Interstitial pneumonias are a confusing and frustrating set of diseases both for the treating physician and for the diagnostic pathologist. One source of the confusion has been the lack of overlapping terms that treating physicians and pathologists use. For example, idiopathic pulmonary fibrosis (IPF) is a clinical term describing a slowly progressive, chronic interstitial pneumonia. Since many of the interstitial pneumonias, including UIP, DIP, and NSIP, fall under this category, it is a non-specific term. Most pathologists who are experts in lung pathology use the terms IPF and UIP to mean the same disease process. To complicate matters even further, European clinicians utilize the term cryptogenic fibrosing alveolitis for IPF. Pathologists also share in the confusion. Terms that were commonly used by pathologists just a few years ago have also undergone an evolution. Bronchiolitis obliterans with organizing pneunomina (BOOP) is no longer used because it has been considered a mixture of terms. Lymphocytic interstitial pneumonia (LIP) is now considered a lymphoproliferative disease. Giant cell interstitial pneumonitis (GIP) is now considered a hard metal pneumoconiosis.
The symptoms vary for each of the pneumonias but most are characterized by a slowly progressive shortness of breath. Chest radiographs reveal a hazy ground glass appearance with linear opacities. Most of the diseases are progressive and are treated with corticosteroids.
SYNONYMS Idiopathic interstitial pneumonia
Usual Interstitial Pneumonitis UIP Desquamative interstitial pneumonitis DIP Acute interstitial pneumonitis AIP
Accelerated interstitial pneumonitis
Non-specific interstitial pneumonia/fibrosis NSIP INCIDENCE Usual Interstitial Pneumonitis Most common of idiopathic pneumonias Desquamative interstitial pneumonitis Uncommon Acute interstitial pneumonitis Uncommon Non-specific interstitial pneumonia/fibrosis Uncommon AGE RANGE-MEDIAN Usual Interstitial Pneumonitis Average age 51 years
Range 40-70 years
Desquamative interstitial pneumonitis Average age 42 years Acute interstitial pneumonitis Average age 28 years Non-specific interstitial pneumonia/fibrosis
EPIDEMIOLOGIC ASSOCIATIONS CHARACTERIZATION Cigarette smokers 90% of DIP patients have this history
PATHOGENESIS CHARACTERIZATION GENERAL May start with a focus of acute lung injury
Fibroblastic foci are sites of acute injury
Macrophages mediate process with cytokines including:
Monocyte chemotactic peptide
Expression and regulation of hemeoxygenase 1 in healthy human lung and interstitial lung disorders
Essi Lakari, MD
Piritta Pylkäs, Med Cand
Petra Pietarinen-Runtti, MD, PhD
Paavo Pääkkö, MD, PhD
Ylermi Soini, MD, PhD
Vuokko L. Kinnula, MD, PhD
Hum Pathol 2001;32:1257-1263. Abstract quote
Hemeoxygenase 1 (HO-1) has been implicated in the protection of lung tissue against exogenous oxidant exposure. However, the expression and cellular distribution of HO-1 in human lung continue to be poorly characterized.
The localization of HO-1 was studied in histopathologically healthy lung from nonsmoking patients with a carcinoid or other lung tumor (5 cases), pulmonary sarcoidosis (13 cases), and chronic interstitial pneumonias (9 cases, usual interstitial pneumonia; 10 cases, desquamative interstitial pneumonia). Immunostaining was graded from 0 (no immunoreactivity) to +++ (intense immunoreactivity). In healthy lung, HO-1 was localized to alveolar macrophages with reactivity varying from moderate to intense, and in bronchial epithelium, alveolar epithelium, endothelium, and interstitium, the immunoreactivity was not detectable or was very low. Sarcoidosis and interstitial pneumonias showed intense HO-1 immunoreactivity in alveolar macrophages in most of the cases and weak to intense immunoreactivity in the granulomas of sarcoidosis. The immunoreactivity of interstitium was negative or weak in the fibrotic areas of the lung and also in the samples of bronchoalveolar lavage fluid obtained from the patients with UIP. Western blotting indicated that HO-1 is up-regulated by exposure of monocytes to formylated peptide, fMLP, which causes respiratory burst in the cells, and that inhibition of HO-1 by tin protoporphyrin potentiates the injury of fMLP-exposed cells.
