Case 2 -
Bronchiolocentric and NSIP-like Interstitial Fibrosis in ABCA3 Homozygous Mutation Carrier
Patrizia Morbini, University of Pavia, Pavia, Lombardy, Italy
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A 52-years old male presented with persistent exertion dyspnea and chronic cough. His past clinical records were unremarkable; smoking history was negative. Lung function tests showed mild restrictive dysfunction and 14% DLCO reduction. CT scan showed diffuse ground glass opacities with centrilobular reticular infiltrates and bronchiectases. Minimal apical honeycombing was observed. Serology for ANA, ENA and ANCA was within normal limits. No bird exposure was reported. A videothoracoscopic lung biopsy was performed. A patient’s younger brother had long been suffering of fatigue, attributed to congestive heart failure. Their second degree female cousin had been diagnosed with interstitial lung fibrosis at the age of 13. The patient is alive 5 years after disease presentation, with minimal progression of the disease at functional and imaging studies.
Case 2 - Figure 1
Low power view of lung parenchyma showing topographic heterogeneity characterized by the alternance of fibrotic areas and normal alveolar structures.
Case 2 - Figure 2
Centrilobular scarring extending from the peribronchiolar area associated with mucus plugging.
Case 2 - Figure 3
Diffuse homogeneous scarring of a subpleural lobule mostly consistent with NSIP. Peribronchial metaplasia is present in the centrilobular area. Other lobules are minimally altered.
Case 2 - Figure 4
High power view of the fibrosis shown in figure 3.
Case 2 - Figure 5
Centrilobular scarring extending from the peribronchiolar area associated with inflammatory infiltrates.
Case 2 - Figure 6
Centrilobular scarring extending from the peribronchiolar area associated with prominent peribronchiolar metaplasia. A membranous bronchus in the lower left corner presents a mild infilammatory infiltrate.
Case 2 - Figure 7
Isolated constrictive bronchiolitis with normal surrounding parenchyma.
Case 2 - Figure 8
Isolated constrictive bronchiolitis with inflammatory infiltrates in a otherwise unaffected lobule.
Case 2 - Figure 9
CT scan of the index patient showing reticulo-nodular infiltrates and ground glass opacities.
Case 2 - Figure 10
Low power view of the lung biopsy taken from the left lower lobe of the younger cousin of the index patient showing severe interstitial fibrosis with honeycombing.
Case 2 - Figure 11
High power view of the sample shown in figure 9, highlighting fibroblast foci with peribrochiolar location and diffuse fibrosis.
Case 2 - Figure 12
Low power view of the lung biopsy taken from the left upper lobe of the younger cousin of the index patient showing interstitial fibrosis with centrilobular accentuation.
Case 2 - Figure 13
CT scan of the younger cousin of the index patient showing interstitial fibrosis and peripheral honeycombing.
