Intraluminal fibromyxoid lesions in bronchiolitis obliterans organizing pneumonia are high capillarized

doi:10.1016/S0046-8177(99)90036-9

Human Pathology

Volume 30, Issue 10, October 1999, Pages 1192-1196

https://doi.org/10.1016/S0046-8177(99)90036-9 Get rights and content

Abstract

Bronchiolitis obliterans organizing pneumonia (BOOP) and usual interstitial pneumonia (UIP; ie, cryptogenic fibrosing alveolitis of mural type, CFA) are clinically and histologically distinguishable interstitial lung diseases. Both contain intraluminal lesions of newly formed fibromyxoid connective tissue. In BOOP, the fibromyxoid lesions are susceptible to complete reversal, but in UIP they are supposed to participate in the remodeling of the interstitium. Our hypothesis was that capillarization of the intraluminal fibromyxoid lesions is more frequent in BOOP compared with UIP. In this study, we stained diagnostic thoracoscopic or open lung biopsy specimens of patients with BOOP (n = 9) and IUP (n = 10) with antibodies against human laminim, von Willebrand factor, and CD34 to reveal the microvasculature of intraluminal fibromyxoid lesions. Our results show that in BOOP there is abundant capillarization in the newly formed intraluminal fibromyxoid lesions often reminiscent of granulation tissue. The mean number of capillaries per area unit (mm²) was 107 ± SD 74 in samples stained for laminin, 103 ± SD 46 for von Willebrand factor, and 63 ± SD 36 for CD34. In marked contrast, in UIP, the corresponding accounts were significantly lower, being 14 ± SD 15 for laminin (P < .003, 11 ± SD 14 for von Willebrand factor (P < .001) and 6 ± SD 6 for CD34 (P < .001). The intraobserver (P < .001) and interobserver correlations (P < .002) were highly significant, showing that our results are reproducible. We conclude that the content and nature of the newly formed intraluminal connective tissue, for example, in the form of vascular growth factors, are different in BOOP and in UIP, and this partly leads to the different clinical course of these diseases.

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Cited by (49)