In conclusion, these data show differential distribution of HO-1 in human lung cells and strongly suggest the importance of HO-1, especially in the defense of alveolar macrophages in normal human lung and in the inflammatory, but not in the fibrotic, stage of interstitial lung disorders.
NITRIC OXIDE SYNTHASE
Inducible Nitric Oxide Synthase, but Not Xanthine Oxidase, Is Highly Expressed in Interstitial Pneumonias and Granulomatous Diseases of Human Lung
Essi Lakari, MD
Ylermi Soini, MD, PhD
Marjaana Säily, MD, PhD
Pirjo Koistinen, MD, PhD
Paavo Pääkkö, MD, PhD
and Vuokko L. Kinnula, MD, PhD
Am J Clin Pathol 2002;117:132-142 Abstract quote
We assessed the distribution and expression of inducible nitric oxide synthase (i-NOS), endothelial nitric oxide synthase (e-NOS), and xanthine oxidase (XAO) in usual interstitial pneumonia, desquamative interstitial pneumonia, and granulomatous diseases.
The material consisted of biopsy specimens from 5 healthy subjects (nonsmokers), 9 patients with usual interstitial pneumonia, 11 with desquamative interstitial pneumonia, 14 with sarcoidosis, and 8 with extrinsic allergic alveolitis. i-NOS was expressed intensively in inflammatory but not in fibrotic lesions. It was expressed most prominently in alveolar macrophages and alveolar epithelium of all disorders and in the granulomas of sarcoidosis and extrinsic allergic alveolitis. In contrast with i-NOS, e-NOS was expressed prominently in control lung tissue samples but also in granulomas of sarcoidosis and extrinsic allergic alveolitis.
Reverse transcription–polymerase chain reaction performed on bronchoalveolar lavage fluid samples from patients with sarcoidosis or usual interstitial pneumonia and from healthy subjects indicated positivity for XAO, but immunohistochemical analysis in samples from healthy lung and all parenchymal lung disorders showed no immunoreactivity for XAO. i-NOS has an important role in the pathogenesis of interstitial lung diseases, being up-regulated during the inflammatory but not during the fibrotic disease stage.
p53 Gene alteration in atypical epithelial lesions and carcinoma in patients with idiopathic pulmonary fibrosis
Hidenori Kawasaki, MD
Tsutomu Ogura, MD
Tomoyuki Yokose, MD
Kanji Nagai, MD
Yutaka Nishiwaki, MD
Hiroyasu Esumi, MD
Hum Pathol 2001;32:1043-104 Abstract quote
Idiopathic pulmonary fibrosis (IPF) is well known to be associated with lung cancer. Several atypical epithelial lesions are frequently observed in the fibrotic area in IPF patients, and they have been suspected to be related to lung cargingenesis. Several studies have suggested that p53 protein accumulation and mutation occur in the early pathogenesis of squamous cell carcinoma of the lung, suggesting some abnormality of the p53 tumor-suppressor gene in interstitial lung diseases.
To examine the cause of the high frequency of lung cancer in IPF, we examined the p53 changes in atypical epithelial lesions and carcinoma in patients with IPF by immunohistochemistry and mutational analysis.