Case 2 - Figure 14
The family tree showed a remarkable degree of cross-marriages. White symbols represent subject unavailable for genetic tests, gray symbols represent non-mutated relatives, red-and-grey symbols carriers of one mutated ABCA3 allele and red symbols the carriers of the homozygous ABCA3 gene mutation. The index patient is indicated with a black arrow, the cousin with a green arrow. All siblings of the index patient carry the mutation, one of them homozygous. This brother suffers of respiratory insufficiency and has a severely abnormal lung CT scan.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Pathological description The histopathological slides showed a patchy fibrotic process, characterized by
areas of interstitial scarring in an otherwise uninvolved alveolar background. The distribution of the
fibrotic lesions was predominantly centrilobular; however, a certain number of diffusely fibrotic
secondary lobules were observed in the subpleural region. In centrilobular areas, lesions of different
severity were observed, spanning from simple lymphocytic infiltration of the submucosa of terminal
bronchioli, to inflammatory infiltrates associated with mild fibrosis limited to the bronchiolar walls,
to severe bronchiolar scarring and fibrosis of the alveolar septa surrounding the small airways,
associated with peribronchiolar metaplasia and mucus plugging. The fibrosis was dense, eosinophilic and
homogeneous. The portions of the lobules not involved in the scarring were unremarkable. Membranous
bronchi showed lymphocytic infiltrates and mild submucosal scarring. Sparse interstitial lymphocytic
infiltrates were present. Pigmented macrophages, granulomas, giant cells and bronchiolitis obliterans or
organizing pneumonia were not observed. In areas of diffuse lobular fibrosis, the histopathological
features closely resembled fibrotic NSIP, with fibrotic thickening of otherwise conserved septa,
homogeneous fibrosis, and absence of fibroblast foci, remodelling or honeycomb cysts. Histopathological
study of affected relatives The histopathological slides form the affected 13 year old cousin were
available for review. Two surgical samples had been taken from the upper and the lower left lobes. The
sample from the lower lobe showed diffuse honeycombing, fibrosis and smooth muscle proliferation, without
residual normal tissue. Fibroblast foci and bronchiolar metaplasia were prominent, consistent with an
UIP pattern. The sample from the upper lobe showed limited architectural changes, with centrilobular
inflammation and fibrosis. Fibroblast foci and small aggregates of multinucleated giant cells engulfing
cholesterol clefts were observed in centrilobular areas. Granular pink material of alveolar-proteinosis
type was observed in some alveolar spaces. CT scan in this patient showed diffuse reticulo-nodular
fibrosis and peripheral honeycombing. Genetic analysis DNA was extracted from the peripheral blood of
the two affected siblings and the genes coding for surfactant protein C (SP-C) and ATP binding cassette
transporter A3 protein (ABCA3) were fully sequenced. An homozygous mutation in the ABCA3 gene was found,
resulting in an aminoacid substitution (Gly/Asp) at position 964. No mutations were found in the SP-C
gene. The genealogic tree of the family was reconstructed, and the presence of the identified mutation
was investigated in all available family members. The same homozygous mutation was identified in the
older brother of the index patient, who complained of severe dyspnea, attributed to chronic heart
failure. CT scan in this patient evidenced a pattern of diffuse interstitial fibrosis and ground glass
opacities. VATS biopsy could not be performed due to the severely compromised respiratory function. A
relevant number of heterozygous carriers was identified in the family, all of whom presented normal
respiratory function tests. Protein analysis Western blot analysis of the bronchoalveolar lavage fluid
in the affected subjects showed very low or absent SP-C content, with reduced levels of normal SP-B and
presence of an isoform of abnormal molecular weight No material was available for immunohistochemical
studies and for electron microscopy.
The main differentials that should be considered on a purely
histopathological basis are diffuse interstitial fibrosis with UIP or NSIP pattern, and diseases
characterized by centrilobular fibrosis/bronchiolitis such as hypersensitivity pneumonia, respiratory
bronchiolitis, and constrictive bronchiolitis. From a clinical point of view, the most relevant
differential diagnosis includes hypersensitivity pneumonia and collagen vascular disease The presence of
familiarity finally indicates the opportunity of analyzing the genes whose mutations have been so far
associated with familial pulmonary fibrosis, TERT and TERc and SP-C.
Bronchiolocentric and NSIP-like interstitial fibrosis in ABCA3 homozygous mutation carrier.
The histopathological evaluation of this case, as most often happens, took place without any knowledge
of the presence of affected relatives. The case discussion will thus first address the histopathological
features of the case, and successively the issues related to the familiarity and the genetic abnormality
that was found in the patient.
At a first glance, two main features dominate the present case: bronchiolar and peribronchiolar
scarring and NSIP-like panlobular fibrosis. One further aspect is the presence of morphologically normal
areas, especially at the periphery of the lobules, somehow reminding of the architectural heterogeneity
observed in UIP.
