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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.


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SYNONYMS Idiopathic interstitial pneumonia
Interstitial pneumonitis
Usual Interstitial Pneumonitis
Desquamative interstitial pneumonitis
Acute interstitial pneumonitis
Hamman-Rich Syndrome
Accelerated interstitial pneumonitis
Idiopathic ARDS
Non-specific interstitial pneumonia/fibrosis
Usual Interstitial Pneumonitis
Most common of idiopathic pneumonias
Desquamative interstitial pneumonitis
Acute interstitial pneumonitis
Non-specific interstitial pneumonia/fibrosis
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


Cigarette smokers 90% of DIP patients have this history


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.

Extracellular matrix metalloproteinase inducer in interstitial pneumonias.

First Department of Medicine, Hokkaido University Hospital, Sapporo 060-8638, Japan.


Hum Pathol. 2006 Aug;37(8):1058-65. Abstract quote

Extracellular matrix metalloproteinase inducer (EMMPRIN), a glycosylated transmembrane protein that induces matrix metalloproteinases (MMPs), is minimally expressed in the normal adult lung.

We previously reported that it is up-regulated in murine bleomycin-induced lung injury. In this study, we determined the expression of EMMPRIN and its association with MMP-2, MMP-7, and MMP-9 in interstitial pneumonias (IPs). We performed immunohistochemistry for EMMPRIN and MMPs on lung tissue from 22 subjects with various IPs.

We did bronchoalveolar lavage (BAL) on 9 of these subjects and 13 others with IPs to measure the soluble EMMPRIN in BAL fluid. For comparison, immunohistochemistry or BAL was done on 14 subjects without IPs. The staining intensity for each protein was scored from 0 to 3 in various epithelial cell types. Soluble EMMPRIN in BAL fluid was measured by an enzyme-linked immunosorbent assay. Extracellular matrix metalloproteinase inducer was prominent in abnormal epithelial cells. It was more prominent in hyperplastic type II cells, compared with epithelium in alveolar bronchiolization. It was also elevated in BAL fluid from the subjects with IPs. Matrix metalloproteinases were expressed in cells expressing EMMPRIN, although the profile of MMPs varied among the different abnormal epithelial cell types with MMP-2 and MMP-7 in hyperplastic type II cells and MMP-7 and MMP-9 in cells showing squamous metaplasia and cells comprising bronchiolization.

These results suggest a role of EMMPRIN in reepithelialization in IPs.
The Role of Microvascular Injury in the Evolution of Idiopathic Pulmonary Fibrosis

Cynthia M. Magro, MD,1 James Allen, MD,2 Amy Pope-Harman, MD,2 W. James Waldman, PhD,1 Patrick Moh, PhD,3 Susan Rothrauff, PA-C,4 and Patrick Ross, Jr, MD, PhD

Am J Clin Pathol 2003;119:556-567 Abstract quote

Interstitial lung disease compatible with idiopathic pulmonary fibrosis (IPF) developed in 19 previously healthy patients. Although interstitial and/or honeycomb parenchymal fibrosis was present in all, there were patchy areas of paucicellular septal capillary injury along with corroborative direct immunofluorescent evidence of a humorally mediated microvascular injury syndrome.

Significantly elevated factor VIII levels were seen in 17 of 18 patients tested. Antiphospholipids were present in all 18 patients tested, comprising antibodies of phosphatidylethanolamine, beta-2 glycoprotein, phosphatidylcholine, and/or phosphatidylserine. Anti-Ro and/or anti-ribonucleoprotein (RNP) antibodies were seen in 4 patients. Serologic evidence of infection with cytomegalovirus (CMV) was found in 9 patients and parvovirus B19 (B19) in 9 patients; 1 patient was not tested. Molecular studies revealed B19 DNA in 6 of 6 B19-seropositive patients. In situ hybridization studies revealed CMV RNA in pulmonary cells in patients with serologic evidence of active CMV infection despite the absence of cytopathic changes typical of CMV infection.

Antiphospholipid antibodies, antiendothelial cell antibodies, and/or endotheliotropic viral infections related to B19 and CMV may be of pathogenetic importance to the evolution of IPF. This report underscores the potential importance of microvascular injury in the evolution of IPF.


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.


Chest radiograph

Interstitial linear opacities with hazy ground glass appearance on chest radiographs

Honeycomb appearance with advanced disease


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
Flu-like symptoms
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

Honeycomb lung

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


Acute Exacerbation (Acute Lung Injury of Unknown Cause) in UIP and Other Forms of Fibrotic Interstitial Pneumonias.

Departments of Pathology and Radiology, University of British Columbia, Vancouver, BC, Canada.