We examined 19 lung cancer patients with IPF who underwent surgical resection for lung cancer in our institute. Paraffin-embedded tissues were treated by microwave and stained with an anti-p53 antibody (RSP53) by the avidin–biotin–peroxidase complex method. Mutations in exons 5 through 8 of the p53 gene were also examined by polymerase chain reaction mediated single-strand conformation polymorphism (polymerase chain reaction–single-strand conformation polymorphism) analysis and DNA sequencing. p53 protein was immunohistochemically detected in 13 (62%) of 21 squamous cell carcinomas, 3 (60%) of 5 squamous metaplasia with atypia, 16 (54%) of 30 squamous metaplasia, and 1 (4%) of 26 other hyperplastic lesions. p53 mutation was detected in 12 (57%) of 21 squamous cell carcinomas, 2 (40%) of 5 squamous metaplasia with atypia, 7 (23%) of 30 squamous metaplasia, and 0 (0%) of 26 other hyperplastic lesions.
In conclusion, there are frequent p53 gene alterations in squamous metaplasia, which is distributed in the peripheral zone of the fibrotic area in patients with IPF. The present findings might provide a clue to the molecular mechanisms underlying the high incidence of lung cancer, especially peripheral-type squamous cell carcinoma in IPF patients, and suggest that p53 gene alterations play an important role in the early stages of lung carcinogenesis in patients with IPF. 9.
LABORATORY/RADIOLOGIC/OTHER TESTS CHARACTERIZATION Chest radiograph
Interstitial linear opacities with hazy ground glass appearance on chest radiographs
Honeycomb appearance with advanced disease
GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION Usual Interstitial Pneumonitis UIP Desquamative interstitial pneumonitis DIP Respiratory brochiolitis-associated interstitial lung disease (RB-ILD) Considered a variant of DIP
Also called smoker's bronchiolitis
Acute interstitial pneumonitis AIP (Hamman-Rich Syndrome) Severe dyspnea over 1-2 days with high fever
Respiratory failure rapidly ensues
Non-specific interstitial pneumonia/fibrosis NSIP
A diagnosis of exclusion
Should consider a several diseases before this diagnosis is made:
Collagen vascular disease
Drug reactions (amiodarone, nitrofurantoin)
Inhalation of organic dust
Slowly resolving acute lung injury
Inadequately sampled UIP or BOOP
End-stage of interstitial lung disease characterized by large cysts composed of thick firm fibrous tissue resembling a honeycomb, most prominent in the subpleura and bases
HISTOLOGICAL TYPES CHARACTERIZATION Usual Interstitial Pneumonitis UIP
Temporal heterogeneity is the hallmark with variation in the degree of involvement and appearance of the interstitial infiltrate
Alternating zones of inflammation, fibrosis, honeycomb change, and normal lung
Inflammatory cells usually lymphocytes, plasma cells, and mast cells-in general the inflammation is scant and the diagnosis should be questioned if prominent
No hyaline membranes are present
Intimal proliferation and medial thickening of the muscular pulmonary arteries
Desquamative interstitial pneumonitis DIP Temporal uniformity
Increased macrophages within alveolar spaces
Often interstitial fibrosis
Respiratory brochiolitis-associated interstitial lung disease (RB-ILD) Considered a variant of DIP
Patchy rather than diffuse process and localized to peribronchiolar parenchyma
Respiratory bronchiolitis-associated interstitial lung disease and its relationship to desquamative interstitial pneumonia.
Yousem SA, Colby TV, Gaensler EA.
Department of Pathology, Presbyterian University Hospital of Pittsburgh, Pennsylvania.
Mayo Clin Proc 1989 Nov;64(11):1373-80 Abstract quote
Respiratory bronchiolitis is a mild inflammatory reaction commonly noted in asymptomatic cigarette smokers.
We reviewed 18 cases of respiratory bronchiolitis-associated interstitial lung disease (RB/ILD), which had been diagnosed on the basis of clinical evaluation and open-lung biopsy. All patients were cigarette smokers. The sex distribution of the patients was approximately equal, and their mean age was 36 years. Chest roentgenograms showed reticular or reticulonodular infiltrates in 72% of the patients.
