Republished: smoking-related interstitial fibrosis (SRIF): pathologic findings and distinction from other chronic fibrosing lung diseases.

Smoking-related interstitial fibrosis (SRIF) is a common, histologically striking finding in smokers that must be distinguished from the idiopathic interstitial pneumonias and other chronic interstitial fibrosing lesions. It is characterised by marked thickening of alveolar septa by fibrosis composed of thick collagen bundles that have a distinctive hyalinised quality and often are admixed with variable numbers of hyperplastic smooth muscle fibres. There is minimal accompanying inflammation. This fibrosis is usually most prominent in subpleural and centrilobular parenchyma, but can be present elsewhere as well. It is accompanied by emphysema and respiratory bronchiolitis. Most patients are asymptomatic or only mildly symptomatic, and the clinical course is stable in most. This paper reviews the pathologic features of SRIF in detail, its differentiation from more ominous interstitial fibrosing processes, and the clinical implications of its diagnosis.

Smoking-related interstitial fibrosis (SRIF), pathogenesis and treatment of usual interstitial pneumonia (UIP), and transbronchial biopsy in UIP.

This review focuses on three selected topics of current interest that are related to chronic fibrosing lung disorders and are important for pathologists. First, the clinical and pathologic features of smoking-related interstitial fibrosis (SRIF) are highlighted. SRIF is a common finding in smokers that has striking histologic changes but only mild associated clinical manifestations. It is characterized by marked alveolar septal fibrosis composed of a distinct form of hyalinized collagen deposition. The process is present mainly in subpleural and centrilobular parenchyma and is associated with emphysema and respiratory bronchiolitis. Second, important aspects of the pathogenesis and treatment of usual interstitial pneumonia (UIP) are reviewed. The current theory proposes that UIP is caused by tiny foci of acute lung injury (manifest pathologically by fibroblast foci) that occur and recur in the interstitium over many years. Inflammation may be present as a secondary phenomenon, but is not the primary cause, and therefore anti-inflammatory agents have little effect. The recurrent injury leads to permanent fibrosis, through a process that is considered to represent a form of abnormal wound healing. Multiple therapies have been attempted that are aimed largely at interrupting the fibrosing process, but none have been successful. The cause of the injury is unknown, but a role for aspiration due to gastroesophageal reflux is a popular current theory, and there is some evidence that anti-reflux therapy may be beneficial. Genetic predisposition has been implicated in the etiology of familial cases, and there is evidence that telomere shortening may be important in sporadic cases. Third, the use of transbronchial biopsy (TBB) in diagnosing UIP is reviewed. TBB can provide a surprising amount of information and is especially useful in certain situations, such as elderly or very sick patients in whom surgical lung biopsy carries increased morbidity and mortality.

Beyond a consensus classification for idiopathic interstitial pneumonias: progress and controversies.

Histopathological classification schemes provide the underpinnings for separating idiopathic interstitial pneumonias into clinically meaningful groups. An interdisciplinary classification system based on a combination of evidence and expert opinion was published in 2002 and set the stage for controversy in several areas, including not only nomenclature but also the role of surgical lung biopsy and pathologists in diagnosis. We provide a brief overview of the clinical and histological features of the idiopathic interstitial pneumonias, and focus on selected topics of interest that have emerged in recent years.

Pulmonary disease due to aspiration of food and other particulate matter: a clinicopathologic study of 59 cases diagnosed on biopsy or resection specimens.

