Yoshizawa A, Motoi N, Riely GJ, Sima CS, Gerald WL, Kris MG, Park BJ, Rusch VW, Travis WDImpact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Mod Pathol 24: 653-664

Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Modern Pathology (Impact Factor: 6.19). 01/2011; 24(5):653-64. DOI: 10.1038/modpathol.2010.232
Source: PubMed
ABSTRACT
A new lung adenocarcinoma classification is being proposed by the International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society (IASLC/ATS/ERS). This proposal has not yet been tested in clinical datasets to determine whether it defines prognostically significant subgroups of lung adenocarcinoma. In all, 514 patients who had pathological stage I adenocarcinoma of the lung classified according to the Union for International Cancer Control/American Joint Committee on Cancer 7th Edition, and who had undergone a lobectomy with mediastinal lymph node dissection were retrospectively reviewed. Comprehensive histological subtyping was used to estimate the percentage of each histological subtype and to identify the predominant subtype. Tumors were classified according to the proposed new IASLC/ATS/ERS adenocarcinoma classification. Statistical analyses were made including Kaplan-Meier and Cox regression analyses. There were 323 females (63%) and 191 males (37%) with a median age of 69 years (33-89 years) and 298 stage IA and 216 stage IB patients. Three overall prognostic groups were identified: low grade: adenocarcinoma in situ (n=1) and minimally invasive adenocarcinoma (n=8) had 100% 5-year disease-free survival; intermediate grade: non-mucinous lepidic predominant (n=29), papillary predominant (n=143) and acinar predominant (n=232) with 90, 83 and 84% 5-year disease-free survival, respectively; and high grade: invasive mucinous adenocarcinoma (n=13), colloid predominant (n=9), solid predominant (n=67) and micropapillary predominant (n=12), with 75, 7170 and 67%, 5-year disease-free survival, respectively (P<0.001). Among the clinicopathological factors, stage 1B versus 1A (P<0.001), male sex (P<0.008), high histological grade (P<0.001), vascular invasion (P=0.002) and necrosis (P<0.001) were poorer prognostic factors on univariate analysis. Both gross tumor size (P=0.04) and invasive tumor size adjusted by the percentage of lepidic growth (P<0.001) were significantly associated with disease-free survival with a slightly stronger association for the latter. Multivariate analysis showed the prognostic groups of the IASLC/ATS/ERS histological classification (P=0.038), male gender (P=0.007), tumor invasive size (P=0.026) and necrosis (P=0.002) were significant poor prognostic factors. In summary, the proposed IASLC/ATS/ERS classification of lung adenocarcinoma identifies histological categories with prognostic differences that may be helpful in identifying candidates for adjunctive therapy. The slightly stronger association with survival for invasive size versus gross size raises the need for further studies to determine whether this adjustment in measuring tumor size could impact TNM staging for small adenocarcinomas.

Full-text

Available from: Akihiko Yoshizawa, Feb 02, 2015
Impact of proposed IASLC/ATS/ERS
classification of lung adenocarcinoma:
prognostic subgroups and implications for
further revision of staging based on analysis
of 514 stage I cases
Akihiko Yoshizawa
1,2
, Noriko Motoi
1,3
, Gregory J Riely
4
, Cami S Sima
5
, William L Gerald
1,{
,
Mark G Kris
4
, Bernard J Park
6
, Valerie W Rusch
6
and William D Travis
1
1
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA;
2
Department of
Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan;
3
Department of Diagnostic Pathology,
the Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan;
4
Thoracic Oncology
Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA;
5
Epidemiology and Biostatistics,
Memorial Sloan-Kettering Cancer Center, New York, NY, USA and
6
Thoracic Surgery Service, Memorial
Sloan-Kettering Cancer Center, New York, NY, USA
A new lung adenocarcinoma classification is being proposed by the International Association for the Study of
Lung Cancer, American Thoracic Society and European Respiratory Society (IASLC/ATS/ERS). This proposal
has not yet been tested in clinical datasets to determine whether it defines prognostically significant subgroups
of lung adenocarcinoma. In all, 514 patients who had pathological stage I adenocarcinoma of the lung classified
according to the Union for International Cancer Control/American Joint Committee on Cancer 7th Edition, and
who had undergone a lobectomy with mediastinal lymph node dissection were retrospectively reviewed.
Comprehensive histological subtyping was used to estimate the percentage of each histological subtype and to
identify the predominant subtype. Tumors were classified according to the proposed new IASLC/ATS/ERS
adenocarcinoma classification. Statistical analyses were made including Kaplan–Meier and Cox regression
analyses. There were 323 females (63%) and 191 males (37%) with a median age of 69 years (33–89 years) and
298 stage IA and 216 stage IB patients. Three overall prognostic groups were identified: low grade:
adenocarcinoma in situ (n ¼ 1) and minimally invasive adenocarcinoma (n ¼ 8) had 100% 5-year disease-free
survival; intermediate grade: non-mucinous lepidic predominant (n ¼ 29), papillary predominant (n ¼ 143) and
acinar predominant (n ¼ 232) with 90, 83 and 84% 5-year disease-free survival, respectively; and high grade:
invasive mucinous adenocarcinoma (n ¼ 13), colloid predominant (n ¼ 9), solid predominant (n ¼ 67) and
micropapillary predominant (n ¼ 12), with 75, 7170 and 67%, 5-year disease-free survival, respectively
(Po0.001). Among the clinicopathological factors, stage 1B versus 1A (Po0.001), male sex (Po0.008), high
histological grade (Po0.001), vascular invasion (P ¼ 0.002) and necrosis (Po0.001) were poorer prognostic
factors on univariate analysis. Both gross tumor size (P ¼ 0.04) and invasive tumor size adjusted by the
percentage of lepidic growth (Po0.001) were significantly associated with disease-free survival with a slightly
stronger association for the latter. Multivariate analysis showed the prognostic groups of the IASLC/ATS/ERS
histological classification (P ¼ 0.038), male gender (P ¼ 0.007), tumor invasive size (P ¼ 0.026) and necrosis
(P ¼ 0.002) were significant poor prognostic factors. In summary, the proposed IASLC/ATS/ERS classification of
lung adenocarcinoma identifies histological categories with prognostic differences that may be helpful in
Received 2 November 2010; revised 30 November 2010; accepted 30 November 2010; published online 21 January 2011
Correspondence: Dr WD Travis, MD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York,
NY 10065, USA. E-mail: travisw@mskcc.org
{
Deceased.