Am J Surg Pathol. 2007 Feb;31(2):277-84. Abstract quote

Acute exacerbation of usual interstitial pneumonia (UIP) is a condition in which patients with UIP, and occasionally other forms of fibrotic interstitial lung disease, develop rapid respiratory failure, accompanied by extensive radiologic infiltrates. The pathologic features of this condition are ill-defined in the literature and the outcome is unclear.

We report 12 such patients, 9 with underlying UIP, 2 with underlying fibrotic nonspecific interstitial pneumonia, and 1 with underlying chronic hypersensitivity pneumonitis, who underwent surgical lung biopsy for diagnosis. High-resolution computed tomography data were available in 11 cases and showed the presence of extensive bilateral ground-glass opacities, sometimes accompanied by focal consolidation, superimposed on underlying fibrosis.

Three microscopic patterns of acute lung injury were seen: diffuse alveolar damage (DAD), organizing pneumonia (OP), and a pattern of numerous very large fibroblast foci superimposed on underlying fibrosis. After the biopsy, all patients were treated with steroids, in some instances accompanied by cyclophosphamide or azathioprine. Ten patients survived the acute episode and were discharged with survival times of 1 to 11 months; of these cases, 6 showed a pattern of OP or OP plus extensive fibroblast foci; 2 a pattern of extensive fibroblast foci only; and 2 a pattern of DAD. Both patients who died had histologic DAD.

We conclude that acute exacerbation of UIP and other fibrotic lung diseases produces a variety of pathologic patterns on biopsy, and that patients with OP or extensive fibroblast foci as the acute pattern seem to do better than those with DAD. Our data also imply that survival (of the acute episode) may be better than the literature suggests.

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

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

Katzenstein AL, Zisman DA, Litzky LA, Nguyen BT, Kotloff RM.

Am J Surg Pathol 2002 Dec;26(12):1567-77 Abstract quote

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.

Increased macrophages within alveolar spaces
Often interstitial fibrosis
Minimal inflammation
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.

Idiopathic bronchiolocentric interstitial pneumonia.

Yousem SA, Dacic S.

Department of Pathology, University of Pittsburgh Medical Center, Presbyterian University Hospital, Pittsburgh, Pennsylvania.


Mod Pathol 2002 Nov;15(11):1148-53 Abstract quote

The authors report 10 patients with a distinctive idiopathic bronchiolocentric interstitial pneumonia having some histologic similarities to hypersensitivity pneumonitis. Bronchiolocentric interstitial pneumonia has a marked predilection for women (80%) and occurs in middle age (40-50 years).

Chest radiographs and pulmonary function tests show interstitial and restrictive lung disease, while the histologic appearance is that of a centrilobular inflammatory process with small airway fibrosis and inflammation that radiates into the interstitium of the distal acinus in a patchy fashion. Granulomas are not identified. At a mean followup of approximately 4 years in nine patients, 33% of patients were dead of disease and 56% had persistent or progressive disease suggesting a more aggressive course than hypersensitivity pneumonitis and nonspecific interstitial pneumonia, the two major disease processes in the differential diagnosis.

Whether Bronchiolocentric interstitial pneumonia is a unique entity or not, the pattern of bronchiocentric injury to the lung in the absence of known causes and its clinical presentation as interstitial lung disease, warrants further investigation of this unusual interstitial process.


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


Temporally uniform interstitial inflammatory and fibrosing process with varying amounts of inflammation and fibrosis

Alveolar pneumocyte hyperplasia


Airway-centered Interstitial Fibrosis: A Distinct Form of Aggressive Diffuse Lung Disease.

Churg A, Myers J, Suarez T, Gaxiola M, Estrada A, Mejia M, Selman M.

Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada; dagger Department of Pathology, Mayo Clinic, Rochester, Minnesota; and double dagger Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico.

Am J Surg Pathol. 2004 Jan; 28(1): 62-8. Abstract quote  

SUMMARY: We describe 12 patients with a form of interstitial lung disease characterized pathologically by small airway-centered interstitial fibrosis and metaplastic bronchiolar epithelium extending around and often linking fibrotic and sometimes heavily muscularized bronchioles. Clinically, patients presented with chronic cough and progressive dyspnea. One was a current light smoker and two were ex-smokers.

In 8 patients, a history of possible inhalational exposures, including wood smoke, birds, cotton, pasture, chalk dust, agrochemical compounds, and cocaine use, was elicited. Pulmonary function tests showed moderate to severe physiologic abnormalities, in most instances indicating a restrictive lung disease with decreased peripheral flow rates. Chest radiographs revealed predominantly diffuse reticulonodular infiltrates in the central lung fields, with thickening of the bronchial walls and decreased lung volumes. Chest computed tomography demonstrated peribronchovascular fibrosis and interstitial thickening. Bronchoalveolar lavage showed a mild increase in lymphocytes in 4 subjects. Patients were treated with corticosteroids and bronchodilators.

