studies showing similar outcomes for both lobectomy and sublobar resection.62 A study of 2008

patients over 65 undergoing resection of T1a lung adenocarcinomas showed similar outcomes for
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patients undergoing lobectomy and segmentectomy.63 However, those who had wedge resections had

worse outcomes.63

Radiologists can play a role in surgical planning with precise description of tumor size, location and

relevant anatomical considerations. While segmentectomy can be performed for central tumors, most

tumors evaluated in studies supporting sublobar resections have been peripherally located within the

T
outer third of the lung.62 Tumors considered for segmentectomy should be confined to the anatomic

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segmental boundaries without crossing intersegmental planes.62 There is no clear consensus on this

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topic64 for many reasons, for example, histological factors that may not be recognized before resection

such as the presence of STAS65 or small amounts of micropapillary pattern of tumor66 have been shown

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to significantly increase the likelihood of recurrence in those undergoing sublobar resections compared
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to lobectomy. Randomized trials currently in progress are hoped to give clarity to this issue.67,68

Conclusion
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The study of the lung adenocarcinoma spectrum has undergone dramatic changes since the most recent
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WHO Classification of Tumors published in 2015. Various histological subtypes of adenocarcinoma are

now organized into a spectrum ranging from indolent preinvasive lesions to aggressive forms of invasive
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adenocarcinoma with poor prognosis. Research has focused on the integration of molecular and genetic

analysis of adenocarcinomas into the diagnosis and treatment of lung adenocarcinoma resulting in the
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proliferation of novel targeted therapies. Studies have shown correlation between imaging findings in

lung adenocarcinoma, histologic features, and patient prognosis. A good understanding of the
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pathologic subtypes of the lung adenocarcinoma spectrum in terms of histological and imaging features,

their pattern of growth on imaging, management, staging and tumor genetics, is essential in the

diagnosis and treatment of patients with lung adenocarcinoma.

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