Modern Pathology (2011) 24, 653664
& 2011 USCAP, Inc. All rights reserved 0893-3952/11 $32.00 653
www.modernpathology.org
Page 1
identifying candidates for adjunctive therapy. The slightly stronger association with survival for invasive size
versus gross size raises the need for further studies to determine whether this adjustment in measuring tumor
size could impact TNM staging for small adenocarcinomas.
Modern Pathology (2011) 24, 653–664; doi:10.1038/modpathol.2010.232; published online 21 January 2011
Keywords:
adenocarcinoma; adenocarcinoma in situ; bronchioloalveolar carcinoma; lung; micropapillary;
minimally invasive adenocarcinoma; solid
Lung adenocarcinoma is a global public he alth
problem as it is the most common histological
subtype of lung cancer and worldwide lung cancer
is the most common cause of major cancer incidence
and mortality.
1
Histological subclassification of lung
adenocarcinoma has been a great challenge for many
reasons. The tumor is very heterogeneous from every
aspect: pathology, molecular, clinical, radiology and
surgery. In the past decade numerous advances have
taken place within each specialty for lung adeno-
carcinoma, pa rticularly in molecular biology with
the discovery that EGFR mutations are a marker
for responsiveness to tyrosine kinase inhibitors.
2,3
Pathological and radiological studies have also
revealed significant prognostic subsets of lung
adenocarcinoma.
4–6
However, neither the 2004
(WHO) World Health Organization nor the Noguchi
classifications address very well the tumors with
mixtures of histological types which result in
classification of 90 and 60% of all resected lung
adenocarcinomas as mixed subtype and as type C,
respectively.
4,5,7
Because of these rapidly evolving
advances in the field of lung adenocarcinoma, there
is a need for impro vement in stratification of
histological categories according to prognosis com-
pared with the previous classifications.
With this background, the International Associa-
tion for the Study of Lung Cancer, American
Thoracic Society and European Respiratory Society
(IASLC/ATS/ERS), have sponsored a project to
develop an International Multidi sciplinary Lung
Adenocarcinoma Classification.
8
In this new classi-
fication (Table 1) there are several major changes for
surgically resected tumors: (1) the term bronchio-
loalveolar carcinoma (BAC) is no longer used and
the growt h pattern of BAC is referred to as lepidic
pattern; (2) adenocarcinoma in situ is proposed
for small (r3 cm) solitary adenocarcinomas with
pure lepidic growth lacking invasion; (3) minimally
invasive adenocarcinoma (MIA) is proposed
for small (r3 cm) lepidic predominant tumors with
r0.5 cm of invasion; (4) invasive adenocarcinomas
are now classified according to the predominant
subtype after performing comprehensive histologi-
cal subtyping with semiquantitative assessment of
each subtype in 5% increments;
4
(5) micropapillary
adenocarcinoma is added as a major subtype
because of its poor prognostic significance in multi-
ple studies of early stage lung adenocarcinoma;
9–11
(6) former mucinous BACs are now classified as
invasive mucinous adenocarcinomas recognizing
that most of these tumors will have invasive
components, less expression of TTF-1, frequent
KRAS mutations, characteristic CT finding primarily
of consolidation rather than ground glass opacities,
worse prognosis than non-mucinous lepidi c
predominant ad enocarcinomas and lack of respon-
siveness to tyrosine kinase inhibitors;
12–19
and (7)
clear cell and signet ring adenocarcinoma are
recognized to represent cytological changes that
occur in multiple histological subtypes rather than
in separate histological subtype.
20,21
We sought to explore the prognostic significance
of this classification in a large series of surgically
resected stage I lung adenocarcinomas. As most of
these stage I patients did not receive neoadjuvant
chemotherapy or adjuvant therapy, this study
allowed for exploration of the prognostic signifi-
cance of the proposed new histological subsets with
minimal impact of chemotherapy.
Patients and methods
Patients
We evaluated a retrospective series of resected,
preoperatively untreated stage I adenocarcinomas
Table 1 2011 International Association for the Study of Lung
Cancer, American Thoracic Society and European Respiratory
Society international multidisciplinary classification of lung
adenocarcinoma
a
Preinvasive lesions
Atypical adenomatous hyperplasia
Adenocarcinoma in situ (r3 cm, formerly bronchioloalveolar
carcinoma)
Non-mucinous and/or mucinous
Minimally invasive adenocarcinoma (a r3 cm lepidic
predominant tumor with r5 mm invasion)
Non-mucinous and/or mucinous
Invasive adenocarcinoma
Lepidic predominant (formerly non-mucinous
bronchioloalveolar carcinoma pattern)
Acinar predominant
Papillary predominant
Micropapillary predominant
Solid predominant with mucin
Variants
Invasive mucinous adenocarcinoma (formerly mucinous
bronchioloalveolar carcinoma) and
Mixed mucinous/non-mucinous
Colloid
Fetal
Enteric
a
From Travis et al.
8
Classification of lung adenocarcinoma
654 A Yoshizawa et al
Modern Pathology (2011) 24, 653664
Page 2
of the lung from Memorial Sloan-Kettering Canc er
Center. Clinical data were retrieved from the
Thoracic Surgical Database. This project was
approved by the Memorial Sloan-Kettering Cancer
Center institutional review board. These tumors
were resected between January 1995 and November
2005. In all, 539 cases met the 2004 WHO criteria
for adenocarcinoma and were considered as stage I
according to the 6th edition Union for Interna-
tional Cancer Control/American Joint Committee on
Cancer TNM classification and 25 cases were
excluded after applying the new 7th Edition Union
for International Cancer Control/American Joint
Committee on Cancer TNM classification.
22,23
A
subset of 366 of these cases was previously reported
to validate a grading system based on tumor
architecture.
