Squamous Metaplasia: Indicator of Acute Exacerbation and
Poor Prognostic Factor in Usual Interstitial Pneumonia
Masatake Hara, Mikiko Hashisako, Yasuhiko Yamano, Takeshi Johkoh, Yasuhiro Kondoh, Hiroyuki Taniguchi, Junya Fukuoka
Nagasaki University, Nagasaki Educational and Diagnostic Center of Pathology (NEDCP), Tosei General Hospital, Kinki Central Hospital
Results
If a histologic predictive marker is identifiable by pathologists, pathologists can give
a warning of future AE occurrence, then clinician may change the way of follow-up
for their patients. We reviewed cases of UIP to find indicators which could predict
AE.
Event-free survival
Acute Exacerbation (AE) is a lethal factor in patients with usual interstitial
pneumonia (UIP). Some reports have suggested clinical features that predict AE
such as body mass index (BMI), modified Medical Research Council scale, forced
vital capacity (FVC)1, and Krebs von den Lungen-6 (KL-6)2. However, pathologic
indicators that predict AE are still unknown at present.
C
B
A
C
Squamous
metaplasia (-)
Squamous
metaplasia (+)
Days
Figure 3. Event (AE) free survival in UIP patients
with and without squamous metaplasia
Consecutive 284 cases of VATS
from 2009 to 2012
Excluded 174 cases because of
other histological patterns
110 case of definite or
E
D
Excluded 19 cases with definite
connective tissue disease or
hypersensitive pneumonia
91 cases
Methods
Histologic candidates for the predictive marker of AE were mostly selected based
on the characteristic findings as seen in cases of acute lung injury (ALI)3, and
reported prognostic marker of UIP4.
The 12 histologic candidates are stated below.
Organizing pneumonia focus
Epithelial denudation
Fibrin
Type II pneumocytes
Kuhn’s hyaline
Interlobular septal widening
Edema (air space)
Neutrophilic infiltration
Edema (interstitium)
Alveolar hemorrhage
Squamous metaplasia
Fibroblastic focus
Two observers graded each of the 12 histologic candidates into scores of 0 to 3
and classified them into negative (0) or positive (1, 2, 3). The consensus were
obtained afterwards by discussion which also included another pathologist.
Clinical data such as smoking status, BMI, pulmonary function test, serological
markers of interstitial pneumonia, and patients’ status with follow-up term were
also collected.
The judgement of AE was given by experienced pulmonologists based on the
criteria in Japan.5
Association between the classifications of each candidates and AE was
investigated using Fisher’s exact test and logistic regression.
Survival analysis was performed by log rank test. Kaplan-Meier curves were also
plotted.
IHC: CK14/p40
Figure 1. Squamous metaplasia
A) Squamous metaplasia in microscopic honeycombing (circle).
B) Squamous metaplasia (circle) beside a fibroblastic focus (arrow head).
C) Squamous metaplasia covering alveolar septal walls (circle).
D) Classical squamous metaplasia.
E,F) Squamous metaplasia, H&E (E) and Immunohistochemistry for CK14 and p40 (F).
Age (y.o.)
Male : Female
Smoking history
Current or ex-smoker
Never smoker
BMI
%VC (%)
%FEV1.0 (%)
%FVC (%)
%DLCO (%)
PaO2 (Torr)
LDH (IU/L)
KL-6 (U/mL)
SP-D (ng/mL)
Death (n)
AE (n=20)
67.0 ± 6.2
14 (70%) : 6 (30%)
Non AE (n=71)
63.4 ± 7.0
52 (73%) : 19 (27%)
10 (50%)
10 (50%)
25.2 ± 3.6
73.3 ± 13.9
84.6 ± 14.1
72.6 ± 14.2
52.1 ± 13.6
74.7 ± 8.98
264 ± 53.8
1619 ± 1088
375 ± 310
15 (75%)
55 (77%)
16 (23%)
23.9 ± 3.0
92.3 ± 21.0
98.4 ± 20.5
91.5 ± 21.5
64.7 ± 20.3
84.5 ± 12.1
241 ± 157
1326 ± 1209
273 ± 219
23 (32%)
p-value
<.05
NS
<.05
NS
<.01
<.01
<.01
<.01
<.01
<.01
<.05
NS
<.01
• During the median follow-up of 40 months, 20 cases developed
AE.
• 38 patients were dead. Mortality was 75% (15/20) in AE and 32%
(23/71) in non-AE.
AE (n=20)
Non-AE (n=71)
Squamous metaplasia (+)
18
42
Squamous metaplasia (-)
2
29
Table 2. Sensitivity and specificity of squamous metaplasia
Days from Surgical lung biopsy
• Sensitivity is 0.90 and specificity is 0.41.
Figure 2. Cumulative incidence of AE
Contact Information: [email protected]
Days
Figure 4. Kaplan-Meier overall survival in UIP
patients with and without squamous metaplasia
• A median duration until the onset of AE was 497 days (4-2139 days) (Figure 2).
• Histologically, squamous metaplasia showed positive association to the event of AE
(RR was 4.65 [1.36, 17.7], p=0.015).
• Fibroblastic foci, known as poor prognostic factor in UIP, did not associate with AE (p=0.34).
• Squamous metaplasia was associated with a worse event free survival in UIP patients (p=0.035)
(Figure 3).
• Cases with squamous metaplasia showed significant worse prognosis compared to those without
squamous metaplasia (p=0.049) (Figure 4).
Discussion
Table 1. Patient characteristics
Cumulative probability
probable UIP pattern
F
Squamous
metaplasia (+)
log-rank p=0.049
log-rank p=0.035
Objectives
Squamous
metaplasia (-)
Overall Survival
Background
• This study suggest that squamous metaplasia is a histologic predictive marker of AE first time
ever.
• Why didn’t other characteristic findings for ALI associate with AE? It may be because ALI itself is
not a trigger for AE. However, if epithelial injury generally causes squamous metaplasia6, can
severe epithelial injury of UIP be reflected as squamous metaplasia?
• There are some ways to apply these results to clinical practice. For example, clinicians can pay a
careful attention to emerging ground-glass opacity on CT in follow-up term. These results suggest
that pathologists have great potential to contribute to the clinical practice of interstitial pneumonia.
• The limitations are that patient number was small and the study was retrospective. It is necessary
to collect more cases and validate data prospectively.
Conclusion
We found that squamous metaplasia in UIP could predict an acute exacerbation and a poorer
prognosis.
References
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