Follow-up data were available in 10 patients. In 5 patients, the disease progressed and 4 of them died. Two patients remained stable and 3 improved or healed. We propose that these findings represent a distinct airway-centered disease that mostly behaves as an interstitial lung disease and may exhibit a poor outcome.
Terminal Diffuse Alveolar Damage in Relation to Interstitial Pneumonias
An Autopsy Study

Alexandra J. Rice, MBBChir,1 Athol U. Wells, MD,2 Demos Bouros, MD,3 Roland M. du Bois, MD,2 David M. Hansell, MD,4 Vlasis Polychronopoulos, MD,5 Dimitris Vassilakis, MD,3 Jonathan R. Kerr, MD,6 Timothy W. Evans, MD,7 and Andrew G. Nicholson, DM

Am J Clin Pathol 2003;119:709-714 Abstract quote

Acute exacerbations of idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis (IPF/CFA) are rare and typically terminal events, but their relationship to underlying patterns of idiopathic interstitial pneumonias is unknown.

We reviewed autopsy material from patients who died of diffuse alveolar damage in the clinical setting of pulmonary fibrosis, both idiopathic and with background fibrosing alveolitis with connective tissue disorders (FA-CTDs), and compared them with cases of acute interstitial pneumonia. Of 15 patients with acute exacerbations of IPF/CFA (n = 12) or FA-CTD (n = 3), 12 had a background pattern of usual interstitial pneumonia and 3 had fibrotic nonspecific interstitial pneumonia. All cases of fibrotic nonspecific interstitial pneumonia were seen in association with FA-CTD. The cause of acute exacerbations is unknown, but our data suggest that toxic effects of oxygen and triggering infection are unlikely causes.

In patients with CTDs, it remains uncertain whether the acute exacerbation is related to the fibrosis, the associated CTD, or a combination of these factors. Acute exacerbations of IPF/CFA may be a more common terminal event than previously thought.


Surgical pathology of granulomatous interstitial pneumonia.

Cheung OY, Muhm JR, Helmers RA, Aubry MC, Tazelaar HD, Khoor A, Leslie KO, Colby TV.

Departments of Pathology and Laboratory Medicine, Radiology, and Division of Pulmonary Medicine, Mayo Clinic, Scottsdale, AZ; the Departments of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN; the Mayo Clinic, Jacksonville, FL; and the Department of Pathology, Queen Elizabeth Hospital, Hong Kong.

Ann Diagn Pathol 2003 Apr;7(2):127-138 Abstract quote

Agranulomatous interstitial pneumonia is a form of diffuse lung disease in which granulomas are a component of the histologic findings. The differential diagnosis is quite broad, but most cases represent examples of either sarcoidosis, diffuse granulomatous infections, or hypersensitivity pneumonitis.

"Hot tub lung" is a recently described form of granulomatous interstitial pneumonia that appears to have some features of diffuse infections and some features of hypersensitivity pneumonitis.

The pathologist's approach to these conditions can be facilitated by giving careful attention to the anatomic distribution of the granulomas, the qualitative features of the granulomas, and the histologic changes in the lung tissue around and away from the granulomas. These features, along with the results of cultures and special stains for micro-organisms and clinical and radiologic correlation allow for a diagnosis in the vast majority of cases.


Enlarged airspaces surrounded by fibrosis and lined by hyperplastic bronchiolar or alveolar epithelium

May have adjacent bronchiectasis

Chronic Hypersensitivity Pneumonitis.

Churg A, Muller NL, Flint J, Wright JL.

From the Departments of *Pathology and daggerRadiology, University of British Columbia, Vancouver, British Columbia, Canada.

Am J Surg Pathol. 2006 Feb;30(2):201-208. Abstract quote  

Hypersensitivity pneumonitis (HP) is traditionally divided on clinical grounds into acute, subacute, and chronic stages. Most biopsy specimens come from patients in the subacute stage, in which there is a relatively mild, usually peribronchiolar, chronic interstitial inflammatory infiltrate, accompanied in most cases by poorly formed interstitial granulomas or isolated giant cells. However, the pathologic features in the chronic, ie, fibrotic stage, are poorly defined in the literature. These features are important to recognize because the chronic stage of HP is often associated with a poor prognosis.