A few characteristics allow a fairly simple exclusion of UIP in this case: no fibroblastic foci or
microscopic honeycomb cysts were observed, and the fibrosis totally lacked a subpleural/paraseptal
accentuation, as typically observed in UIP. NSIP was also excluded due to the not homogeneous
distribution of the interstitial fibrosis.
A few diseases are known that can associate centrilobular inflammation and fibrosis and more diffuse
interstitial fibrosis, namely hypersensitivity pneumonia (HP) and respiratory bronchiolitis/interstitial
lung disease (RB/ILD). HP is an immunologic reaction caused by the exposure to animal antigens, mostly
aviarian, or fungi, and is characterized histologically by centrilobular chronic interstitial pneumonia
with small, non-necrotizing granulomas composed of epithelioid histiocytes and giant cells. Sometimes
isolated interstitial giant cells are the clue to the diagnosis. Foci of bronchiolitis obliterans
organizing pneumonia (BOOP) can also be present. Although interstitial fibrosis is not a feature of the
subacute disease, recently a chronic fibrotic evolution of HP has been described (Churg, 2006), which can
take the aspects of UIP or, less frequently, NSIP. Clinical and laboratory data, as well as the presence
of giant cells or granulomas on histological sections are essential to recognize as chronic HP cases of
"atypical" interstitial fibrosis. In the present case, careful revision of the patient history excluded
any exposure to antigens, serum precipitins were absent, and no granulomas, histiocytes or giant cells
could be observed in the interstitium. The degree of inflammation was also less severe than what is
normally observed in HP. The probability of chronic HP was ranked as low.
RB/ILD is another condition that can cause peribronchiolar scarring and inflammation and interstitial
fibrosis. The fibrosis is usually dense, homogeneous, and can involve whole lobules, although isolated
stellate scars are often observed (Yousem 2006). RB/ILD is caused by chronic inhalation of tobacco
smoke, which is reflected in the presence of large amounts of pigmented, smoker macrophages in the small
airways and adjacent airspaces. The patient was a life-long non-smoker, as testified by the complete
absence of smoker macrophages in his lung samples. Passive exposure to tobacco smoke was deemed
improbable from the patient anamnesis. RB/ILD was excluded from the diagnostic differential.
Focusing on the small airway pathology, another diagnosis to be considered was constrictive
bronchiolitis (CB). CB is a condition in which the bronchiolar lumina are severely narrowed or
obliterated by submucosal scarring. The scarring involves the bronchiolar wall but does not extend into
the peribronchiolar alveolar septa. The scarring often completely obliterates the bronchiolar lumen. OB
is often the result of infection, drug reaction, exposure to fumes and toxins, and can be a manifestation
of collagen vascular diseases (CVD). Absolute exclusion of infection, toxic fumes or drug exposure was
impossible in the present case, however they were considered improbable; furthermore the extension of
fibrosis in the parenchyma was more diffuse than that observed in isolated CB. A component of
constrictive bronchiolitis was however clearly present in our case, and its coexistence with NSIP-like
fibrosis was considered a strong indicator of a possible collagen vascular disease. Both entities can in
fact be associated with different types of CVD (rheumatoid arthritis, Sjogren syndrome, dermatomyositis)
and it is well recognized that the presence of more than one histopathological pattern in a single lung
biopsy is a useful clue to this diagnosis.
Although serological data did not confirm this hypothesis, collagen vascular disease was considered at
the top of our differential diagnosis list, given that not exceptionally the pulmonary dysfunction
precedes the appearance of serological markers.
The provisional histopathological diagnosis, shared by more than one component of the Italian Group
for Pleuropulmonary Pathology, was centrilobular fibrosis with aspects of constrictive bronchiolitis and
NSIP-like scarring, mostly consistent with collagen vascular disease.
As described in the case history, a careful review of patient's history highlighted a familiar
relationship with another patient previously evaluated in our center. A first-degree female cousin
presented at 13 years of age with restrictive dysfunction. Her history was positive for GERD and
repeated respiratory problems starting at 18 months of age. Lung biopsy and CT scan at the time of
presentation had shown UIP-like honeycombing in the lower lobes and prevalent centrilobular inflammation
and fibrosis in the upper lobes.