24
Histological Evaluation
All resected specimens were formalin fixed and
stained with hematoxylin and eosin in the routine
manner. As needed, mucin stains were performed
to evaluate for mucin. Slides were evaluated micro-
scopically by AY with problem cases reviewed
by NM and WDT. The average number of slides
from each case we reviewed in our study was 8.6
(range: 1–31).
Histological classification was according to the
IASLC/ATS/ERS classification of lung adenocarci-
nomas and the 2004 WHO classification (Table 1).
8
According to our previous paper by Motoi et al and
the IASLC/ATS/ERS criteria, each tumor was re-
viewed using comprehensive histological subtyping,
recording the percentage, in 5% increments, of each
histological component.
4
Tumors were classified as
adenocarcinoma in situ (Figure 1), MIA (Figure 2),
and invasive adenocarcinomas (Figure 3) which
was further divided into lepidic predominant
(Figure 3a), papillary predominant (Figure 3b),
acinar predominant (Figure 3c), micropapillary
predominant (Figure 3d), solid predominant (Figure
3e), invasive mucinous adenocarcinoma (Figure 4)
and colloid predominant adenocarcinoma (Figure 5).
The predominant pattern is defined as the pattern
with the largest percentage, not necessarily 50% or
greater.
4
Tumor size was measured according to 1) total
tumor size and 2) size according to only the invasive
component not including the lepidic growth.
Total tumor size was assessed by standard gross
measurement. Size of the invasive component
was measured in two ways. In cases wherein the
tumors were small, so the invasive component
could be measured under the microscope on a single
slide, the areas of invasion were measured at 20 or
40 magnification on an Olympus BX51 micro-
scope using a ruler. However, in most cases where-
in the tumor was large, and the size of invasion
could not be measured on a single slide under
the microscope, the total size of invasive tumor
was calculated by multiplying the total size
by the percentage of the invasive (non-lepidic)
component.
We also investigated several histological factors,
which have been reported as significant prognostic
factors of lung adenocarcinoma: (1) visceral pleural
invasion was classified as PL0, PL1 and PL2
according to the Union for International Cancer
Control/American Joint Committee on Cancer TNM
classification, 7th Edition.
25
(2) tumor grade of
differentiation (well, moderately and poorly differ-
entiated) was assessed according to the 2004
WHO,
26
(3) vascular invasion and (4) necrosis was
classified as present or absent.
Statistics
Overall survival was estimated using the Kaplan–
Meier method, with patients followed from time
Figure 1 Adenocarcinoma in situ, non-mucinous. (a) This tumor shows a circumscribed nodule with lepidic growth consisting of
alveolar wall thickening by atypical pneumocyte proliferation. No solid area of invasive growth is seen. (b) The pneumocytes show
cellular crowding along the alveolar wall, with no invasion.
Classification of lung adenocarcinoma
A Yoshizawa et al 655
Modern Pathology
(2011) 24, 653664
Page 3
of surgery until death from any cause. Patients alive
at the time of the last available follow-up were
censored. Disease-free survival analysis followed
patients until recurr ence or death from diseas e. To
account for the fact that some patients died of other
causes, disease-free survival was evaluated using
competing risk methods, which estimates the
cumulative incidence function (CIF). Throughout
the paper, disease-free survival results are reported
as 1-CIF, for consistency with the more familiar
Kaplan–Meier estimate. Univariate disease-free sur-
vival comparisons were performed using Gray’s test,
while the disease-free survival multivariate analysis
used Cox proportional hazard model with patients
censored at the time of death from other causes or at
the last follow-up.
All statistical tests were two-sided and used 5%
level of significance. Statistical analysis was con-
ducted using Statistical Analysis System (SAS)
version 9.2 (SAS Institute Inc, Cary, NC, USA) and
the cmprsk package in R (http://www.r-project.org/).
After reviewing the survival data, the hist ological
subtypes were classified into three prognostic
groups, which represented low, intermediate and
high grades of clinical behavior. These prognostic
groups actually revealed that the histological classi-
fication identifies categories of adenocarcinoma
that have different grades of behavior. Therefore,
this ‘tumor grade’ was based purely on the results of
our survival analysis according to the major histo-
logical classification of the tumor and differed from
the traditional ‘differentiation grade’ according to
the 2004 WHO criteria.
26
Results
Clinical Characteristics
Clinical features including age, sex, race, smoking
status and stage are summarized according to
histological subtype in Table 3. Most patients were
female (63%) and stage IA (58%). Median age was
69 years (range: 33–89 years) and median tumor
size was 2.0 cm (range: 0.3–5 cm). In all, 301 tumors
(59%) were located in right lung and 213
tumors (41%) were located in left lung. One patient
Figure 2 Minimally invasive adenocarcinoma, non-mucinous. (a) This tumor consists of mostly lepidic growth but there is a large
subpleural scar with small foci of invasion at the edge of the scar. (b) At the edge of this scar are areas of invasive adenocarcinoma.
(c) These malignant glands infiltrate desmoplastic stroma.
Classification of lung adenocarcinoma
656 A Yoshizawa et al
Modern Pathology (2011) 24, 653664
Page 4
underwent pneumonectomy, 3 patients underwent
bilobectomy, 429 patients (83%) underwent lobect-
omy, 31 patients (6%) underwent segmentectomy
and 50 patients (10%) underwent wedge resection.
2004 WHO histological grade was well, mod erate
and poorly differentiated in 58 (11%), 287 (56%)
and 169 (33%) of cases. Necrosis and vascular
invasion were seen in 97 (19%) and 123 (24%) of
Figure 3 Patterns of invasive adenocarcinoma. (a) Lepidic, this tumor shows a non-mucinous lepidic pattern with crowded atypical
pneumocytes proliferating along the surface of slightly thickened alveolar walls. No invasion is seen. (b) Papillary, this tumor shows
a papillary pattern with cuboidal tumor cells growing along the surface of fibrovascular cores. (c) Acinar, this tumor is composed of
round to oval-shaped glands consisting of atypical epithelial cells showing nuclear hyperchromasia and prominent nucleoli.