Histologically, inflammation of the respiratory bronchioles, filling of the bronchiolar lumens and surrounding alveoli with finely pigmented macrophages, associated interstitial inflammation, and mild fibrosis were noted. In most patients, respiratory improvement ensued when they stopped smoking. Because of histologic similarities to desquamative interstitial pneumonia (DIP), the 18 cases of RB/ILD were compared with 36 cases of DIP.
DIP tended to occur in older persons, caused more severe symptoms, displayed ground glass infiltrates on chest roentgenograms, was characterized by more severe interstitial disease on pulmonary function tests, and was often associated with progressive respiratory disease.
Clinical significance of respiratory bronchiolitis on open lung biopsy and its relationship to smoking related interstitial lung disease.
Moon J, du Bois RM, Colby TV, Hansell DM, Nicholson AG.
Interstitial Lung Disease Unit, London SW3 6NP, UK Department of Pathology, Mayo Clinic, Scottsdale, Arizona, USA.
Thorax 1999 Nov;54(11):1009-14 Abstract quote
BACKGROUND: Respiratory bronchiolitis-associated interstitial lung disease (RBILD) is a rare form of interstitial lung disease which may present in similar fashion to other types of chronic interstitial pneumonia. The purpose of this study was to undertake a clinicopathological review of 10 patients with RBILD and to examine the clinical and imaging data related to its histopathological pattern, in particular the relationship of RBILD to smoking.
METHODS: Thirteen out of 168 retrospectively reviewed patients, from whom biopsy specimens were taken for suspected diffuse lung disease, were identified with a histopathological pattern of RBILD. Three cases were rejected as follow up data were unavailable. The 10 remaining cases constituted the study group and both clinical and imaging data were collected from patients' notes and referring physicians.
RESULTS: Histopathologically, four cases of RBILD overlapped with the pattern of desquamative interstitial pneumonitis (DIP) and nine also had microscopic evidence of centrilobular emphysema. Nine patients were smokers, ranging from 3 to 80 pack years. The one non-smoker had an occupational exposure to the fumes of solder flux. The sex distribution was equal with an age range of 32-65 years. Two patients were clubbed. Lung function tests showed both restrictive and obstructive patterns together with severe reductions in carbon monoxide transfer factor in seven patients. Chest radiographs showed reticular or reticulonodular infiltrates in five patients and a ground glass pattern in two. CT scans were consistent with either DIP or RBILD in six of eight patients. Although seven patients remained stable or improved, either with or without treatment, three patients deteriorated.
CONCLUSIONS: This study adds weight to the hypothesis that smoking can cause clinically significant interstitial lung disease, with deterioration in pulmonary function despite treatment. Given the overlapping histopathological patterns of RBILD and DIP and their strong association with smoking, the term "smoking related interstitial lung disease" is suggested for those patients who are smokers.
Respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease, and desquamative interstitial pneumonia: different entities or part of the spectrum of the same disease process?
Heyneman LE, Ward S, Lynch DA, Remy-Jardin M, Johkoh T, Muller NL.
Department of Radiology, Vancouver Hospital and Health Sciences Centre, University of British Columbia, Canada.
AJR Am J Roentgenol 1999 Dec;173(6):1617-22 Abstract quote
OBJECTIVE: Our objective was to assess high-resolution CT findings of respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease, and desquamative interstitial pneumonia and to determine whether these three entities could be reliably differentiated by radiologic criteria.
MATERIALS AND METHODS: CT scans (1- to 3-mm collimation) were reviewed in 40 patients with pathologically proven respiratory bronchiolitis (n = 16), respiratory bronchiolitis-associated interstitial lung disease (n = 8), or desquamative interstitial pneumonia (n = 16). All patients with respiratory bronchiolitis and respiratory bronchiolitis-associated interstitial lung disease were cigarette smokers, and 85% of the patients with desquamative interstitial pneumonia had a history of smoking. CT scans were independently reviewed by two radiologists who assessed the pattern and distribution of abnormalities.
