—  SPECIALTY CONFERENCE  —

Pulmonary Pathology

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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Clinical History
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.

Differential Diagnoses:
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.

Final Diagnosis:
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.

Histopathology
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.

Familiarity
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.

Literature review

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 alveolar pneumocytes.

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
Hamvas 2004
Nogee 2002
Percopo 2004
Tredano 2004
Stevens 2005
SP-C AD present CPI, NSIP Newborns, adolescents, adults Thomas 2002 Chibbar 2004
Nogee 2001
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
Bullard 2005
Yokota 2008
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
Chibbar 2004
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 cases.

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
2002 		Churg et al
2004 		Fukuoka et al
2005 		Mark et al 2008 Present case
Centrilobular inflammation +++ --- +-- ++- ++-
Centrilobular metaplasia ++- +-- +++ ++- +++
Centrilobular fibrosis ++- +++ ++- +-- ++-
Lobular interstitial inflammation +-- +-- --- ++- ---
Lobular interstitial fibrosis --- +-- --- +++ ++-
Lobular scarring --- ++- --- ++- ---
BOOP +-- --- --- +++ ---

Conclusion(s):
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.

References:
  1. Abou Taam R, Jaubert F, Emond S, Le Bourgeois M, Epaud R, Karila C, Feldmann D, Scheinmann P, de Blic J. Familial interstitial disease with I73T mutation: A mid- and long-term study. Pediatr Pulmonol 2009;44:167-75.

  2. Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie M, Vulto I, Phillips JA 3rd, Lansdorp PM, Greider CW, Loyd JE. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 2007;356:1317-26.

  3. Brasch F, Griese M, Tredano M, Johnen G, Ochs M, Rieger C, Mulugeta S, Müller KM, Bahuau M, Beers MF. Interstitial lung disease in a baby with a de novo mutation in the SFTPC gene. Eur Respir J 2004;24:30-9

  4. Brasch F, Schimanski S, Mühlfeld C, Barlage S, Langmann T, Aslanidis C, Boettcher A, Dada A, Schroten H, Mildenberger E, Prueter E, Ballmann M, Ochs M, Johnen G, Griese M, Schmitz G. Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency. Am J Respir Crit Care Med 2006;174:571-80

  5. Bullard JE, Wert SE, Whitsett JA, Dean M, Nogee LM. ABCA3 mutations associated with pediatric interstitial lung disease. Am J Respir Crit Care Med 2005;172:1026-31.

  6. Bullard JE, Nogee LM. Heterozygosity for ABCA3 mutations modifies the severity of lung disease associated with a surfactant protein C gene (SFTPC) mutation. Pediatr Res 2007;62:176-9.

  7. Cheong N, Zhang H, Madesh M, Zhao M, Yu K, Dodia C, Fisher AB, Savani RC, Shuman H. ABCA3 is critical for lamellar body biogenesis in vivo. J Biol Chem 2007;282:23811-7

  8. Chibbar R, Shih F, Baga M, Torlakovic E, Ramlall K, Skomro R, Cockcroft DW, Lemire EG. Nonspecific interstitial pneumonia and usual interstitial pneumonia with mutation in surfactant protein C in familial pulmonary fibrosis. Mod Pathol 2004;17:973-80.

  9. Churg A, Myers J, Suarez T, Gaxiola M, Estrada A, Mejia M, Selman M. Airway-centered interstitial fibrosis: a distinct form of aggressive diffuse lung disease. Am J Surg Pathol 2004;28:62-8

  10. Churg A, Muller NL, Flint J, Wright JL. Chronic hypersensitivity pneumonitis. Am J Surg Pathol 2006;30:201-8.

  11. Crossno PF, Polosukhin VV, Blackwell TS, Johnson JE, Markin C, Moore PE, Worrell JA, Stahlman MT, Phillips JA 3rd, Loyd JE, Cogan JD, Lawson WE. Identification of early interstitial lung disease in an individual with genetic variations in ABCA3 and SFTPC. Chest 2010;137:969-73.

  12. Deterding R, Fan LL. Surfactant dysfunction mutations in children's interstitial lung disease and beyond. Am J Respir Crit Care Med 2005;172:940-1

  13. Diaz de Leon A, Cronkhite JT, Katzenstein AL, Godwin JD, Raghu G, Glazer CS, Rosenblatt RL, Girod CE, Garrity ER, Xing C, Garcia CK. Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations. PLoS One 2010;5:e10680.

  14. Doan ML, Guillerman RP, Dishop MK, Nogee LM, Langston C, Mallory GB, Sockrider MM, Fan LL. Clinical, radiological and pathological features of ABCA3 mutations in children. Thorax 2008;63:366-73

  15. Edwards V, Cutz E, Viero S, Moore AM, Nogee L. Ultrastructure of lamellar bodies in congenital surfactant deficiency. Ultrastruct Pathol 2005;29:503-9.

  16. Fukuoka J, Franks TJ, Colby TV, Flaherty KR, Galvin JR, Hayden D, Gochuico BR, Kazerooni EA, Martinez F, Travis WD. Peribronchiolar metaplasia: a common histologic lesion in diffuse lung disease and a rare cause of interstitial lung disease: clinicopathologic features of 15 cases. Am J Surg Pathol 2005;29:948-54.