Artificial intelligence identifies inflammation and confirms fibroblast foci as prognostic tissue biomarkers in idiopathic pulmonary fibrosis
2021, Human Pathology
Citation Excerpt :
The acute exacerbation of IPF can manifest histologically as OP or extensive FF superimposed on the UIP pattern [45]. Compared with the samples from patients with cryptogenic OP, which is characterized by reversible disease course, decreased vascularity and apoptosis of intraluminal fibrosis have been reported in the samples from patients with IPF [46,47]. Both OP and FF have been associated with a decline in FVC% at six-month follow-up [9].
A large number of fibroblast foci (FF) predict mortality in idiopathic pulmonary fibrosis (IPF). Other prognostic histological markers have not been identified. Artificial intelligence (AI) offers a possibility to quantitate possible prognostic histological features in IPF. We aimed to test the use of AI in IPF lung tissue samples by quantitating FF, interstitial mononuclear inflammation, and intra-alveolar macrophages with a deep convolutional neural network (CNN). Lung tissue samples of 71 patients with IPF from the FinnishIPF registry were analyzed by an AI model developed in the Aiforia® platform. The model was trained to detect tissue, air spaces, FF, interstitial mononuclear inflammation, and intra-alveolar macrophages with 20 samples. For survival analysis, cut-point values for high and low values of histological parameters were determined with maximally selected rank statistics. Survival was analyzed using the Kaplan-Meier method. A large area of FF predicted poor prognosis in IPF (p = 0.01). High numbers of interstitial mononuclear inflammatory cells and intra-alveolar macrophages were associated with prolonged survival (p = 0.01 and p = 0.01, respectively). Of lung function values, low diffusing capacity for carbon monoxide was connected to a high density of FF (p = 0.03) and a high forced vital capacity of predicted was associated with a high intra-alveolar macrophage density (p = 0.03). The deep CNN detected histological features that are difficult to quantitate manually. Interstitial mononuclear inflammation and intra-alveolar macrophages were novel prognostic histological biomarkers in IPF. Evaluating histological features with AI provides novel information on the prognostic estimation of IPF.
Cryptogenic organizing pneumonia
2016, Revue des Maladies Respiratoires
La pneumopathie organisée est une réaction inflammatoire particulière du parenchyme pulmonaire donnant lieu à un syndrome clinico-pathologique. Elle est dite secondaire lorsqu’une cause a pu être identifiée et cryptogénique dans le cas contraire. La présentation clinique habituelle est caractérisée par l’apparition subaiguë de symptômes généraux et respiratoires, avec classiquement des condensations plurifocales à l’imagerie thoracique.
La pneumopathie organisée cryptogénique est caractérisée histologiquement par la présence de bourgeons de tissu conjonctif intra-alvéolaires. La pathogenèse débute par une lésion de l’épithélium alvéolaire conduisant à un dépôt de fibrine dans les espaces aériens, puis une migration de fibroblastes produisant une matrice myxoïde intra-alvéolaire. Une caractéristique remarquable de la pneumopathie organisée est la résolution complète de ces bourgeons fibroblastiques sous traitement corticoïde, contrairement à ce qui s’observe en cas de fibrose pulmonaire. La réponse clinique aux corticostéroïdes est habituellement rapide et excellente. Les rechutes sont fréquentes mais généralement sans gravité.
Si les caractéristiques clinico-pathologiques de la pneumopathie organisée cryptogénique sont maintenant bien établies, il reste de nombreuses questions à élucider, notamment les mécanismes impliqués dans la réversibilité des lésions pulmonaires, et la place des traitements d’épargne corticoïde, tels que les macrolides à effet immunomodulateur.
Organizing pneumonia is a particular type of inflammatory reaction of the lung which gives rise to a clinico-pathological syndrome. It is called “secondary” when a cause such as an infection, a drug toxicity, or a connective tissue disease can be identified, or “cryptogenic” when no cause is identified. The clinical picture is usually characterized by the subacute onset of fever, fatigue, cough and dyspnea, with multiple subpleural areas of consolidation on thoracic imaging.
Organizing pneumonia is characterised by the presence of buds of endoalveolar connective tissue. These result from an injury to the alveolar epithelium, followed by the deposition of fibrin in the alveolar spaces, and the migration of fibroblasts which produce a myxoid endoalveolar matrix. A remarkable feature of organizing pneumonia is the complete disappearance of these endoalveolar buds with corticosteroid treatment, in sharp contrast with what is seen in pulmonary fibrosis. The clinical response to corticosteroids is usually prompt and excellent. Relapses are frequent but usually benign.
As the clinical, imaging and pathological characteristics of organizing pneumonia are now well established, many questions remain unanswered, such as the mechanisms involved in the complete reversibility of the pulmonary lesions, and the role of steroid-sparing treatments such as immunomodulatory macrolides.
Lymphatics in non-tumoral pulmonary diseases. Review
2013, Revue de Pneumologie Clinique
Bien que moins étudiée que la microcirculation sanguine, il apparaît bien que la circulation lymphatique joue un rôle important dans la pathologie pulmonaire non tumorale. Cette courte revue générale fait le point de l’actualité des connaissances actuelles (en excluant la lymphangioléïomyomatose qui sera traitée dans un autre article). Ainsi, un remodelage lymphatique a été mis en évidence aussi bien dans l’asthme que dans les pathologies interstitielles fibrosantes. Ce remodelage peut à la fois répondre à un nouvel équilibre de la fluidique locale mais peut être également un facteur de progression du processus fibrosant. Par ailleurs, les relations entre les lymphatiques juxta-alvéolaires et les granulomes dans la sarcoïdose permettent de mieux comprendre les mécanismes pathogéniques de cette affection.