(d) Micropapillary, this tumor shows glandular cells growing in small papillary tufts lacking fibrovascular cores. (e) Solid, this tumor is
composed of solid sheets of tumor cells.
Classification of lung adenocarcinoma
A Yoshizawa et al 657
Modern Pathology
(2011) 24, 653664
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the cases, respectively. Visceral pleural invasion
(PL1 or PL2) was seen in 103 cases (20%).
25
No patient received neoadjuvant therapy; adju-
vant chemotherapy and/or radiation therapy was
administered in 8 patients (2%) with unknown
adjuvant therapy status in 20 (4%).
Pathological Characteristics
The distribution of histological subtypes according
to the 2004 WHO and the IASLC/ATS/ERS classifi-
cations is summarized in Table 2. According to the
2004 WHO classification, 95% of the cases were
classified as mixed subtype. Only one tumor was
classified as non-mucinous BAC or adenocarcinoma
in situ according to the 2004 WHO and IAS LC/ATS/
ERS classifications, respectively.
According to the IASLC/ATS/ERS classification,
seven of the eight MIA cases were non-mucinous
and the eighth case with mucinous features also had
a minor non-mucinous component, but no cases of
mucinous adenocarcinoma in situ were seen in this
study. For the 29 lepidic predominant non-muci-
nous tumors, the percent lepidic growth averaged
55% (range: 40–90%) and in seven cases it was only
40%. For the 12 mucinous aden ocarcinomas,
the percent lepidic growth averaged 57% (range:
40–80%) and in two cases there was only 40%
lepidic growth, so there was 60% invasion.
The greatest impact of the adjustment of mean
tumor size from total gross measurement to mean
invasive tumor size (Table 3) was with MIA
(1.3–0.2 cm, 84% reduction), lepidic predominant
(2.3–1 cm, 57% reduction) and mucinous adenocar-
cinoma (2.5–1. 1 cm, 56% reduction).
After adjustment for the percentage of lepidic
growth, T-size factor status was downgraded from
T1b to T1a in 52 cases, from T2a to T1a in 9 cases
and from T2a to T1b in 11 cases. Thus T-factor status
was decreased in 72 patients (14%) of the total
cohort. When this method was used to determine
TNM staging, 3 of 25 cases that were excluded from
the total 539 cases would have been downstaged
from stage IIA to stage IB, However these cases were
not included in this study as they do not meet the
Union for International Cancer Control/American
Joint Committee on Cancer 7th Edition stage 1
criteria.
Survival Analysis
In all, 70 patients (14%) died of disease and 105
(21%) died of other causes or unknown cause during
the study follow-up. Of the remaining 320 (62%)
patients alive at the time of analysis, 12 had
recurrent disease, 4 were diagnosed with new lung
cancers and 304 had no evidence of disease. A total
of 89 patients recurred or died from disease,
counting as events in the disease-f ree survival
Figure 4 Mucinous adenocarcinoma. (a) This mucinous adenocarcinoma shows lepidic growth along the alveolar walls, and also
invasive acinar growth with penetration of fibrous stroma. (b) This area of the mucinous tumor shows an acinar pattern of invasion.
Figure 5 Colloid adenocarcinoma. This tumor consists of pools of
mucin filling air spaces with well-differentiated malignant glands
growing along the edges of the surrounding connective tissue.
Classification of lung adenocarcinoma
658 A Yoshizawa et al
Modern Pathology (2011) 24, 653664
Page 6
analysis. Median clinical follow-up was 4 years
(range: 0.02–13.3 years).
With 95% of the patients classified into mixed
group, the WHO classification did not provide a
useful stratification with respect to disease-free
survival (P ¼ 0.48).
According to disease-free survival, three overall
prognostic groups with low, intermediate and high-
grade clinical behavior were identified (Table 4,
Figure 6a and b). Low grade comprised of adeno-
carcinoma in situ (n ¼ 1) and MIA (n ¼ 8), both with
100% disease-free survival at 5 years. Inter-
mediate-grade tumors consisted of non-mucinous
lepidic predominant (n ¼ 29, disease-free survival at
5 yrs ¼ 90%), acinar predominant (n ¼ 232, disease-
free survival at 5 yrs ¼ 84%) and papillary predomi-
nant (n ¼ 143, disease-free survival at 5 yrs ¼ 83%)
adenocarcinomas. High-grade tumors included:
solid predominant (n ¼ 67, disease-free survival at
5 yrs ¼ 70%), micropapillary predominant (n ¼ 12,
disease-free survival at 5 yrs ¼ 67%), colloid predo-
minant (n ¼ 9, disease-free survival at 5 yrs ¼ 71%)
and invasive mucinous and mixed mucinous/
non-mucinous (n ¼ 13, disease-free survival at
5 yrs ¼ 76%).
There was no significant difference with respect
to disease-free survival between any two histo-
logical subtypes belonging to the same risk group.
Table 2 Adenocarcinoma subtypes by International Association for the Study of Lung Cancer, American Thoracic Society and European
Respiratory Society and 2004 World Health Organization classifications
IASLC/ATS/ERS Number (%) 2004 WHO Number (%)
NA Mixed subtype (MS) 490 (95)
Adenocarcinoma in situ 1 (0.2) BAC, non-mucinous 1 (0.2)
Minimally invasive adenocarcinoma, non-mucinous 7 (1.4) NA (included in mixed subtype) 0
MIA, mixed mucinous and non-mucinous 1 (0.2) NA (included in mixed subtype) 0
Invasive adenocarcinoma
Lepidic predominant 29 (5.6) NA (included in mixed subtype) 0
Acinar predominant 232 (45.1) Acinar 6 (1.2)
Papillary predominant 143 (27.8) Papillary 11 (2.1)
Micropapillary predominant 12 (2.3) NA 0
Solid predominant 67 (13) Solid 1 (0.2)
Variants
Invasive mucinous adenocarcinoma
(and mixed mucinous/non-mucinous)
13 (2.5) No pure M BAC (included in mixed subtype) 0
Colloid predominant 9 (1.8) Colloid 4 (0.8)
NA 0 Signet ring 1 (0.2)
Abbreviations: NA, not applicable; WHO, World Health Organization.