Aspiration of particulate matter is a well-recognized complication in debilitated patients at autopsy but is not widely recognized in surgical pathology material. We have encountered a surprising number of cases on biopsy or resection specimens, and most were unsuspected clinically and pathologically. This study was undertaken to clarify clinical and pathologic features that facilitate the diagnosis of food/particulate matter aspiration pneumonia. Fifty-nine patients were identified with an average age of 57 (range 26 to 85), and a male/female ratio of 2:1. Common presenting symptoms (information available in 36 cases) included dyspnea (14), fever (9), and cough (6). A history of recurrent pneumonia was present in 9. Radiographic data were available in 34 cases. Bilateral infiltrates or nodules were found in 17 cases, whereas the changes were unilateral in 17. Solitary nodules clinically suspicious for neoplasm were present in 13. Aspiration was suspected clinically in only 4 of the 45 cases in which the clinical impression or differential diagnosis was stated. Predisposing factors for aspiration were identified in 32 patients, including esophageal or gastric causes (19), drug use (10), and neurologic conditions (6). Histologically, bronchiolitis obliterans-organizing pneumonia was present in 52 (88%) cases, usually in combination with multinucleated giant cells, acute bronchopneumonia/bronchiolitis, and/or suppurative granulomas. Foreign material was identified in all cases, including most commonly vegetable or food remnants (54 cases), and less often talc or microcrystalline cellulose (7), crospovidone (4), and kayexalate (2). Particulate matter aspiration pneumonia is a more common cause of lung infiltrates and nodules than generally appreciated. The diagnosis should be suspected when multinucleated giant cells, acute bronchopneumonia/bronchiolitis, and/or suppurative granulomas are found in a background of bronchiolitis obliterans-organizing pneumonia. The presence of foreign material confirms the diagnosis.

Fibroblast activation protein: a serine protease expressed at the remodeling interface in idiopathic pulmonary fibrosis.

Fibroblast activation protein (FAPalpha) is a member of the cell surface dipeptidyl peptidase (DPP) family of serine proteases. In its dimer form, FAPalpha exhibits gelatinase, collagenase, and DPP activity in vitro. Reactive fibroblasts in healing wounds and stromal fibroblasts associated with epithelial tumors express FAPalpha. Idiopathic pulmonary fibrosis (IPF) is a disease of the lung characterized by progressive fibrosis with no clear etiology or molecular marker for disease activity. Recently, it has been shown that fibroblast FAPalpha expression is induced in liver cirrhosis, with an expression pattern distinct from alpha-smooth muscle actin (alpha-SMA). In this study, we determine whether FAPalpha expression is selectively induced in areas of ongoing tissue remodeling characterized by fibroblast foci in IPF. Human lung tissue was obtained from patients with IPF, centrilobular emphysema, and normal lung. Immunohistochemical studies were performed using anti-FAPalpha antibody and antibodies against alpha-SMA and CD26 (DPPIV), another member of the DPP family. We found that FAPalpha was not expressed in normal human lung tissue or tissue with evidence of centriacinar emphysema, but was induced in all patients with IPF and With a pattern distinct from that of CD26 found primarily on hyperplastic alveolar epithelium. Specifically, FAPalpha was detected in fibroblast foci and in fibrotic interstitium and not in the interstitium of adjacent architecturally normal lung. Alveolar/airway epithelium and vascular smooth muscle did not express FAPalpha. This is the first report of FAPalpha expression in IPF and our results suggest that FAPalpha is selectively induced in fibrotic foci, but not in normal or emphysematous lung. Future studies will address whether FAPalpha may be used as a marker for disease activity in IPF.

Transbronchial biopsy in usual interstitial pneumonia.

BACKGROUND: Usual interstitial pneumonia (UIP) is a slowly progressive, usually fatal form of idiopathic interstitial pneumonia for which there is no effective treatment. Transbronchial biopsy (TBB) has been utilized only to exclude other diseases such as sarcoidosis, lymphangitic carcinoma, and infection, for example, but TBB is generally considered to have little role in confirming UIP. OBJECTIVE: To determine whether diagnostic changes of UIP can be appreciated on TBB specimens. DESIGN: Retrospective analysis of TBB specimens from patients with proven UIP. SETTING: Two study sites in the United States. PARTICIPANTS: Twenty-one patients with UIP confirmed by surgical lung biopsy and/or lung explant, and 1 patient with UIP confirmed by clinical and radiographic findings along with follow-up information. MEASUREMENTS AND RESULTS: Adequate tissue for diagnosis was available in 18 cases; in 7 cases (32% overall), there were varying combinations of interstitial fibrosis in a patchwork pattern along with fibroblast foci and/or honeycomb change. These features were considered diagnostic of UIP. Interstitial fibrosis along with fibroblast foci or honeycomb change were seen in two other cases, but the fibrosis lacked a patchwork pattern, and these features were considered consistent with UIP. Nonspecific interstitial fibrosis alone was found in nine cases. CONCLUSIONS: In summary, characteristic histologic features of UIP can be identified on TBB specimens more often than previously appreciated. TBB may be more useful in confirming UIP than previously recognized.

