METAPLASIA OF BRONCHIAL EPITHELIUM
A
POSTMORTEM STUDY
RUSSELL W. WELLER, M.D.
WITH THE TECHNICAL ASSISTANCE OF ELEANOR HTJRSHMAN,
B.S.
Department of Pathology, Hahnemann Medical College and Hospital,
Philadelphia, Pennsylvania
Squamous metaplasia of bronchial epithelium is commonly seen in various
pathologic processes, apparently as a result of atypical epithelial regeneration.
Virchow19 was first to describe metaplasia in 1884. He stated that metaplasia was
a direct transformation of one well-characterized tissue into another equally well
characterized, but morphologically and functionally different tissue. Within the
next few years it became generally agreed that the metaplastic tissue actually
arose from the undifferentiated basal cells of the bronchus. The pluripotential
qualities of the basal cells, including the capacity of neoplastic growth, were
first theorized by Hansemann 5 and Ribbert.13
Schridde14 demonstrated that the esophagus and bronchi in the earlier stages
of development are lined by a single layer of cuboidal cells. These gradually are
doubled, and by the tenth week goblet cells and ciliated columnar epithelial
cells are present. In the bronchi, development stops at this time; but in the
esophagus, the cells degenerate, desquamate and are replaced by transitional
and finally by stratified squamous epithelium. Schridde assumed that when the
bronchus was involved in a pathologic process its regenerative attempts progressed to the same stage that the esophagus attains in the embryo.
Pagel10 called attention, in 1927, to bronchial epithelial metaplasia in bronchiectasis. He believed that this metaplasia was a transitional stage to cancer.
Fried 2 and Weller20 • 21 reported cases of carcinoma of the lungs in which they
thought there was evidence that the disease resulted from excessive epithelial
regeneration following chronic inflammation of the bronchi. Stewart and Allison16
described a microscopic "oat-cell" carcinoma in a surgically removed lung that
they believed was primarily bronchiectatic. The point of origin was not established. In 39 cases of bronchial carcinoma Lindberg 7 ' 8 found 38 per cent with
metaplastic epithelium. He stressed the fact that all cases with metaplastic
epithelium were squamous-cell carcinomas. Womack and Graham 23 described 3
patients with congenital cystic disease of the lung and highly atypical metaplasia, which they apparently suspected to be early neoplasms. Dibenzanthracene,9 which produces lung tumors in rats, often produces an accompanying
epithelial metaplasia.
Many observers have noted squamous metaplasia following various diseases
such as measles,4 diphtheria, 4 pertussis,15 and influenza.1'17 Experimentally,
metaplasia has also been produced in animals following the introduction of such
Received for publication February 11, 1953.
Dr. Weller is Assistant Professor of Pathology.
768
32
16
64
48
80
96,
112
128
TOTAL NUMBER AUTOPSIES STUDIED
D
P
O
P
FEMALES
MALES
H
Metaplasia
I
Transitional
s
Squamous
I Dormant
Proliferative
F I G . 1. Incidence of metaplasia including cytologic morphology and activity, age and
sex of patients. The top portion of chart depicts general incidence of metaplasia in the
total series of autopsies along with breakdown into transitional and squamous epithelial
types and subdivision of these types into dormant, and proliferative groupings according
to criteria of growth described in text of paper. The middle portion shows almost equal
incidence of metaplasia in younger adult and older adult groups. T h e lower portion emphasizes the higher incidence of metaplasia in males.
16
32
48
64
80
96
112
128
No chronic inflammatory or neoplastic disease
Chronic respiratory
inflammation
(active or healed)
I
Primary
lung
carcinoma
71%
I
Metaplasia
F I G . 2. Incidence of bronchial metaplasia in normal lungs and in inflammatory and neoplastic disease. Chart shows higher incidence of bronchial metaplasia in chronic inflammatory and neoplastic pulmonary disease than in lungs where the diseases are absent. The
small number of primary lung tumors renders this group questionably significant.
769
770
WELLER
materials as formalin,3 benzpyrene,18 and Aludrin. 6 Wolbach's22 observation of
squamous metaplasia in the respiratory tracts of rats fed a vitamin A-deficient
diet is also well appreciated.
The author's interest in bronchial epithelial metaplasia was aroused by the
frequent findings of cytologic atypicality in metaplastic bronchial epithelium of
lungs surgically removed and at autopsy. This observation gave rise to the
thought that careful systematic study of bronchi at autopsy might afford some
insight into the pathogenesis of pulmonary neoplasms. Peterson and his associates,12 apparently thinking along the same lines, described 5 minute bronchogenic neoplasms in a study of lung sections from routine autopsies. Three of the
photomicrographs presented by the latter authors were not demonstrative of
16
32
48
64
80
96
112
128
Trachea, larger
and smaller bronchi
Large
Larger bronchi
( 1 0 - 2 0 mm)
B9
Smaller
(2-7
bronchi
mm)
•
Metaplasia
F I G . 3. Incidence of metaplasia in various-sized bronchi. C h a r t reveals higher incidence
of metaplasia in larger bronchi alone, and in larger and smaller bronchi simultaneously, t h a n
in smaller bronchi alone.
convincingly malignant tumors to this writer. The recent reports of a "carcinoma
in situ" by Papanicolaou and Koprowska11 appear to this writer to be based on
rather controversial evidence, if the photomicrographs presented by the authors
are truly illustrative of the tumors. In the bronchi that are described as "proliferative" in this paper, at least 2 cases present a microscopic picture resembling
the lesion described by Papanicolaou and Koprowska.