Two to 19% of idiopathic pulmonary fibrosis (IPF) patients have at least one affected first degree
relative (Lawson 2006). Mutations in a limited number of genes have so far been linked to isolated
familial pulmonary fibrosis (FPF), accounting for less than 10% of FPF cases. Mutations in genes coding
for telomerase reverse transcriptase and telomerase RNA, regulating telomere length, have been found in
adult-onset FPF (Armanios 2007, Diaz de Leon 2010), while the onset of respiratory symptoms in neonatal
or pediatric age is often associated with mutations in genes coding for proteins involved in surfactant
metabolism. A phenotype of early onset pulmonary fibrosis and abnormal surfactant proteins in particular
can be associated with mutations in the gene coding for the surfactant protein C (SP-C) but also in the
one coding for the ATP binding cassette transporter A3
protein (ABCA3). Both genes were sequenced in the index patient and in his younger cousin,
highlighting an homozygous G/A mutation at nucleotide 2891 of the ABCA3 gene in the codon 12 resulting in
one amino acid substitution (Gly/Asp) at position 964. The bioinformatic analysis of this novel mutation
identified a high risk associated with the A allele, which putatively causes the abolishment of a protein
domain. How this abnormality can affect the pulmonary tissue and induce different patterns of pulmonary
fibrosis (and other histopathological manifestations) is still matter of debate (see the literature
review section for further comments).
Familial pulmonary fibrosis with ABCA3 gene mutation
From the familial analysis, the observed mutation seems to have a complete penetrance, given that all
homozygous subjects present respiratory symptoms, although with different age at presentation and a
heterogeneous histopathological pattern, while heterozygous carriers are asymptomatic. The frequent
consanguineous marriages that occurred in the family over the generations are clearly responsible for the
transmission of two equally mutated alleles to the offsprings. Possible explanation for the different
histological patterns observed in the presented case and in the younger cousin are discussed in the
literature review section.
ABCA3 and surfactant gene defects in lung disease
The ABCA3 gene is a member of the family of ABC transporters, which includes also multi-drug
resistance proteins and the cystic fibrosis transmembrane conductance regulator (van der Deen 2005).
ABCA3 codes for a large protein with multiple membrane-spanning domains expressed on the limiting
membrane of lamellar bodies in type II pneumocytes, and has been recognised as an essential lipid
transporter in surfactant metabolism (Yamano 2001, Cheong 2007). ABCA3 absence leads to decreased
phosphatidylcholine phosphatidylglycerol content in surfactant, dysgenesis of the lamellar bodies, and
impaired surfactant secretion in the alveolar spaces.
The lamellar bodies in electron micrographs from lung tissue of infants with surfactant deficiency and
ABCA3 mutations show electrondense inclusions and are structurally immature. A decreased expression of
ABCA3 in both isolated type II pneumocytes and lungs alters the expression, localization, and processing
of SP-B and SP-C proteins (Cheong 2007, Brasch 2006)). In general, the surfactant protein A is normally
detected by immunohistochemistry in lung tissue from patients with lung disease caused by ABCA3
mutations, while SP-B and C are affected. Absence of mature SF-C protein and reduction or abnormalities
of SP-B in BALF, reported in our case as in literature (Brasch 2006) highlight the complex interaction
between ABCA3 and SP-B not only in the formation of lamellar bodies and processing of SP-C but also in
the apical secretion pathway (Brasch 2006).
More than 150 different pathogenic mutations have been described affecting different domains of the
ABCA3 gene, with an autosomic recessive form of transmission. Some of the described mutations are
associated with a more severe disease, suggesting a genotype-phenotype correlation that depends on the
function of the impaired domain, however available data are too limited to correlate different mutations
with disease manifestations (Whitsett 2010, Brasch 2006).