Classification of usual interstitial pneumonia in patients with interstitial lung disease: assessment of a machine learning approach using high-dimensional transcriptional data.

BACKGROUND: Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease that distorts pulmonary architecture, leading to hypoxia, respiratory failure, and death. Diagnosis is difficult because other interstitial lung diseases have similar radiological and histopathological characteristics. A usual interstitial pneumonia pattern is a hallmark of idiopathic pulmonary fibrosis and is essential for its diagnosis. We aimed to develop a molecular test that distinguishes usual interstitial pneumonia from other interstitial lung diseases in surgical lung biopsy samples. The eventual goal of this research is to develop a method to diagnose idiopathic pulmonary fibrosis without the patient having to undergo surgery. METHODS: We collected surgical lung biopsy samples from patients with various interstitial lung diseases at 11 hospitals in North America. Pathology diagnoses were confirmed by an expert panel. We measured RNA expression levels for 33 297 transcripts on microarrays in all samples. A classifier algorithm was trained on one set of samples and tested in a second set. We subjected a subset of samples to next-generation RNA sequencing (RNAseq) generating expression levels on 55 097 transcripts, and assessed a classifier trained on RNAseq data by cross-validation. FINDINGS: We took 125 surgical lung biopsies from 86 patients. 58 samples were identified by the expert panel as usual interstitial pneumonia, 23 as non-specific interstitial pneumonia, 16 as hypersensitivity pneumonitis, four as sarcoidosis, four as respiratory bronchiolitis, two as organising pneumonia, and 18 as subtypes other than usual interstitial pneumonia. The microarray classifier was trained on 77 samples and was assessed in a test set of 48 samples, for which it had a specificity of 92% (95% CI 81-100) and a sensitivity of 82% (64-95). Based on a subset of 36 samples, the RNAseq classifier had a specificity of 95% (84-100) and a sensitivity of 59% (35-82). INTERPRETATION: Our results show that the development of a genomic signature that predicts usual interstitial pneumonia is feasible. These findings are an important first step towards the development of a molecular test that could be applied to bronchoscopy samples, thus avoiding surgery in the diagnosis of idiopathic pulmonary fibrosis. FUNDING: Veracyte.

Respiratory bronchiolitis: a clinicopathologic study in current smokers, ex-smokers, and never-smokers.

The clinical and pathologic features of 109 cases of respiratory bronchiolitis (RB) identified from review of 156 consecutive surgical lung biopsy specimens were studied. A total of 107 of the 109 cases (98%) occurred in smokers, including all 83 current smokers and 24 of 49 ex-smokers (49%). RB persisted in some patients for many years after stopping smoking, occurring in one third of patients 5 years after quitting, and in one patient 32 years afterwards. A correlation was found between degree of cytoplasmic pigmentation of macrophages and number of pack-years smoked and also between the presence of peribronchiolar fibrosis and number of pack-years. No correlation was found between pulmonary function test results and pathologic findings. A desquamative interstitial pneumonia-like reaction was observed in six individuals. One patient each with a desquamative interstitial pneumonia-like reaction and one with RB were diagnosed based on clinical findings with desquamative interstitial pneumonia and RB-associated interstitial lung disease, respectively. No histologic features distinguished desquamative interstitial pneumonia from a desquamative interstitial pneumonia-like reaction or RB-associated interstitial lung disease from RB. Five cases of variant RB were encountered that resembled RB except that macrophage cytoplasm lacked pigment. All occurred in never-smokers, and their significance is unknown. RB is an accurate histologic marker of cigarette smoking, and it may be found many years after smoking ceases. There are no reliable histologic features to distinguish RB-associated interstitial lung disease from RB or desquamative interstitial pneumonia-like reactions from desquamative interstitial pneumonia.

Usual interstitial pneumonia: histologic study of biopsy and explant specimens.