Table 3 Clinical features according to IASLC/ATS/ERS histological subtype
Histological subtype N
(%)
Mean
age yrs
(range)
Sex
(M/F)
Race
W/O
Smoking
C/F/N (MPY)
Stage
1A/B
Mean gross
size cm
(range)
Mean
invasive
size cm
(range)
AIS or MIA
a
9 68 (52–81) 4/5 6/3 0/8/1 (23) 9/0 1.3 (0.5–2) 0.2 (0–0.3)
Lepidic predominant 29 (5.6) 69 (43–84) 17/12 28/1 1/22/5 (19) 17/12 2.3 (0.9–4.6) 1 (0.3–2.8)
Acinar predominant 232 (45.1) 68 (33–89) 71/161 209/23 29/158/45 (36) 138/94 2.1 (0.3–5.0) 1.9 (0.3–5.0)
Papillary predominant 143 (27.8) 67 (42–87) 55/88 130/13 20/104/18 (46) 88/55 2.2 (0.7–5.0) 1.9 (0.6–5.0)
Micropapillary predominant 12 (2.3) 72 (61–86) 6/6 12/0 2/7/3 (38) 6/6 2.8 (1.5–5.0) 2.8 (1.5–5.0)
Solid predominant 67 (13) 66 (43–83) 29/38 62/5 15/50/1 (59) 28/39 2.5 (0.5–5.0) 2.5 (0.5–5.0)
Invasive mucinous and mixed
mucinous/non-mucinous
Adenocarcinoma
13 (2.5) 71 (54–85) 4/9 13/0 5/5/3 (37) 7/6 2.5 (0.5–3.6) 1.1 (0.3–1.8)
Colloid predominant 9 (1.8) 62 (49–77) 5/4 9/0 3/4/2 (38) 5/4 2.5 (1.3–5.0) 2.3 (1.0–5.0)
Total 514 68 (33–89) 191 (37%)/
323 (63%)
469 (91%)/
45 (9%)
75 (15%)/
358 (70%)/
78 (15%)
b
(41)
298
(58%)/
216
(42%)
2.2 (0.3–5.0) 1.9 (0–5.0)
Abbreviations: AIS, adenocarcinoma in situ; ATS, American Thoracic Society; C, current; ERS, European Respiratory Society; F, former;
IASLC, International Association for the Study of Lung Cancer; MIA, minimally invasive adenocarcinoma; MPY, mean pack years; N, never;
O, other; W, white.
a
This category includes: 1 AIS, 7 non-mucinous MIA and 1 mixed mucinous/non-mucinous MIA.
b
Three patients with unknown smoking status.
Classification of lung adenocarcinoma
A Yoshizawa et al 659
Modern Pathology
(2011) 24, 653664
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Considering this, as well as the small sampl es sizes
observed for most of the histological subtypes, we
further conducted survival analysis according to
low (n ¼ 9), intermediate (n ¼ 404) and high-grade
(n ¼ 101) groupings and found 5-year disease-free
survival of 100, 84 and 71%, respectively
(Po0.001). Table 5 summarizes the univariate
association between clinical factors and disease-free
survival. Higher stage (Po0.001), male gender
(P ¼ 0.008), necrosis (Po0.001), poor differentiation
(Po0.001) and vascular invasion (P ¼ 0.002) were all
associated with worse disease-free survival.
For overall survival, the three grading categories
determined by IASLC/ATS/ERS classification were
not significantly different (P ¼ 0.06) with respect to
overall survival, likely because of the low number of
patients, lack of events in the low-grade group and
death due to other causes. However, patients with
intermediate grade had significantly better overall
survival, compared with high-grade patients
(P ¼ 0.02).
According to the Union for International Cancer
Control/American Joint Committee on Cancer, TNM
classification, disease-free survival for patients with
T1a (r2 cm) tumors was significantly better com-
pared with that for T1b (42cm or r3 cm) tumors
Table 4 Survival according to IASLC/ATS/ERS adenocarcinoma
histological subtypes
IASLC/ATS/ERS classification
subtypes
Number
(%)
Disease-free
survival at 5 years
Low grade
Adenocarcinoma in situ 1 (0.2%) 100%
Minimally invasive
adenocarcinoma, non-mucinous
7 (1%) 100%
Minimally invasive
adenocarcinoma, mixed
mucinous and non-mucinous
1 (0.2%) 100%
Intermediate grade
Lepidic predominant 29 (6%) 90%
Acinar predominant 232 (45%) 84%
Papillary predominant 143 (28%) 83%
High grade
Micropapillary predominant 12 (2%) 67%
Solid predominant 67 (13%) 70%
Colloid predominant 9 (2%) 71%
Invasive mucinous
adenocarcinoma, mixed
mucinous/non-mucinous
13 (3%) 76%
Abbreviations: ATS, American Thoracic Society; ERS, European
Respiratory Society; IASLC, International Association for the Study of
Lung Cancer.
Disease-free survival estimates (1-CIF or cumulative index function)
are calculated based on the competing risk analysis.
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
AIS,MIA (n=9)
DFS at 5 yr (%)
P<0.001
Low grade (n=9)
Intermediate grade (n=404)
High grade (n=101)
DFS at 5 yr (%)
100
84
71
100
90
83
84
76
71
70
67
012345678910
0
1
2
34
5678910
012345678910
Years after surgery
Years since sur
g
er
y
Years after surgery
Lepidic (n=29)
PAP (n=143)
Acinar (n=232)
Mucinous (n=13)
Colloid (n=9)
Solid (n=67)
MPAP (n=12)
0.2
0.1
0.0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
p(overall) = 0.06
p(Intermediate grade vs High grade) = 0.02
High grade
Deaths/No patients OS at 5 years
61%
75%
74%
46/101
129/404
3/9
Intermediate grade
Low grade
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Probability of Recurrence of DOD
Probability of DFS
Probability of OS
Figure 6 (a) Disease-free survival (DFS) for all histological categories (Po0.001). The favorable group includes adenocarcinoma in situ
(AIS) and minimally invasive adenocarcinomas (MIA) with 100% 5-year disease-free survival. Disease-free survival for the intermediate
group was 90, 83 and 84% for lepidic predominant, papillary (PAP) predominant and acinar predominant, and adenocarcinomas,
respectively. Disease-free survival for the unfavorable group was 70, 67, 71 and 76% for solid predominant, micropapillary (MPAP)
predominant colloid predominant, and mucinous and mixed adenocarcinomas, respectively. (b) Disease-free survival according to
combined histological groupings according to low, intermediate and high-grade clinical aggressiveness. (c) Overall survival (OS)
according to combined histological groupings according to low, intermediate and high-grade clinical aggressiveness.