The mechanisms by which ABCA3 abnormalities can lead to lung tissue damage can only be inferred at
present from analogous diseases. In SP-C defects, it has been suggested that the defective processing
and accumulation of unprocessed pro-surfactant proteins in type II alveolar pneumocytes can cause cell
injury and death, which is considered to be the first step in the abnormal cell death and repair process
leading to pulmonary fibrosis, either UIP and NSIP (Chibbar 2004). It has been demonstrated that mutated
SP-C precursor causes endoplasmic reticulum stress, caspase activation and apoptosis (Mulugeta 2005,
Crossno 2010), a feature also observed in sporadic IPF. It is possible that the accumulation of pro-SP-C
consequent to lamellar body dysfunction in ABCA3 mutations may exert a similar toxicity and damage to
Genetic abnormalities in the genes involved in surfactant metabolism have been increasingly correlated
with pulmonary dysfunction, although with different age distribution and pattern of manifestation.
The following table summarizes the available literature data on mutations described in these genes
with epidemiologic, clinical and histopathological correlations.
|Mutated protein ||Transmission ||Familiarity or consaguineity ||Histological pattern of disease ||Onset in involved relatives ||Reference|
|Age of onset: neonatal, infancy |
|SP-B ||AR ||Present ||PAP ||Newborns ||Edwards 2005|
|SP-C ||AD ||Absent ||PAP, CPI, NSIP, ||Brasch 2004|
|SP-C ||AD ||present ||CPI, NSIP ||Newborns, adolescents, adults ||Thomas 2002 Chibbar 2004|
|Abou Taam 2009|
|SP-C & ABCA3 ||Compound het ||absent/present ||NA ||Newborns, adults ||Bullard 2007|
|ABCA3 ||AR ||absent/present ||pDIP, PAP, CPI ||Newborns, children ||Shulenin 2004|
|ABCA3 ||AR ||NA ||PAP, pDIP, NSIP ||NA ||Doan 2007|
|Age of onset: adolescent |
|SP-C ||AD ||present ||UIP ||Adults, newborns ||Chibbar 2004|
|ABCA3 ||AR ||absent ||UIP || ||Young 2008|
|ABCA3 ||AR ||present ||UIP ||Adults ||Present report|
|Age of onset: adult |
|SP-C ||AD ||present ||UIP, NSIP, DIP ||Adolescents, newborns, adults ||Thomas 2002|
|Van Moorsel 2010|
|SP-C & ABCA3 ||Compound het ||present ||UIP ||Newborns, adults ||Crossno 2010|
|ABCA3 ||AR ||present ||BIP/NSIP ||Adolescents ||Present report|
|SF-A2 ||AD ||present ||UIP, BAC ||Adults ||Wang 2009|
SP-B: surfactant protein B; SP-C: surfactant protein C; SP-A2: surfactant protein A2; AD:
autosomic dominant; AR: autosomic recessive; NA: not assessed; PAP: pulmonary alveolar proteinosis;
CPI: chronic pneumonia of infancy; NSIP: non specific interstitial pneumonia; pDIP: pediatric
desquamative pneumonia; UIP: usual interstitial pneumonia; BAC: bronchioloalveolar carcinoma; BIP:
bronchiolocentric interstitial pneumonia
While most cases have been described in infants, making gene-determined surfactant dysfunction one of
the main differentials in neonatal respiratory distress, mutations in ABCA3, SP-C and most recently SP-A2
proteins have also been involved in diseases manifesting in older subjects. As it has been described in
most FPF series, the age of disease onset for adult patients with mutations in genes involved in
surfactant metabolism is generally lower than the mean age of disease manifestation of sporadic IPF.
As far as histopahology is concerned, a high degree of morphological overlap is present in pediatric
respiratory distress associated with different gene mutations, where the affected lungs show features of
alveolar proteinosis, desquamative pneumonia, so-called chronic pneumonia of infancy, and interstitial
inflammation and fibrosis resembling non-specific interstitial pneumonia. UIP has never been observed in
children. All above patterns have been described in infants carrying two mutated ABCA3 alleles, although
a slight preferential association with pDIP appears from the reported series.