The pathologic findings in biopsy and subsequent explant specimens from 20 patients with usual interstitial pneumonia (UIP) were reviewed to refine histologic criteria for diagnosis, to identify factors that may confound diagnosis, and to assess the relationship of UIP and nonspecific interstitial pneumonia (NSIP). One case of NSIP was also identified and included for comparison. Surgical biopsies from 15 of the 20 UIP cases were diagnosed as UIP, whereas 5 showed only nondiagnostic changes. An important new observation is that areas resembling nonspecific interstitial pneumonia (NSIP-like areas) are present in the majority of UIP cases in both biopsy and explant specimens, and they are extensive in some. Ten of the 15 UIP biopsies were considered straightforward, with typical patchy interstitial fibrosis, honeycomb change, and fibroblast foci. Five cases were considered difficult because of prominent NSIP-like areas in two, extensive honeycomb change in one, superimposed diffuse alveolar damage in one, and superimposed bronchiolitis obliterans-organizing pneumonia in one. The most helpful feature for diagnosing UIP in difficult cases was the presence of a distinct patchwork appearance to the characteristic uneven or variegated parenchymal involvement along with evidence of architectural derangement. No explant showing UIP was preceded by biopsy findings of NSIP, and the one NSIP case appeared similar at biopsy and explant. NSIP or NSIP-like areas and UIP may reflect different mechanisms of fibrosis related either to different severity of injury or to different injuries.

Smoking-related interstitial fibrosis (SRIF): pathologic findings and distinction from other chronic fibrosing lung diseases.

Smoking-related interstitial fibrosis (SRIF) is a common, histologically striking finding in smokers that must be distinguished from the idiopathic interstitial pneumonias and other chronic interstitial fibrosing lesions. It is characterised by marked thickening of alveolar septa by fibrosis composed of thick collagen bundles that have a distinctive hyalinised quality and often are admixed with variable numbers of hyperplastic smooth muscle fibres. There is minimal accompanying inflammation. This fibrosis is usually most prominent in subpleural and centrilobular parenchyma, but can be present elsewhere as well. It is accompanied by emphysema and respiratory bronchiolitis. Most patients are asymptomatic or only mildly symptomatic, and the clinical course is stable in most. This paper reviews the pathologic features of SRIF in detail, its differentiation from more ominous interstitial fibrosing processes, and the clinical implications of its diagnosis.

Biopsy-site changes in lung adenocarcinoma with prior core needle biopsy: a potential pitfall in the assessment of stromal invasion.

Although biopsy-site changes are known to cause diagnostic difficulties in thyroid and breast specimens, especially when assessing invasion, such changes have not been described in the lung. Assessment of invasion is important in lung cancers to distinguish bronchioloalveolar carcinoma [adenocarcinoma in situ (AIS)] from invasive adenocarcinoma. The aim of this study was to determine whether biopsy-site changes occur in the lung and whether they may impact this differential diagnosis. Lobectomy specimens were examined from patients whose previous core needle biopsies showed well-differentiated adenocarcinoma with a lepidic pattern. There were 26 adenocarcinomas, including 14 minimally invasive adenocarcinomas, 2 invasive well-differentiated adenocarcinomas, and 10 AISs. Biopsy-site changes were identified in 9 of 26 (35%), including 4 minimally invasive adenocarcinomas, 3 AISs, and 2 well-differentiated adenocarcinomas. The interval between biopsy and resection ranged from 12 to 45 days (mean, 26.1 d). The biopsy sites consisted of a linear scar composed of collagen and plump fibroblasts, ranging from 2.0 to 13.1 mm in length and 0.5 to 1.6 mm in width. Scattered lymphocytes and plasma cells were present in 8 cases, pigment-laden macrophages in 4, and foreign body giant cells in 3. Benign entrapped lung epithelium was present within the scar in all 9 and entrapped malignant epithelium in 4. Biopsy-site changes can be identified in a significant proportion of lung tumors after core needle biopsy. They need to be distinguished from tumor-related stromal reactions that are considered an indication of invasion and are important in the differentiation of AIS and invasive adenocarcinoma.