RESULTS: The predominant abnormalities in respiratory bronchiolitis were centrilobular nodules (12 [75%] of 16 patients) and ground-glass attenuation (six [38%] of 16). No single abnormality predominated in the respiratory bronchiolitis-associated interstitial lung disease group; findings included ground-glass attenuation (four [50%] of eight), centrilobular nodules (three [38%] of eight), and mild fibrosis (two [25%] of eight). All patients with desquamative interstitial pneumonia showed ground-glass attenuation, and 10 (63%) of the 16 showed evidence of fibrosis.
CONCLUSION: The significant overlap between the CT findings of respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease, and desquamative interstitial pneumonia is consistent with the concept that they represent different degrees of severity of small airway and parenchymal reaction to cigarette smoke.
Respiratory bronchiolitis associated interstitial lung disease (RB-ILD) presenting with haemoptysis.
McWilliams AM, Lake FR.
Department of Respiratory Medicine, Royal Perth Hospital, Western Australia, Australia.
Respirology 2000 Dec;5(4):385-7 Abstract quote
Respiratory bronchiolitis associated interstitial lung disease is an uncommon condition in current or ex-smokers. The presentation is non-specific, but haemoptysis is uncommonly reported in this condition.
We report the case of a 25-year-old woman who presented with significant haemoptysis, dyspnoea, reduced transfer factor and normal clinical examination. In addition, a Medline literature search was performed to review the clinical features and prognosis of this disease. Other causes of haemoptysis were excluded with extensive investigation. The diagnosis was made on thoracoscopic lung biopsy. The patient had significant postoperative complications of prolonged air leak and hydropneumothorax requiring further surgery and prolonged hospital stay. Advice regarding smoking cessation was given. Her pulmonary physiology remains abnormal on follow up but symptoms have improved. Respiratory bronchiolitis-ILD may present with normal examination and radiology.
Haemoptysis in this case may have been associated with the underlying disease but could have been incidental. Diagnosis, in general, requires lung biopsy. As in this patient, lung function does not appear to improve significantly on follow up.
Respiratory bronchiolitis: a clinicopathologic study in current smokers, ex-smokers, and never-smokers.
Fraig M, Shreesha U, Savici D, Katzenstein AL.
Department of Pathology, Upstate Medical University, Syracuse, New York, USA.
Am J Surg Pathol 2002 May;26(5):647-53 Abstract quote
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.
Respiratory bronchiolitis-associated interstitial lung disease: radiologic features with clinical and pathologic correlation.
Park JS, Brown KK, Tuder RM, Hale VA, King Jr TE, Lynch DA.
Department of Radiology, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
J Comput Assist Tomogr 2002 Jan-Feb;26(1):13-20 Abstract quote
PURPOSE: The purpose of this work was to describe the radiographic and CT findings in patients with respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) and to correlate them with clinical, physiologic, and pathologic features.
METHOD: RB-ILD was proved pathologically in all 21 patients. Sixteen (76%) patients were current smokers, and five (24%) patients were ex-smokers. The mean cigarette consumption was 38.7 pack-years. Chest radiographs and CT scans were semiquantitatively analyzed and correlated with clinical findings, physiologic measures, and a pathologic score of disease extent.