We reviewed 13 cases of chronic HP. Where information was available, exposures to the sensitizing agent had generally occurred over a long period of time. Three patterns of fibrosis were seen: 1) predominantly peripheral fibrosis in a patchy pattern with architectural distortion and fibroblast foci resembling, microscopically, usual interstitial pneumonia (UIP); 2) relatively homogeneous linear fibrosis resembling fibrotic nonspecific interstitial pneumonia (NSIP); and 3) irregular predominantly peribronchiolar fibrosis. In some instances, mixtures of the UIP-like and peribronchiolar patterns were found. In all cases, the presence of scattered poorly formed granulomas, or isolated interstitial giant cells, or sometimes only Schaumann bodies indicated the correct diagnosis. In 7 cases, areas of typical subacute HP were present as well.

High-resolution CT scans showed variable patterns ranging from severe fibrosis, in some instances with an upper zone predominance, to predominantly ground glass opacities with peripheral reticulation. We conclude that, at the level of morphology, chronic HP may closely mimic UIP or fibrotic NSIP. If no areas of subacute HP are evident, the presence of isolated giant cells, poorly formed granulomas, or Schaumann bodies is crucial to arriving at the correct diagnosis, and the finding of peribronchiolar fibrosis may be helpful.

Despite the presence of extensive fibrosis, some patients responded to removal from exposure and steroid therapy.
Peribronchiolar metaplasia: a common histologic lesion in diffuse lung disease and a rare cause of interstitial lung disease: clinicopathologic features of 15 cases.

Fukuoka J, Franks TJ, Colby TV, Flaherty KR, Galvin JR, Hayden D, Gochuico BR, Kazerooni EA, Martinez F, Travis WD.

Laboratory of Population Genetics, National Cancer Institute, Bethesda, MD, USA.
Am J Surg Pathol. 2005 Jul;29(7):948-54. Abstract quote  

Peribronchiolar metaplasia (PBM) is a histologic lesion consisting of peribronchiolar metaplasia (PBM) of bronchiolar-type epithelium. Although widely recognized, PBM has received little attention in the pathologic literature and is not known to have clinical significance.

We identified 15 cases in which PBM was the only major histologic finding in surgical lung biopsies from patients with interstitial lung disease (PBM-ILD), and we reviewed the clinical, imaging, and pathologic findings. The mean age was 57 years (range, 44-74 years) with 13 females and 2 males. One patient had been a welder with fume and asbestos exposure; another had pigeon exposure. Smoking history was available for 13 patients: three current smokers, one cocaine user, two former smokers, and seven never smokers. Three patients had collagen vascular disease. One had elevated serum antinuclear antibody titers. Pulmonary function data were available for 10 patients: one obstructive, five restrictive, two mixed obstructive and restrictive, and two normal.

Computerized tomography in 7 patients showed mosaic attenuation in 3 patients and air trapping in 1 patient; no bronchiectasis, septal lines, or honeycombing were seen in any cases. All 11 patients with available follow-up are alive; 4 of them have experienced symptomatic improvement (follow-up, 0.6-6.9 years; mean, 2.4 years). PBM was found focally in other interstitial lung diseases, which were assessed for this lesion: 59% of usual interstitial pneumonia (17 of 29), 50% of nonspecific interstitial pneumonia (10 of 20), desquamative interstitial pneumonia (3 of 6), hypersensitivity pneumonitis (9 of 18), and 11% of respiratory bronchiolitis (2 of 18).

In summary, PBM is a common histologic finding in various interstitial lung disorders. It is rarely the sole major lung biopsy finding in patients presenting with interstitial lung disease (PBM-ILD). Patients are mostly older women, with mild symptoms and CT findings. Survival appears to be favorable.


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
Smoking-related interstitial lung disease.

Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Ann Diagn Pathol. 2008 Dec;12(6):445-57 Abstract quote

Pulmonary diseases associated with tobacco smoking are a complex group of disorders ranging from chronic obstructive pulmonary disease (COPD) to lung cancer. Interstitial lung diseases (ILDs) have only recently been linked to smoking.

The ILDs related to smoking include respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, and pulmonary Langerhans cell histiocytosis. The relationship of smoking with each of these entities has been largely established on the weight of epidemiologic evidence. Although they have been retained as distinct and separate conditions in various classifications of interstitial lung diseases, these 3 entities share a number of clinical, radiologic, and pathologic features suggesting that they represent a spectrum of patterns of interstitial lung disease occurring in predisposed individuals who smoke.

Evaluation of histologic features, particularly in surgical lung biopsy samples, is important in making the distinction between these disorders. However, even after tissue biopsy, it may sometimes be difficult to clearly separate these entities. The importance of making the distinction between them lies in the different clinical management strategies used.

Further experimental evidence, including genetic information, may be important in improving our understanding of these diseases.


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

Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008

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