The incidence of metaplasia in an unselected group of lungs removed at autopsy, and a •correlation of metaplasia with anatomic location, age, sex, chronic
pulmonary inflammation and primary lung cancer were determined in the following manner. From each of 128 unselected autopsies of persons ranging in
age from newborn to 86 years, 21 representative sections of the trachea and the
large and small bronchi were dissected (Fig. 4). It was found that this number of
sections from each autopsy produced a fairly representative study of the tracheo-
METAPLASIA OF BRONCHIAL EPITHELIUM
771
bronchial tree. The large bronchi are defined as those ranging from 10 to 20 mm.
in diameter, and this group included the section taken from the trachea just
proximal to the carina. The small bronchi are those ranging from 2 to 7 mm. in
diameter. These sections were dissected either from fresh or formalin-fixed
lungs.
In order to avoid confusion it is necessary to define sharply the descriptive
terms used. The term squamous metaplasia indicates a change to stratified
squamous epithelium. Transitional metaplasia indicates a change to stratified
epithelium consisting of slightly irregular cuboidal and occasional low columnar
F I G . 4. Sketch of tracheobronchial tree with darkened areas
representing sections cut for study.
cells 4 to 7 layers thick, with no intercellular bridges. During this study it was
found that the metaplastic epithelium varied greatly from well-differentiated
squamous or transitional to atypical metaplastic epithelium, with increased
numbers of undifferentiated basal cells, frequent mitotic figures, focal epithelial
downgrowth and variations in nuclear size, staining and polarity. When such
active growth characteristics are present the squamous or transitional metaplasia is termed proliferative (Figs. 5 and 6). If this growth activity is absent the
term dormant is employed (Figs. 7 and 8).
In the 128 autopsies, 41 cases revealed metaplastic epithelium, representing
a general incidence of 32 per cent. Sixteen of these cases were of squamous type
772
WELLER
and 25 were of transitional type (Fig. 1). The cellular activity in the metaplastic
epithelium was almost equally divided between proliferative and dormant types,
there being 21 cases of proliferative epithelial metaplasia and 20 cases of dormant
metaplasia. However, in the 16 cases of squamous metaplasia, 12 or 75 per cent
were of the proliferative type, whereas the 25 cases of transitional metaplasia
revealed only 9 or 36 per cent of the apparently more rapidly growing, atypical,
proliferative epithelium (Fig. 1). One might assume from these figures that
atypical proliferative activity is definitely more common in true squamous metaplasia than in transitional metaplasia.
As noted by previous observers,9 metaplasia was most commonly seen in the
lower trachea and in the large and small bronchi (39 per cent), whereas there was
definitely a lower incidence of metaplasia limited to the small bronchi (24 per
cent) (Fig. 3). In many cases metaplastic epithelium extended into the ducts of
the bronchial glands and often the mucoid columnar epithelium of the gland
itself was metaplastic, thereby resembling the metaplastic changes commonly
seen in the cervix uteri.
In the 6 autopsies performed on infants under 2 years of age, no metaplasia
was found. In the 13- to 40-year age group, with 18 cases, 7 or 39 per cent revealed metaplasia. In the 41- to 86-year age group, representing 104 autopsies,
34 or 33 per cent revealed metaplasia (Fig. 1). These figures seem to indicate that
metaplasia appears at least as frequently in the young to middle age groups as it
does in the older age group. Metaplasia appears to be much more frequent in
men, appearing in 36 per cent of the autopsies of males compared to 20 per cent
among the female (Fig. 1). Niskanen9 found no appreciable difference in the
sex incidence of metaplasia.
In patients with no inflammatory or neoplastic disease there was a 23 per cent
incidence of metaplasia (Fig. 2). In chronic inflammatory disease of the lungs 41
per cent of our cases revealed metaplastic epithelium. This figure agrees fairly
well with the 50 per cent incidence found by Niskanen.9 In primary lung cancer,
71 per cent of our 7 cases revealed metaplasia compared to a 2.5 per cent incidence in Niskanen's series and 38 per cent in Lindberg's study.7 • 8
We were unable to demonstrate a single metaplastic focus that could be called
premalignant, carcinoma in situ, or minute carcinoma. Any pathogenetic correlation between bronchial epithelial metaplasia and neoplasms is to this writer
highly speculative. The increased incidence of metaplasia in primary lung cancer,
in chronic inflammation and in males may well be secondary epithelial response
to a primary disease.
SUMMARY AND
CONCLUSIONS
A study of bronchial epithelium in postmortem lungs was undertaken in an
unselected group of cases ranging in age from stillborn to 86 years. The general
F I G . 5 (left upper). Squamous metaplasia, proliferative type, with mitoses and nuclear
atypicality. X 430.
F I G . 6 (left lower). Transitional metaplasia, proliferative type, with nuclear atypicalities.
F I G . 7 (right upper). Squamous metaplasia, dormant type, with nonmetaplastic epithelium at right. X 100.
F I G . 8 (right lower). Transitional metaplasia, dormant type, with normal bronchial epithelium a t top. X 100.
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"WELLER
incidence of metaplasia was 32 per cent. Metaplasias were classified either as
transitional or squamous and subclassified as dormant or proliferative. There was
no great variation in the incidence of squamous metaplasia between younger to
middle age and older age groups.
The highest incidence of metaplasia (71 per cent) was found in patients with
primary lung carcinoma. The next highest incidence (41 per cent) was found in
patients with chronic inflammatory disease of the lungs. The incidence in males
was 36 per cent as compared with 20 per cent in females.
In no instance was epithelium noted that convincingly appeared to be undergoing, or to have undergone, neoplastic change.
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