Comparison of monoclonal napsin A, polyclonal napsin A, and TTF-1 for determining lung origin in metastatic adenocarcinomas.

Thyroid transcription factor 1 (TTF-1) is currently the best immunohistochemical marker for carcinomas of lung origin. Our aim was to compare napsin A to TTF-1 for identifying pulmonary origin in metastatic adenocarcinoma and its mimics. One hundred fifty-five metastatic carcinomas (55 pulmonary, 100 nonpulmonary) were stained with monoclonal napsin A and TTF-1, and most also with polyclonal napsin A. The sensitivity of monoclonal napsin A, polyclonal napsin A, and TTF-1 for metastatic adenocarcinomas of pulmonary origin was 76%, 81%, and 82%, respectively. Two lung carcinomas were diffusely positive for monoclonal napsin A, but negative or equivocal for TTF-1. TTF-1 stained 9 of 100 nonpulmonary carcinomas (all thyroid), monoclonal napsin A stained 12 of 100 (4 sites), and polyclonal napsin A stained 27 of 91 (8 sites). Napsin A is expressed in a wider variety of metastatic nonpulmonary carcinomas than TTF-1, and the monoclonal antibody is more specific. Napsin A is a useful adjunct to TTF-1, because occasional lung adenocarcinomas are TTF-1 negative but napsin A positive.

The relationship between p16 expression and high-risk human papillomavirus infection in squamous cell carcinomas from sites other than uterine cervix: a study of 137 cases.

p16 is known to be an excellent surrogate marker of human papillomavirus infection in squamous cell carcinoma of the cervix. Recent studies have demonstrated a link between human papillomavirus infection and a subset of head and neck squamous cell carcinomas, especially from the oropharynx. The aims of this study were to determine the incidence of p16 expression in squamous cell carcinomas of noncervical origin and to assess its utility as a surrogate marker of human papillomavirus infection in various noncervical primary sites. One hundred thirty-seven squamous cell carcinomas from 5 primary sites, including 34 from the oropharynx (tonsil and base of tongue), 43 cases from nonoropharyngeal head and neck sites, and 20 cases each from the lung, esophagus, and skin, were retrieved from our surgical pathology archives. Immunohistochemistry for p16 was performed on each case. All p16-positive cases and 21 p16-negative cases were further tested for both high-risk and low-risk human papillomavirus by in situ hybridization. p16 expression was detected in 54 cases overall, including 25 (74%) of 34 oropharyngeal squamous cell carcinomas, 8 (19%) of 43 nonoropharyngeal head and neck squamous cell carcinomas including 3 of 4 from the sinonasal cavity, 6 (30%) of 20 esophageal squamous cell carcinomas, 7 (35%) of 20 lung squamous cell carcinomas, and 8 (40%) of 20 skin squamous cell carcinomas. Of the 54 p16-positive cases, 30 were positive for high-risk human papillomavirus, including 24 (96%) of 25 from the oropharynx, 5 (63%) of 8 from nonoropharyngeal head and neck sites, and 1 (17%) of 6 from the esophagus. All 7 lung and 8 skin cases tested were negative. All p16-positive cases were negative for low-risk human papillomavirus. In selected head and neck squamous cell carcinomas, mainly from the oropharynx and sinonasal cavity, p16 positivity correlates well with high-risk human papillomavirus infection. p16 is not a reliable indicator of high-risk human papillomavirus infection in squamous cell carcinomas of the lung, skin, and esophagus.

Subclassification of non-small cell lung carcinomas lacking morphologic differentiation on biopsy specimens: Utility of an immunohistochemical panel containing TTF-1, napsin A, p63, and CK5/6.