RESULTS: The major radiographic findings were bronchial wall thickening in 16 patients (76%) and ground-glass opacity in 12 patients (57%). The predominant initial CT findings were central bronchial wall thickening (proximal to subsegmental bronchi) in 19 patients (90%), peripheral bronchial wall thickening (distal to subsegmental bronchi) in 18 patients (86%), centrilobular nodules in 15 patients (71%), and ground-glass opacity in 14 patients (67%), None of these CT findings had a significant zonal predominance. Other findings were upper lung predominant centrilobular emphysema (57%) and patchy areas of hypoattenuation (38%) with a lower lung predominance. Radiologic findings were similar in both current and ex-smokers. The amount of ground-glass opacity correlated inversely with arterial oxygen saturation ( r = -0.67, p = 0.04), and the areas of hypoattenuation correlated with alveolar-arterial oxygen gradient ( r = 0.56, p = 0.04). The extent of centrilobular nodules correlated with the extent of macrophages in respiratory bronchioles ( r = 0.53, p = 0.03) and with chronic inflammation of respiratory bronchioles ( r = 0.57, p = 0.02). The extent of ground-glass opacity correlated with the amount of macrophage accumulation in the alveoli and alveolar ducts ( r = 0.56, p < 0.01 and r = 0.54, p = 0.04, respectively). At follow-up CT after steroid treatment and smoking cessation, in nine patients, the extent of bronchial wall thickening, centrilobular nodules, and ground-glass opacity had decreased, but the areas of hypoattenuation had increased (p < 0.05).
CONCLUSION: The CT findings of RB-ILD are centrilobular nodules, ground-glass opacity, and air trapping. These radiologic features, in patients with a history of heavy cigarette smoking, may differentiate RB-ILD from other interstitial lung diseases.
Acute interstitial pneumonitis AIP (Hamman-Rich Syndrome)
Temporally uniform though variable in intensity interstitial fibroblast proliferation with variable amounts of associated chronic inflammation
Resembles organizing stage of diffuse alveolar lung damage
May have remnants of hyaline membranes
Fibroblasts with relatively little collagen deposition
Alveolar epithelial hyperplasia
Non-specific interstitial pneumonia/fibrosis NSIP
Temporally uniform interstitial inflammatory and fibrosing process with varying amounts of inflammation and fibrosis
Alveolar pneumocyte hyperplasia
Enlarged airspaces surrounded by fibrosis and lined by hyperplastic bronchiolar or alveolar epithelium
May have adjacent bronchiectasis
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES Diffuse alveolar damage (DAD) Usual Interstitial Pneumonitis UIP Temoral heterogeneity Desquamative interstitial pneumonitis DIP
Must distinguish from DIP-like reactions in many other diseases including UIP and eosinophilic granuloma
There is temporal uniformity of changes in this disease
Acute interstitial pneumonitis AIP (Hamman-Rich Syndrome) Temporal uniformity Non-specific interstitial pneumonia/fibrosis NSIP Must rule out secondary causes of interstitial pneumonia
PROGNOSIS AND TREATMENT CHARACTERIZATION Prognostic Factors
Idiopathic interstitial fibrosis: the clinical relevance of pathologic classification.
Katzenstein A-L A, Myers JL.
Am J Respir Crit Care Med 1998;157:1301–15.
Bad-prognosis lesions (UIP) versus generally good-prognosis lesions (DIP, bronchiolitis obliterans organizing pneumonia [BOOP], respiratory bronchiolitis with interstitial lung disease, nonspecific interstitial pneumonia, extrinsic allergic alveolitis)
Usual Interstitial Pneumonitis UIP Male and clinical evidence of advanced disease associated with poorer prognosis Desquamative interstitial pneumonitis DIP Better prognosis than UIP Acute interstitial pneumonitis AIP (Hamman-Rich Syndrome) Fulminant and rapidly progressive Non-specific interstitial pneumonia/fibrosis NSIP Overall good prognosis
No deaths if patients were grouped according to no fibrosis
5 Year Survival Usual Interstitial Pneumonitis UIP Death in 60%
Median survival of 4-5 years
Desquamative interstitial pneumonitis DIP Death in 25%
Survival usually 12 years
Acute interstitial pneumonitis AIP (Hamman-Rich Syndrome) Death in 70% Non-specific interstitial pneumonia/fibrosis NSIP Death in 11% Treatment Corticosteroids with cytotoxic agents such as cyclophosphamide
Katzenstein and Askin's Surgical Pathology of Non-Neoplastic Lung Disease. Volume 13. W.B. Saunders 1997
Am J Surg Pathol 2000:24;19-33.
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