Classification of lung adenocarcinoma
660 A Yoshizawa et al
Modern Pathology (2011) 24, 653664
Page 8
(P ¼ 0.04; Figure 7a), and the difference became even
more pronounced when size was adjusted for the
amount of invasive size (Po0.001, Figure 7b).
Cox Regression
A multivariate analysis adjusting for gender, stage,
tumor size, differentiation, presence of necrosis and
of vascular invasion indicated that histological
grading remained significantly associated with
disease-free survival (Table 6), with patients in the
high-risk grou p having an increased risk of death,
compared with the intermediate/low-risk group and
to the intermediate-risk group alone (HR ¼ 1.68,
95% CI: 1.03–2.75, P ¼ 0.038, for both comparisons).
Other independent predictors of an increased risk of
death of disease or recurrence were: male gender
(HR ¼ 1.8, P ¼ 0.007), tumor size adjusted for lepidic
growth (HR ¼ 1.3, P ¼ 0.026) and tumor necrosis
(HR ¼ 1.5, P ¼ 0.00 2).
Discussion
Our data show the proposed IASLC/ATS/ERS
classification identifies histological subsets of lung
Table 5 Association between clinical factors and disease-free
survival
Factor Number (%) 5-year DFS P-value
Stage
IA 298 (58%) 88% o0.001
IB 216 (42%) 74%
Sex
Female 323 (63%) 86% 0.008
Male 191 (37%) 76%
Grade
Well/moderate 345 (67%) 87% o0.001
Poor 169 (33%) 72%
Necrosis
No 416 (81%) 87% o0.001
Yes 97 (19%) 63%
Visceral pleural invasion
PL0&1 411 (80%) 83% 0.09
PL2 103 (20%) 77%
Vascular invasion
No 391 (76%) 85% 0.002
Yes 123 (24%) 74%
Race
White 469 (91%) 82% 0.97
Other 45 (9%) 82%
Ever smoker
No 78 (15%) 90% 0.07
Yes 433 (84%) 81%
Abbreviation: DFS, disease-free survival.
DFS estimates (1-CIF or cumulative index function) are calculated
based on the competing risk analysis.
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
012345
67
10
Years after surgery
98
012
3
4
567 10
Years after surgery
98
T1a (n=259)
T1b (n=152)
DFS at 5 years
p=0.04
p <0.001
88%
80%
T1a (n=320)
T1b (n=111)
DFS at 5 years
88%
73%
Probability of DFS
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Probability of DFS
Figure 7 Disease-free survival (DFS) comparing T1a (r2cm)
versus T1b (42cm or r3 cm). (a) T1a and T1b defined according
to gross tumor size (P ¼ 0.04). (b) T1a and T1b defined according
to invasive size (Po0.001).
Table 6 Multivariate survival analysis for disease-free survival
Factor HR (95% CI) P-value
Tumor grade by IASLC/ATS/ERS
classification (high versus
intermediate/low)
1.7 (1.03–2.75) 0.038
Gender (male versus female) 1.79 (1.17–2.74) 0.007
Stage (IB versus IA) 1.40 (0.84–2.33) 0.19
Tumor size
a
1.29 (1.03–1.62) 0.026
2004 WHO histological grade
(poor versus moderate/well)
1.05 (0.62–1.78) 0.86
Necrosis (yes versus no) 2.15 (1.32–3.50) 0.002
Vascular invasion (yes versus no) 1.49 (0.95–2.34) 0.085
Abbreviations: ATS, American Thoracic Society; ERS, European
Respiratory Society; IASLC, International Association for the Study
of Lung Cancer; WHO, World Health Organization.
a
Adjusted for percentage of lepidic growth.
Classification of lung adenocarcinoma
A Yoshizawa et al 661
Modern Pathology
(2011) 24, 653664
Page 9
adenocarcinoma with significant differences in
prognosis. As patients with surgically resected stage I
non-small cell lung cancer have survivals of 73%
for stage IA and 58% for stage IB,
27
there is a great
need to predict which patients will recur in ord er to
develop strategies for choosing which patients
may benefit by adjuvant therapy. In our stage I lung
adenocarcinomas we found the histological sub-
types proposed according to the new classification
fell into three major prognostic categor ies or grades
of behavior. Two categories (adenocarcinoma in situ
and MIA) had 100% 5-year disease-free survival. In
the future, such patients may represent candidates
for limited surgical resection; however, it can be
very difficult for a pathologist to exclude invasion
on the basis of frozen section and the role of frozen
section in this setting still needs to be defined.
8
Lepidic, acinar and papillary predominant adeno-
carcinomas had an intermediate clinical behavior
with 5-year disease-free survival between 83 and
90%. Finally, a poor prognostic group consisted of
the four categories solid, micropapillary, and colloid
predominant as well as invasi ve mucinous adeno-
carcinoma with 5-year disease-free survival between
67 and 76%. Not only do these histological subtypes
fall into overall pr ognostic categories or grades
of behavior as we demon strate in this study, but
Sica G et al have shown that the detailed data
derived from comprehensive histological subtyping
appear to be useful for developing a more elaborate
grading system for lung adenocarcinoma according
to tumor architecture.
24
In our series, the adenocarcinoma in situ and MIA
cases comprised less than 2%, the 29 lepidic
predominant adenocarcinomas, comp rised 5.6%,
and the remaining 93% of cases represented
predominantly invasive adenocarcinomas. These
predominantly invasive adenocarcinomas, comprise
the largest subset of tumors and presented the
greatest challenge of this new classification because
they are composed of a complex heterogeneous
mixture of the different histological patterns. By
using the method of comprehensive histological
subtyping,
4
we were able to classify the tumors
according to the predominant subtype and identify
prognostically significant categories.