The availability of targeted therapies has created a need for precise subtyping of non-small cell lung carcinomas (NSCLCs). The aim of this study was to assess the utility of immunohistochemical markers in subtyping poorly differentiated NSCLC and to compare the results of immunohistochemical staining on biopsies with the corresponding resections. Thirty-nine cases of NSCLC that could not be further classified on biopsy and had subsequent resection specimens were identified. Classification of the tumor was based on the resection specimen using the World Health Organization criteria. All biopsies and resections were stained with CK7, TTF-1, napsin A (novel aspartic proteinase of the pepsin family), p63, CK5/6, and 34ßE12. The specimens included 20 adenocarcinomas (ACs), 15 squamous cell carcinomas (SCCs), and 4 large-cell carcinomas (LCCs). TTF-1 was positive in biopsies from 16 of 20 ACs, 2 of 4 LCCs, and none of the SCCs. p63 was positive in all 15 SCCs, 2 of 20 ACs (both were also positive for TTF-1 and napsin A), and none of the LCCs. CK5/6 was positive in 11 of 15 SCCs (all p63 positive) but none of the ACs or LCCs. Napsin A stained 11 of 19 ACs (all TTF-1 positive) but none of the other tumors. Staining for CK7 was present in 19 of 19 ACs and 9 of 15 SCCs. 34ßE12 stained both SCCs (15 of 15) and ACs (12 of 20). The combination of TTF-1, napsin A, p63, and CK5/6 allowed an accurate classification of 30 of39 (77%) cases. Of 232 pairs of slides (biopsy and resection) stained with immunohistochemical markers, 12 (5%) showed discrepancies in immunohistochemical staining between biopsies and their corresponding resections. Immunohistochemical staining using a combination of TTF-1, napsin A, p63, and CK5/6 allows subclassification of poorly differentiated NSCLCs on small lung biopsies in most cases. Discrepancies in immunohistochemical staining between biopsies and resections are uncommon.

Biopsy findings in acute pulmonary histoplasmosis: unusual histologic features in 4 cases mimicking lymphomatoid granulomatosis.

Most examples of pulmonary histoplasmosis, including histoplasmoma and chronic histoplasmosis, are characterized by typical necrotizing granulomatous inflammation. Only disseminated histoplasmosis is recognized as causing a different reaction which consists of ingestion of organisms by macrophages without granuloma formation. The histologic features of acute pulmonary histoplasmosis are not well described as this form of the disease is rarely biopsied. We report the biopsy findings in 4 cases of acute pulmonary histoplasmosis, which seem to be unique to this form of Histoplasma infection. There were 3 men and 1 woman who ranged in age from 40 to 68 years. All presented acutely with fever and other flu-like symptoms. Radiographically, a solitary nodular infiltrate was present in 3 and bilateral reticulonodular infiltrates in one. Histologically, all 4 biopsies showed a nodular parenchymal inflammatory infiltrate composed of lymphocytes and histiocytes filling alveolar spaces and expanding the adjacent interstitium. Areas of parenchymal necrosis were additionally present in 3 cases. Vasculitis composed of lymphocytes and histiocytes was present in all, and was striking in 3, resulting in a resemblance to grade 1 lymphomatoid granulomatosis (LYG). Tip-offs to the correct diagnosis were small necrotizing granulomas scattered within the lymphohistiocytic infiltrate (3 cases), scattered histiocyte aggregates, and a few multinucleated giant cells. The diagnosis was confirmed in all by the presence of Histoplasma yeasts in Grocott methenamine silver-stained slides. Acute pulmonary histoplasmosis may cause a lymphohistiocytic infiltrate with necrosis and vasculitis that is suggestive of LYG. This observation emphasizes the importance of examining special stains for organisms before diagnosing grade 1 LYG.

Lymphomatoid granulomatosis: insights gained over 4 decades.

Lymphomatoid granulomatosis is a rare lymphoproliferative disease involving predominantly the lung, and there is uncertainty about its relationship to lymphoma. It affects mainly middle-aged adults, although there is a wide age range, and men are affected almost twice as often as women. Multiple nodular, usually bilateral, infiltrates are seen radiographically, and extrapulmonary involvement, especially of skin and nervous system, occurs in more than one third of the patients. Mortality rates are high, and treatment modes are not well established. Morphologically, there is a nodular polymorphous mononuclear cell infiltrate with prominent vascular infiltration and often necrosis. Varying numbers of large, often atypical, CD20-positive B-lymphocytes are present within a background containing numerous CD3-positive small T lymphocytes and scattered admixed plasma cells and histiocytes. Evidence of Epstein-Barr virus infection can be shown in most cases by in-situ hybridization for Epstein-Barr virus RNA. The infiltrate is graded as 1 to 3 based on the proportion of large B cells. Morphologically, there is overlap in grades 2 and 3 with variants of large B-cell lymphoma, and many such cases show evidence of monoclonality by polymerase chain reaction. It is suggested that lymphoma (T-cell rich large B-cell or diffuse large B-cell) be diagnosed in addition to lymphomatoid granulomatosis in grades 2 and 3 to appropriately communicate the nature of the disease to clinicians.

