Evaluation of the Interstitial Histological Lesions in Pulmonary Langerhans Cell Histiocytosis
Halide Nur URER1, Hatice DINCER2
1Department of Pathology, 1University of Health Sciences Turkey, Haseki Training and Research Hospital, ISTANBUL, TURKEY
2University of Health Sciences Turkey, Istanbul Training and Research Hospital, ISTANBUL, TURKEY
Keywords: Histiocytosis, Langerhans-Cell, Pulmonary fibrosis, Smoking
Pulmonary Langerhans cell histiocytosis is a cystic lung disease characterized by the proliferation of parenchymal dendritic cells.
The disease can become chronic or even cause pulmonary fibrosis. Our aim in this study was to investigate the typical histological findings and
interstitial fibrosis in pulmonary Langerhans cell histiocytosis cases.
Material and Method: In the study, cases that had undergone diagnostic resection were screened. Smoking, histological stage (subacute,
subacute-chronic), and cystic and eosinophilic granulomas were confirmed in the cases. In addition to emphysema, chronic nonspecific
bronchiolitis, interstitial fibrosis (subpleural-paraseptal fibrosis, peribronchial fibrosis, fibrotic nonspecific interstitial pneumonia),
honeycomb-type fibrocysts, and unexpected lesions were investigated. Descriptive and comparative (Fisher exact test) statistical analyses were
used in the study (p<0.05).
Results: A total of 27 cases were detected; age distribution was 17-68 (36.4). Smoking was present in 15 (55.5%) cases. Six (22.2%) cases were
subacute, and 21 (7.7%) cases were subacute-chronic histological stage. A cystic lesion was present in 22 (81.4%) cases. All cases had emphysema
accompanying the underlying lesions. Chronic nonspecific bronchiolitis was detected in 14 (51.8%) cases. Interstitial fibrosis was detected in
8 (29.6%) patients. Compared to interstitial fibrosis and nonfibrosis, there was no significant difference between being younger than 39 years,
gender, smoking, and histological stage (p=0.41; 1; 0.69; 0.63, respectively).
Conclusion: There is a risk of developing interstitial fibrosis patterns and honeycomb-type fibrocysts in the progression of pulmonary Langerhans
cell histiocytosis. Histopathological evaluation can play an important role in the detection of risk groups.
Pulmonary Langerhans cell histiocytosis (LCH) is a
cystic lung disease characterized by the proliferation of
parenchymal dendritic cells. A significant portion of adult
cases are related to smoking and only the lung is involved;
others have systemic disease (1-4).
The typical pathological finding is nodular eosinophilic
granulomas composed of bronchiolocentrally located
Langerhans cells and eosinophils (5). In the following
period, centriacinar emphysema develops with airway
destruction and fibroblastic activity, and collagenous
composition increases while inflammation decreases. As
a result, stellate-shaped scars and fibrosis develops around
the cystic spaces. Pulmonary hypertension and interstitial
fibrosis may develop in chronic cases (6,7).
In the tissues of surgical resection, it is possible to diagnose
the disease and determine the fibrotic stage. The disease
that becomes chronic has a risk of resulting in interstitial
fibrosis. Our aim in this study was to investigate the
characteristics of histological lesions in pulmonary LCH
and their relationship with interstitial fibrosis.
The study screened pulmonary LCH cases between the
ages of 17-80 who had undergone surgical resection
between 2003-2021 and reported in the Department of
Pathology. Cases whose preparations were not available
or who were diagnosed with limited biopsy were
excluded. Archival slides of the cases were re-examined.
Immunohistochemical analysis confirmed the accuracy of
the diagnosis. Demographic data and smoking history were
recorded from the case files.
Interstitial, peribronchial eosinophilic granulomas were
accepted as the diagnostic criteria. In the examination, lesions
were grouped as sub-acute and subacute-chronic.
Granulomas consisting of abundant eosinophils without fibrosis
were considered as subacute. Peribronchiolar fibroblastic
proliferation forming stellate-shaped scar nodules
were described as subacute-chronic stage lesions. Emphysema,
chronic nonspecific bronchiolitis, interstitial fibrosis
(subpleural-paraseptal fibrosis, peribronchial fibrosis,
fibrotic nonspecific interstitial pneumonia), honeycombtype
fibrocysts, and atypical lesions accompanying all these
lesions were investigated.
LCH cases with interstitial fibrosis were compared with the
others in the group according to age, gender, smoking, and
The study design has been approved by the local ethics
committee (University of Health Sciences Yedikule Chest
and Thoracic Surgery Research and Training Hospital
Ethics Committee). The study protocol number/date was
In the study, descriptive statistical calculations were performed
regarding the distribution of demographic and histological
lesions. Fisher exact test was used to compare the
characteristics of patients with interstitial fibrosis (p<0.05).