Our data also confirm that cases previously
classified as BAC now fall into five different entities
in the new IASLC/ATS/ERS classification including
(1) adenocarci noma in situ, (2) MIA, (3) lepidic
predominant adenocarcinoma, (4) other invasive
adenocarcinomas with lepidic component (this
includes patients with adv anced lung adenocarci-
noma, although these cases were excluded from this
study) and (5) mucinous adenocarcinoma. The
widely varying clinical behavior of the different
categories observed in this study supports the
rationale in the new classification for discontinuing
use of the term BAC.
The poor prognostic group of solid, micropapil-
lary, invasive mucinous adenocarcinoma and
colloid predominant subtypes are important because
patients with these tumors may be candidates for
adjuvant therapy. There is a growing amount of data
confirming that the solid subtype correlates with
poor prognosis including a study from our group in
a different data set
4
and data from other investiga-
tors.
28,29
The adverse prognosis associated with the
micropapillary pattern, confirms observations in
multiple previous studies and supports the addition
of this new subtype to the classification.
10,11,30–33
However, varied criteria for the diagnosis have been
used with percentage of the micropapillary compo-
nent including as little as 6% of the total tumor and
none of these studies have utilized comprehensive
histological subtyping to define this subgroup
according to the predominant subtype showing
comparison with survival of the other histological
subtypes as we have done.
10,11,30–33
Our finding that
colloid adenocarcinomas also fit into this poor
prognostic group was somewhat surp rising as these
tumors are often regarded as well-differentiated
tumors, but this is the largest series of these tumors
reported where survival analysis compared outcome
with other adenocarcinoma histological types.
Furthermore, no previous studies have ever define d
colloid adenocarcinomas according to the predomi-
nant subtype.
One of the most significant changes in the new
classification is separation of the previous mucinous
BACs into a separate category called invasi ve
mucinous adenocarcinoma. This is based not only
on the different histological appearance, but the
frequent presentation with multiple nodules, lobar
consolidation, multilobar and/or bilateral lung
involvement and frequent KRAS mutations com-
pared with EGFR mutations.
8
Worse survival
for tumors formerly classified as mucinous BAC
compared with those formerly classified as non-
mucinous BAC has been suggested.
18,34–36
However,
the data are limited, other studies have not shown a
significant survival difference,
37
and the histological
criteria have evolved over time.
26
The latter problem
complicates interpretation of the literature on this
topic. Our finding that invasive mucinous adeno-
carcinoma fits with the high-grade clinical behavior
is consistent with the previous literature suggesting
an aggressive clinical course for these tumors.
34,35,38
This is consistent with our finding in this study that
most tumors previously classified as mucinous
BACs actually show invasive growth rather than a
pure lepidic pattern.
Our data also raise the question whether T-factor
staging for tumor size should be based only on the
invasive component rather than total tumor size, in
a manner similar to breast cancer wherein the size of
the in situ component is not included in T-factor
staging.
39
This new way of thinking was a direct
result of introduction of the concept of adenocarci-
noma in situ for smal l solitary lung adenocarcino-
mas with pure lepidic growth. Despite the slightly
stronger association with survival for invasi ve size
Classification of lung adenocarcinoma
662 A Yoshizawa et al
Modern Pathology (2011) 24, 653664
Page 10
versus gross size (P ¼ 0.001 versus 0.04), in our
data set, both approaches appeared to demonst rate
prognostic signifi cance for survival. The potential
for this to impact staging for small lung adenocarci-
nomas needs furth er evaluation to see whether this
could impact the next revision of TNM staging.
Another implication for staging is to use the term
Tis (adenocarcinoma) in distinction from Tis (squa-
mous) for lung cancer that meet criteria for adeno-
carcinoma in situ, just as in breast cancer Tis (ductal
carcinoma in situ) and Tis (lobular carcinoma
in situ).
39
Regarding MIA, again similar to breast
cancer, a new category of Tmi may be introduced for
lung adenocarcinomas that meet criteria for this
new proposed category.
39
As the 7th edition of the
Union for International Cancer Control/American
Joint Committee on Cancer staging system was just
recently publ ished,
22,23
these topics will need to be
the focus of investigation for the next 5 years so that
sufficient validated data is available to determine
which changes need to be made in the 8th edition of
the TNM classification for lung adenocarcinoma
staging.
Another observation in our study was that
disease-free survival was more informative than
overall survival in predicting outcome in these stage I
adenocarcinomas. Overall survival is the method of
survival analysis utilized in most lung cancer
studies. This is because the high mortality of lung
cancer diminishes the impact of the small percen-
tage of patients who die of other causes. However,
in tumor populations such as our series of stage I
adenocarcinomas, where there is a high percentage
of deaths not related to tumor, disease-free survival
more accurately reflects the biological behavior of
the tumors.
In summary, our study of stage I lung ad enocarci-
nomas demonstrates the new IASLC/ATS/ERS
classification identifies prognostically significant
histological subtypes of lung adenocarcinomas
including the low-grade adenocarcinoma in situ
and MIA and the intermediate grade lepidic
predominant, acinar and papillary adenocarcino-
mas. High-grade adenocarcinoma subtypes included
solid, micropapillary, invasiv e mucinous adenocar-
cinoma and colloid predominant adenocarcinomas.
Thus histological subtyping of adenocarcinomas
is a potential a way to stratify patients with stage
I tumors for adjuvant therapy.
Acknowledgement
We gratefully acknowledge the assistance of Kei
Suzuki and Kyuichi Kadota in analyzing the pleura
for visceral pleural invasion.
Disclosure/conflict of interest
The authors declare no conflict of interest.