Core needle biopsy in benign lung lesions: pathologic findings in 159 cases.

Although core needle biopsy has been shown to be an accurate means of diagnosing lung malignancies, there is relatively little information in the literature about its utility in diagnosing specific non-malignant conditions. We reviewed the pathologic findings in 159 core needle biopsies showing benign changes in order to determine the types of processes that can be diagnosed by this technique and the factors that influence accuracy and specificity. There were 155 patients ranging in age from 3 to 86 years (mean 58). Nodules or masses were present radiologically in most. They ranged from 0.5 to 8.0 cm (mean 1.65 cm) in size and 80% measured 2.0 cm or less. Twenty percent were spiculated, and positron emission tomography scans were positive in 48 of 56 cases tested (30% of total). Specific diagnoses were established in 122 (77%) of 159 core needle biopsies, while 24 (15%) were nonspecific and 13 (8%) were nonrepresentative. The most common specific diagnoses were necrotizing granulomatous inflammation (45), scar (28), organizing pneumonia (13), and benign neoplasms (11). A mixture of interstitial fibrosis and chronic inflammation (16) was the most common nonspecific diagnosis. A specific diagnosis was significantly more likely in biopsies with 3 or more cores or with a core length of more than 1 cm. Malignancy was diagnosed on a subsequent biopsy in only one case, and the initial biopsy in that case showed non-specific chronic inflammation and fibrosis. Our findings confirm that core needle biopsy is an accurate method of diagnosing benign lung lesions, yielding specific diagnoses in the majority.

Clinically occult interstitial fibrosis in smokers: classification and significance of a surprisingly common finding in lobectomy specimens.

This study reports the presence of surprisingly frequent and often severe interstitial fibrosis in cigarette smokers with no clinical evidence of interstitial lung disease. Twenty-three lobectomy specimens excised for neoplasms, including 20 from smokers, were extensively sampled, and examined semi-quantitatively for interstitial fibrosis, fibroblast foci, peribronchiolar metaplasia, honey-comb change, emphysema, and respiratory bronchiolitis. Interstitial fibrosis involving greater than 25% of slides was identified in 12 of 20 smokers (60%), but in none of the three never-smokers. Three cases were classified as specific forms of interstitial lung disease, including one each of usual interstitial pneumonia, Langerhans cell histiocytosis, and asbestosis. The remaining 9 cases did not fit with a named interstitial lung disease and were considered to represent examples of smoking-related interstitial fibrosis. This lesion was characterized by varying degrees of alveolar septal widening by collagen deposition along with emphysema and respiratory bronchiolitis. The fibrosis occurred both in subpleural and in deeper parenchyma. It surrounded enlarged airspaces of emphysema, but it also involved non-emphysematous parenchyma. Clinical progression was not documented in any case, although follow-up was short. These observations highlight the spectrum of unexpected fibrosis that is frequently encountered in lobectomy specimens from cigarette smokers. Additional investigation will be required to determine the clinical significance of smoking-related interstitial fibrosis and its relationship, if any, to other smoking-related diseases. It is important, however, that smoking-related interstitial fibrosis be distinguished from specific forms of fibrosing lung disease that may be associated with poor prognoses, especially usual interstitial pneumonia.

Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations.