A total of 29 pulmonary LCH cases were detected. Two cases
were excluded from the study due to the inaccessibility of
the preparations and the fact that the diagnosis had been
made with a transbronchial biopsy. Histopathological
evaluation of the remaining 27 cases was performed.
Demographic and essential pathological findings of the cases are summarized in Table I
. Diagnoses were confirmed
by S-100 and/or CD1a immunohistochemical expression.
Peribronchial eosinophilic granulomas were detected in all
cases (Figure 1). Nodular granulomas contained varying
proportions of Langerhans cells and eosinophils (Figure 2).
Emphysema was present in all cases. Chronic nonspecific
bronchiolitis was detected in 14 (51.8%) cases.
Interstitial fibrosis was detected in 8 (29.6%) patients. The
histologic pattern of the interstitial fibrosis was diverse.
Peribronchial fibrosis, fibrotic type nonspecific interstitial
pneumonia, and subpleural and paraseptal fibrosis patterns
were observed (Figure 3-5). The gender, smoking, and
histological stage findings in cases with interstitial fibrosis
patterns are shown in Table II.
The age range of the eight patients with interstitial fibrosis
patterns was 28-68 years (Figure 6).
When LCH with interstitial fibrosis was compared with
nonfibrotic cases, there was no significant difference regarding
being younger than 39 years of age, gender, smoking,
or histological stage. (p=0.41; 1; 0.69; 0.63, respectively)
Other features of the histological evaluation of the cases are
shown in Table IV. Two cases with honeycomb fibrocysts
were detected. One of these cases had fibrotic nonspecific
interstitial pneumonia and the other had peribronchial
In our study, interstitial fibrosis was found in 29.6% of
subacute and subacute-chronic LCH cases. LCH often
presents with a stable clinical course with spontaneous
regression or smoking cessation. Some patients develop recurrence, pulmonary hypertension, and progression (7).
Lesions accompanying essential histology may be helpful
in predicting the course of the disease.
More than half of all our cases and 62.5% of the cases
with interstitial fibrosis were smokers. It is reported that
smoking causes BRAF signal pathway activity and mutation
in the cell (7-9). In the study of Kamionek et al., 30%
BRAF, KRAS G12C, and MAP2K1 alterations are found in
smokers pulmonary LCH (10). The BRAF V600E mutation
that develops on this pathway leads to cellular aging (11).
Cellular senescence can lead to the development of fibrosis
in pulmonary LCH. Therefore, categorizing pulmonary
LCH according to smoking seems to be a more accurate
Pulmonary LCH creates of the disease complex with smoking-
associated respiratory bronchiolitis and desquamative
pneumonia (12). That is why it is usual for it to accompany
eosinophilic granulomas (13). Eosinophils and Langerhans
cell destructive granulomas cause respiratory bronchiolitis
and centriacinar emphysema (14). In the clinical features,
the development of spontaneous pneumothorax is a typical
finding of the disease (15-17). Fibrotic emphysema develops
in the progression of long-lasting disease (18). The presence
of emphysema in the subacute-chronic stages in our cases
may be a sign that the destructive effect develops early.
It has been suggested that fatal end-stage fibrosis may
develop in pulmonary LCH (19). Honeycomb cysts, old
age, and the obstructive type of respiratory dysfunction
are among the negative factors (10,11,13). Also, histology
may be accompanied by fibrosis along the alveoli in the
interstitium surrounding the severely inflamed nodules
(5,11). In our study, honeycomb fibrocysts as well as
interstitial fibrosis patterns were detected. Peribronchial
fibrosis is common in lesions that become chronic due to
the peribronchial location of eosinophilic granulomas (20).
Fibrotic nonspecific interstitial pneumonia and subpleural/
paraseptal fibrosis may be subtypes of rare progressive
fibrosis. As a result, chronic pulmonary LCH may occur in
a heterogeneous pattern.
In our study, we encountered accompanying rare, organized
pneumonia, bronchiolization, atypical alveolar hyperplasia,
and pleural talcosis. It is emphasized that some of these,
such as organized pneumonia, may develop secondary to
the disease (13). Pleural talcosis is the iatrogenic result of
There are some limitations in our study. Since the first of
these cases were not followed up in a single center, sufficient
information about their prognosis could not be obtained.
For the same reason, clinical and radiological data could
not be accessed.
The histopathological features of pulmonary LCH, which is
rare, may show unexpected diversity. In the advanced stage
of the disease, there is a risk of developing interstitial fibrosis
patterns and honeycomb-type fibrocysts. Histopathological
evaluation helps to identify risk groups. Close follow-up
of patients with pulmonary LCH who are candidates for
interstitial fibrosis are recommended.
Conflict of Interest
As the authors of our manuscript, we declare that there is no conflict
of interest regarding the publication of this paper.
Concept: HNU, Design: HNU, Data collection or processing: HD,
Analysis or Interpretation: HNU, HD, Literature search: HNU, HD,
Writing: HNU, Approval: HNU.
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