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  • Source
    • "The strong prognostic effect of CCP score, which is a quantitative and clinical laboratory independent measure of risk, supports the use of this RNA-based expression assay as an adjunct to conventional pathological features. A major limitation of the IASLC/ATS/ERS classification is that the majority (40%–70%) of cases of stage I lung ADC are intermediate-grade ACI and PAP subtypes [3, 10, 13, 14]. In an attempt to identify a high-risk group among patients with ACI and PAP subtype tumors, we and others have reported that high mitotic counts [22], presence of the cribriform pattern [4], lack of thyroid transcription factor–1 expression [23], immunoinhibitory tumor microenvironment [8], and nuclear estrogen receptor–α expression [24] are indicative of poor prognosis. "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose: The goals of our study were (a) to validate a molecular expression signature (cell cycle progression [CCP] score and molecular prognostic score [mPS; combination of CCP and pathological stage {IA or IB}]) that identifies stage I lung adenocarcinoma (ADC) patients with a higher risk of cancer-specific death following curative-intent surgical resection, and (b) to determine whether mPS stratifies prognosis within stage I lung ADC histological subtypes. Methods: Formalin-fixed, paraffin-embedded stage I lung ADC tumor samples from 1200 patients were analyzed for 31 proliferation genes by quantitative RT-PCR. Prognostic discrimination of CCP score and mPS was assessed by Cox proportional hazards regression, using 5-year lung cancer-specific mortality as the primary outcome. Results: In multivariable analysis, CCP score was a prognostic marker for 5-year lung cancer-specific mortality (HR=1.6 per interquartile range; 95% CI, 1.14-2.24; P=0.006). In a multivariable model that included mPS instead of CCP, mPS was a significant prognostic marker for 5-year lung cancer-specific mortality (HR=1.77; 95% CI, 1.18-2.66; P=0.006). Five-year lung cancer-specific survival differed between low-risk and high-risk mPS groups (96% vs 81%; P<0.001). In patients with intermediate-grade lung ADC of acinar and papillary subtypes, high mPS was associated with worse 5-year lung cancer-specific survival (P<0.001 and 0.015, respectively), compared with low mPS. Conclusion: This study validates CCP score and mPS as independent prognostic markers for lung cancer-specific mortality and provides quantitative risk assessment, independent of known high-risk features, for stage I lung ADC patients treated with surgery alone.
    Full-text · Article · May 2016 · Oncotarget
  • Source
    • "More studies are needed to validate the methods used to measure the pathological tumor size. Lymphatic or vascular invasion has often been reported as being independently associated with a worse prognosis of early-stage NSCLC [6,10,23]. In our study, lymphatic or vascular invasion was observed in 21.9% of clinical stage IA ADCs. "
    [Show abstract] [Hide abstract] ABSTRACT: We analyzed and validated the prognostic utility of the new International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) for clinical stage IA lung adenocarcinoma (ADC) classification of adenocarcinoma (ADC). We retrospectively reviewed 347 patients with clinical stage IA nonmucinous ADC, who had undergone complete resection. The histological subtype was classified according to the predominant subtype, as proposed by the new IASLC/ATS/ERS ADC classification. The histopathological subtypes, defined according to the new IASLC/ATS/ERS ADC classification, were ADC in situ (AIS) in 56 patients (16.1%), minimally invasive ADC (MIA) in 15 (4.3%), lepidic-predominant ADC in 109 (31.4%), papillary-predominant ADC in 70 (20.2%), acinar-predominant ADC in 61 (17.6%), solid-predominant ADC in 30 (8.6%), and micropapillary-predominant ADC in 6 (1.7%). The 5-year disease-free survival (DFS) rate was 100% for both AIS and MIA. All cases of recurrence involved invasive ADC. The 5-year DFS for lepidic-predominant ADC was 99.0%; acinar-predominant ADC, 82.4%; papillary-predominant ADC, 80.8%; solid-predominant ADC, 73.6%; and micropapillary-predominant ADC, 33.3%. The predominant subtype of ADC was significantly correlated with DFS (P<0.0001). Multivariate analysis indicated that the pathological stage was an independent predictor of DFS (P=0.031). Other independent predictors of increased risk of recurrence were the presence of vascular or lymphatic invasion (HR=4.96, P=0.001), and a pathological stage more advanced than IB (HR=2.87, P=0.010). The coincidence between the clinical stage and pathological stage was 79.8%. The stage migration was found in 53.3% of solid-predominat ADC and in 83.3% of micropapillary-predominant ADC. The new IASLC/ATS/ERS ADC classification has prognostic value in predicting the recurrence and survival of patients with clinical stage IA ADC. The frequency of stage migration was found in more than half of solid and micropapillary predominant ADCs. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Jul 2015 · Lung cancer (Amsterdam, Netherlands)
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    • "In February 2011, Travis et al. reported, on behalf of multiple multidisciplinary agencies, a revised classification of lung carcinoma, recognizing new subtypes like lepidic and micropapillary (MPP) [11,12]. The micropapillary pattern in lung adenocarcinoma, characterized by papillary structures with epithelial tufts lacking a central fibrovascular core, has been reported to be a new pathological marker of poor prognosis [13] classification of lung adenocarcinoma, lepidic, acinar and papillary adenocarcinomas had an intermediate clinical behavior, with 83 -90% survival at 5-year, without specific symptoms [12]. It is obvious that evolution of the disease in our case was with at least few years ago, but in context of immunodepression wasn't recognised in due time. "
    [Show abstract] [Hide abstract] ABSTRACT: Even though there are many similarities in symptoms and radiological aspect between pulmonary tuberculosis (TB) and lung neoplasia, there are many differences between them like different etiologies, different consequences, and altogether different management. We present a case of a 59 years old male, heterosexual, who was HIV diagnosed in the last 16 years. He had a good immunological and virusological evolution over the time. In the last 5 months of his life he was diagnosed with pulmonary TB and he received specific treatment. After 4 months of antituberculous treatment patient became asthenic, febrile, with productive cough, and weight loss. Imagistic evolution was unfavorable. The suspicion of pulmonary neoplasm raises in the last 3 weeks of his life. Macroscopic lung examination during autopsy was suggestive rather to a pulmonary TB than a lung neoplasm, with a nodular pattern very similar with nodular TB. Histopathological examination evidenced a lung adenocarcinoma. In HIV patients a delayed or missed diagnosis of lung cancer, can lead to late treatment or wrong treatments, and finally death of patient.
    Full-text · Article · Jun 2015
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