BACKGROUND: Telomerase is an enzyme that catalyzes the addition of nucleotides on the ends of chromosomes. Rare loss of function mutations in the gene that encodes the protein component of telomerase (TERT) have been described in patients with idiopathic pulmonary fibrosis (IPF). Here we examine the telomere lengths and pulmonary fibrosis phenotype seen in multiple kindreds with heterozygous TERT mutations. METHODS AND FINDINGS: We have identified 134 individuals with heterozygous TERT mutations from 21 unrelated families. Available medical records, surgical lung biopsies and radiographs were evaluated retrospectively. Genomic DNA isolated from circulating leukocytes has been used to measure telomere lengths with a quantitative PCR assay. We find that telomere lengths of TERT mutation carriers decrease in an age-dependent manner and show progressive shortening with successive generations of mutation inheritance. Family members without TERT mutations have a shorter mean telomere length than normal, demonstrating epigenetic inheritance of shortened telomere lengths in the absence of an inherited TERT mutation. Pulmonary fibrosis is an age-dependent phenotype not seen in mutation carriers less than 40 years of age but found in 60% of men 60 years or older; its development is associated with environmental exposures including cigarette smoking. A radiographic CT pattern of usual interstitial pneumonia (UIP), which is consistent with a diagnosis of IPF, is seen in 74% of cases and a pathologic pattern of UIP is seen in 86% of surgical lung biopsies. Pulmonary fibrosis associated with TERT mutations is progressive and lethal with a mean survival of 3 years after diagnosis. Overall, TERT mutation carriers demonstrate reduced life expectancy, with a mean age of death of 58 and 67 years for males and females, respectively. CONCLUSIONS: A subset of pulmonary fibrosis, like dyskeratosis congenita, bone marrow failure, and liver disease, represents a "telomeropathy" caused by germline mutations in telomerase and characterized by short telomere lengths. Family members within kindreds who do not inherit the TERT mutation have shorter telomere lengths than controls, demonstrating epigenetic inheritance of a shortened parental telomere length set-point.

Proliferative activity in fibrosing lung diseases: a comparative study of Ki-67 immunoreactivity in diffuse alveolar damage, bronchiolitis obliterans-organizing pneumonia, and usual interstitial pneumonia.

Because diffuse alveolar damage, bronchiolitis obliterans-organizing pneumonia, and usual interstitial pneumonia are all related to acute lung injury, we postulated that the proliferative activity of fibroblasts and epithelium would be similar in all 3, and that of fibroblasts would be similar to skin scars. Ki-67 staining was assessed in 16 usual interstitial pneumonia, 9 bronchiolitis obliterans-organizing pneumonia, and 8 diffuse alveolar damage cases, 5 incidental fibroblast foci, 5 skin scars, and 5 keloids. The proliferative activity of alveolar macrophages was also measured and compared with that of 10 respiratory bronchiolitis cases. The greatest proliferative activity was found in fibroblasts and epithelium of diffuse alveolar damage (25.8% and 41.9%), and it was significantly greater (P = .000) than in usual interstitial pneumonia (1.88% and 2.6%), bronchiolitis obliterans-organizing pneumonia (4.07% and 1.55%), and incidental fibroblast foci (2.9% and 0.44%). The proliferative activity in fibroblasts of diffuse alveolar damage was significantly higher than that of fibroblasts in skin scars (P = .024). In contrast, the proliferative rate of fibroblasts in bronchiolitis obliterans-organizing pneumonia, usual interstitial pneumonia, and incidental fibroblast foci was significantly lower than that in skin scars (P = .000, P = .000, and P = .001) but similar to keloids (P = 1.000). Usual interstitial pneumonia macrophages showed an unexpectedly high proliferative rate (19.5%) that was significantly greater than that in bronchiolitis obliterans-organizing pneumonia (5.5%, P = .000), diffuse alveolar damage (9.01%, P = .007), incidental fibroblast foci (9.5%, P = .036), and respiratory bronchiolitis (11.45%, P = .031). Our results suggest different reactions to acute injury in usual interstitial pneumonia and bronchiolitis obliterans-organizing pneumonia compared with diffuse alveolar damage. The similar low proliferative activity of fibroblasts in usual interstitial pneumonia and keloids supports the hypothesis of abnormal wound healing in usual interstitial pneumonia. The high proliferative activity of macrophages in usual interstitial pneumonia suggests a role in the pathogenesis of usual interstitial pneumonia.