  17. Hamvas A, Nogee LM, White FV, Schuler P, Hackett BP, Huddleston CB, Mendeloff EN, Hsu FF, Wert SE, Gonzales LW, Beers MF, Ballard PL. Progressive lung disease and surfactant dysfunction with a deletion in surfactant protein C gene. Am J Respir Cell Mol Biol 2004;30:771-6.

  18. Lawson WE, Loyd JE. The genetic approach in pulmonary fibrosis: can it provide clues to this complex disease? Proc Am Thorac Soc 2006;3:345-9

  19. Mark EJ, Ruangchira-urai R. Bronchiolitis interstitial pneumonitis: a pathologic study of 31 lung biopsies with features intermediate between bronchiolitis obliterans organizing pneumonia and usual interstitial pneumonitis, with clinical correlation. Ann Diagn Pathol 2008;12:171-80

  20. Mulugeta S, Nguyen V, Russo SJ, Muniswamy M, Beers MF. A surfactant protein C precursor protein BRICHOS domain mutation causes endoplasmic reticulum stress, proteasome dysfunction, and caspase 3 activation. Am J Respir Cell Mol Biol 2005;32:521-30

  21. Nogee LM, Dunbar AE 3rd, Wert SE, Askin F, Hamvas A, Whitsett JA. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med 2001;344:573-9.

  22. Nogee LM, Dunbar AE 3rd, Wert S, Askin F, Hamvas A, Whitsett JA. Mutations in the surfactant protein C gene associated with interstitial lung disease. Chest 2002;121(3 Suppl):20S-21S.

  23. Percopo S, Cameron HS, Nogee LM, Pettinato G, Montella S, Santamaria F. Variable phenotype associated with SP-C gene mutations: fatal case with the I73T mutation. Eur Respir J 2004;24:1072-3.

  24. Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med 2004;350:1296-303.

  25. Steele MP, Speer MC, Loyd JE, Brown KK, Herron A, Slifer SH, Burch LH, Wahidi MM, Phillips JA 3rd, Sporn TA, McAdams HP, Schwarz MI, Schwartz DA. Clinical and pathologic features of familial interstitial pneumonia. Am J Respir Crit Care Med 2005;172:1146-52.

  26. Stevens PA, Pettenazzo A, Brasch F, Mulugeta S, Baritussio A, Ochs M, Morrison L, Russo SJ, Beers MF. Nonspecific interstitial pneumonia, alveolar proteinosis, and abnormal proprotein trafficking resulting from a spontaneous mutation in the surfactant protein C gene. Pediatr Res 2005;57:89-98.

  27. Thomas AQ, Lane K, Phillips J 3rd, Prince M, Markin C, Speer M, Schwartz DA, Gaddipati R, Marney A, Johnson J, Roberts R, Haines J, Stahlman M, Loyd JE. Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir Crit Care Med 2002;165:1322-8.

  28. Tredano M, Griese M, Brasch F, Schumacher S, de Blic J, Marque S, Houdayer C, Elion J, Couderc R, Bahuau M. Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease. Am J Med Genet A 2004;126A:18-26

  29. van der Deen M, de Vries EG, Timens W, Scheper RJ, Timmer- Bosscha H, Postma DS. ATP-binding cassette (ABC) transporters in normal and pathological lung. Respir Res 2005;6:59.

  30. van Moorsel CH, van Oosterhout MF, Barlo NP, de Jong PA, van der Vis JJ, Ruven HJ, van Es HW, van den Bosch JM, Grutters JC. Surfactant protein C mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a dutch cohort. Am J Respir Crit Care Med 2010;182:1419-25

  31. Wang Y, Kuan PJ, Xing C, Cronkhite JT, Torres F, Rosenblatt RL, DiMaio JM, Kinch LN, Grishin NV, Garcia CK. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet 2009;84:52-9

  32. Whitsett JA, Wert SE, Weaver TE. Alveolar surfactant homeostasis and the pathogenesis of pulmonary disease. Annu Rev Med 2010;61:105-19.

  33. Yamano G, Funahashi H, Kawanami O, Zhao LX, Ban N, Uchida Y, Morohoshi T, Ogawa J, Shioda S, Inagaki N. ABCA3 is a lamellar body membrane protein in human lung alveolar type II cells. FEBS Lett 2001;508:221-5.

  34. Yokota T, Matsumura Y, Ban N, Matsubayashi T, Inagaki N. Heterozygous ABCA3 mutation associated with non-fatal evolution of respiratory distress. Eur J Pediatr 2008;167:691-3

  35. Young LR, Nogee LM, Barnett B, Panos RJ, Colby TV, Deutsch GH. Usual interstitial pneumonia in an adolescent with ABCA3 mutations. Chest 2008;134:192-5

  36. Yousem SA, Dacic S. Idiopathic bronchiolocentric interstitial pneumonia. Mod Pathol 2002;15:1148-53

  37. Yousem SA. Respiratory bronchiolitis-associated interstitial lung disease with fibrosis is a lesion distinct from fibrotic nonspecific interstitial pneumonia: a proposal. Mod Pathol 2006;19:1474-9