In the family that we are reporting, a discordant pattern of interstitial fibrosis was present in the
two biopsied patients, with a common centrilobular accentuation, less evident in the younger, where it
was partially obliterated by the severe degree of fibrosis. The UIP pattern (with focal PAP-like
material) observed in the younger patient closely resembled that described by Young et al in a 13 year
old boy with compound heterozygosity for 3 different ABCA3 mutations. The older relative that was
presented in the slide seminar showed a bronchiolocentric/NSIP-like fibrosis.
A divergent histopathological pattern is commonly observed in FPF (Steele 2005). No ABCA3-associated
familial pulmonary fibrosis involving more generations has so far been described to be compared with our
observation, however the same SP-C mutations that cause CPI and NSIP in infants are associated with
interstitial fibrosis with UIP or, less frequently, NSIP pattern in adolescents and adults. A pattern
shift is often observed in members of the same SP-C family, in function of the age of onset, with a
predominance of UIP in adults and adolescents (Thomas 2002, Chibbar 2004). Interestingly, one report
providing a bioptic follow-up in two ABCA3 mutated children showed the progression of fibrosis and
reduction of DIP/PAP features at 4 and 5-year intervals from the first biopsy (Doan, 2008), thus
suggesting a possible fibrotic evolution if the patient survives the exudative phase of the disease.
In pediatric cases, different ABCA3 mutations seem to correlate with different outcomes. For
instance, the E292V mutation which occurs with a high frequency is associated with a milder phenotype and
longer survival (Doan 2007). It is possible that the novel mutation found in our family impairs ABCA3
function in a way compatible with a slower disease evolution, or that it may act as a "first hit" that
increases susceptibility to unknown second offenders triggering the manifestation of the disease. The
"first hit" theory has been proposed to justify the different histological patterns observed in
individuals from the same FPF family (Steele 2005) and the incomplete penetrance of SP-C gene defects.
It has been suggested that SP-C mutation carriers develop the disease only after a "second hit" such as
infectious episodes, which in many patient histories preceded the appearance of clinical symptoms (Thomas
2002). The recently observed compound heterozygosity for SP-C and ABCA3 mutations (Bullard 2007, Crossno
2010), is a further example of "second hit", where ABCA3 mutation can act as a disease modifier
precipitating respiratory dysfunction.
All ABCA3 mutated cases reported so far showed autosomic recessive transmission from related or
unrelated healthy carrier parents. In our family all heterozygous carriers showed no evidence of
respiratory dysfunction. Interestingly, however, in the families described by Bullard et al (Bullard
2007), a relevant number of adult IPF cases were observed in non-tested individuals with high probability
of mutation in only one ABCA3 allele.
ABCA3 mutations have been frequently reported in neonatal respiratory distress and fibrosis without
evidence of familiarity or consanguineity (Shulenin 2004, Bullard 2005, Yokota 2008, Young 2008). This
phenomenon can be explained with a possible high frequency of heterozygous ABCA3 gene variants in the
general population, the presence of a very high number of different mutations and the need of two mutated
alleles for the manifestation of pulmonary disease, as it happens for cystic fibrosis and CFTR gene,
which belongs to the same family of proteins.
This last observation raises also the issue of a possible role of ABCA3 mutations in sporadic
pulmonary fibrosis: it is theorethically possible that two mutation associated with a milder phenotype,
inherited from healthy, non-related carrier parents, caused the development of an interstitial lung
disease that could not be distinguished clinically or histologically from IPF (Deterding 2005). So far
no study reported large-scale ABCA3 gene sequencing in sporadic adult pulmonary fibrosis, nor the
prevalence of ABCA3 gene variants in the general population. Our limited experience and literature data
suggest the opportunity to submit to gene analysis subjects with atypical CT and histological features
(centrilobular fibrosis, atypical NSIP, fibrotic PAP, DIP in non-smokers), rather than classical UIP
Bronchiolocentric and NSIP-like interstitial fibrosis: histopathological considerations
A literature review aimed at finding descriptions of cases showing morphological similarity with the
presented case yielded a group of recent studies describing series of cases characterized by
predominantly centrilobular fibrosis and absence of a clear etiological correlation (de Carvalho 2002,
Yousem 2002, Churg 2004, Fukuoka 2005, Mark 2008). These reports were reviewed to compare the features
they described with our case. In none of them there was indication of familiar disease. In our opinion,
the higher histological similarity was found with the entity defined as "idiopathic bronchiolocentric
interstitial pneumonia", described by Yousem and Dacic in 2002. The Authors described 10 patients
undergoing surgical lung biopsy for shortness of breath, dry cough, wheezing, chest pain, and dyspnea on
exertion. The histological sections showed isolated centrilobular chronic inflammation, and, in 7 cases,
peribronchiolar fibrosis and bronchiolar metaplasia characterized by alveolar wall thickening and
mucostasis in absence of significant remodelling. The main difference with the presented case was the
absence of fibrosis involving whole lobules.
The cases described by Churg et al. as "airway centered interstitial fibrosis" mainly differed in the
extent of peribronchiolar scarring and remodelling, which involved also the arterial branches, and
extended along the bronchial tree to the proximal airways (Churg 2004). CT scan confirmed the extension
of fibrosis along the central airways. Although lobular involvement was documented in these cases, there
appeared to be a higher degree of lobular scarring and structural remodelling, different form the
NSIP-like fibrosis observed in our case.
Fukuoka et al. reported a series of cases characterized by peribronchial metaplasia as the sole
histopathological alteration, which associated with a certain degree of septal fibrosis (Fukuoka 2005).
Although the centrilobular picture was similar to that observed in our case, Fukuoka's series
intentionally excluded peribronchiolar metaplasia associated with NSIP, so our case would not have fitted
within his series.
Finally, Mark and Ruangchira-urai described 31 cases where bronchiolar and interstitial disease
coexisted, defined as "bronchiolitis interstitial pneumonitis" (Mark 2008). In this series predominant
features were bronchiolitis obliterans/organizing pneumonia and interstitial chronic inflammatory
infiltrates, while prominent peribronchiolar fibrosis was not observed.
The most relevant histopathological features distinguishing the present case and the series reported
in literature are summarized in the following table
|Histopathological feature ||Yousem et al|
|Churg et al|
|Fukuoka et al|
|Mark et al 2008 ||Present case|
|Centrilobular inflammation ||+++ ||--- ||+-- ||++- ||++-|
|Centrilobular metaplasia ||++- ||+-- ||+++ ||++- ||+++|
|Centrilobular fibrosis ||++- ||+++ ||++- ||+-- ||++-|
|Lobular interstitial inflammation ||+-- ||+-- ||--- ||++- ||---|
|Lobular interstitial fibrosis ||--- ||+-- ||--- ||+++ ||++-|
|Lobular scarring ||--- ||++- ||--- ||++- ||---|
|BOOP ||+-- ||--- ||--- ||+++ ||---|
To summarize, a histopathological picture characterized by centrilobular fibrosis and
metaplasia and multifocal NSIP-like whole lobule scarring is suggestive in the first place for
smoke-related interstitial lung disease, hypersensitive pneumonia or collagen vascular disease. No
idiopathic lung disease so far described fully reproduces the characteristic of the presented case, where
an homozygous mutation of the ABCA3 gene mutation was presumed to be the cause of the pulmonary disease.
Since in literature a single non-pediatric case of pulmonary fibrosis associated with ABCA3 gene mutation
has been reported, data available so far are insufficient to assess a specific correlation between the
histopathological pattern that we observed and the defect of ABCA3 protein found in the presented family.
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