Whereas lymphatics in pulmonary non-tumoral diseases have been less studied than blood microcirculation, they clearly play a significant role. This review is a short update on lymphatics in various non-tumoral pulmonary diseases, from asthma to interstitial pneumonitis, excluding lymphangioleiomyomatosis. A lymphatic remodelling has been evidenced in asthma as well as in acute or chronic (UIP as NSIP) interstitial lung diseases. Such a remodelling can be explained as a side effect of local changes in fluidics but could also be an active player in the fibrosing process. Moreover the association of juxta-alveloar lymphatics and granulomas provides new insights in the emergence of these lesions in pulmonary sarcoidosis.
Organizing pneumonia
2010, Presse Medicale
La pneumopathie organisée est d’abord une entité anatomopathologique observée dans différentes situations de réparation pulmonaire après une agression, caractérisée par la présence dans les espaces aériens distaux (alvéoles, canaux alvéolaires, bronchioles respiratoires) de bourgeons constitués de fibroblastes dans une matrice extracellulaire lâche.
La même terminologie recouvre également une entité clinique caractérisée par la survenue d’opacités alvéolaires multiples, en plages, particulièrement évocatrices lorsqu’elles sont migratrices. Cette entité se caractérise par une grande corticosensibilité et la grande fréquence des rechutes de la maladie, qui surviennent généralement lors de la décroissance des corticoïdes ou dans les semaines qui suivent leur arrêt. Le diagnostic de certitude nécessite une preuve histologique qui est rarement obtenue lorsque le tableau radioclinique est caractéristique.
Lorsqu’elle survient sans cause identifiée, cette entité est maintenant appelée pneumopathie organisée cryptogénique (anciennement appelée bronchiolite oblitérante avec pneumopathie en voie d’organisation, ou BOOP). La même entité peut s’observer dans des contextes définis (connectivites par exemple), ou avec des causes identifiées (notamment radiothérapie pour cancer du sein, médicaments, infections).
Organizing pneumonia is first of all a pathologic entity observed in different situations of pulmonary repair after aggression. It is characterized by the presence in the distal airways (alveoli, alveolar ducts, and respiratory bronchioli) of fibroblastic buds in a loose extracellular matrix.
The same terminology also describes a clinical entity characterized by the appearance of patches of multiple alveolar opacities, especially suggestive when they are migratory. This entity is characterized by strong sensitivity to corticosteroids and the high frequency of disease relapses, which generally occur when the corticosteroid dose is reduced or in the weeks after treatment stops. Diagnostic certainty requires histologic proof, which is rarely obtained when the radiographic and clinical picture is typical.
When it occurs without an identified cause, this entity is now known as cryptogenic organizing pneumonia (it was previously called bronchiolitis obliterans with organizing pneumonia, or BOOP). The same entity can be observed in other defined contexts (connective tissue disease, for example), or with identified causes (e.g., radiation therapy for breast cancer, drugs, or infections).
The definition of fibrogenic processes in fibroblastic foci of idiopathic pulmonary fibrosis based on morphometric quantification of extracellular matrices
2009, Human Pathology
Citation Excerpt :
In some reports, capillaries in FF have been shown to be barely detectable in IPF [28,29]. In contrast, Masson's body—an organized fibrotic lesion that is manifested in cryptogenic organizing pneumonia—was observed to be highly capillarized [27]. Because the fibrosis of Masson's body is dissoluble, it has been hypothesized that the absence of capillaries in FF may correlate to the poor prognosis of IPF.
There is limited information regarding the process of tissue remodeling in fibroblastic foci associated with idiopathic pulmonary fibrosis. The aim of this study was to identify the different pathologic stages of tissue remodeling in fibroblastic foci based on the histopathologic differences in the glycosaminoglycan distribution and collagen deposition. In addition, we also aimed at clarifying the stage-specific characteristics by taking into consideration the expression pattern of matrix metalloproteinase and angiogenesis. Lung biopsies of 16 patients with idiopathic pulmonary fibrosis were used. The presence of glycosaminoglycans was detected by Alcian blue staining, and type I collagen was detected by immunohistochemical analysis with a primary antibody specific to the cross-linked carboxyterminal telopeptide of type I collagen. The fibroblastic foci characterized by the expression intensity of Alcian blue and telopeptide of type I collagen were divided into 3 groups, namely, Alcian blue⁺telopeptide of type I collagen^weak, Alcian blue⁺telopeptide of type I collagen⁺, and Alcian blue^weaktelopeptide of type I collagen⁺; consequently, 3 new stages were defined—stages I, II, and III, respectively. A significant inverse correlation was observed between the area densities of Alcian blue⁺ and telopeptide of type I collagen⁺ in fibroblastic foci. Stage I was characterized by the expression of matrix metalloproteinase-2 and tissue inhibitor of matrix metalloprotease-2 in fibroblasts and the overlying epithelium of fibroblastic foci, and also the absence of capillary angiogenesis. In contrast, the expression of these proteins was attenuated in stage III, except for that of matrix metalloproteinase-2 in fibroblasts. In stages II and III, capillary angiogenesis was observed. Lymphangiogenesis was undetected in all the 3 stages. Thus, pathologic staging helps understand the roles of the factors involved in tissue remodeling in idiopathic pulmonary fibrosis.
Characterization of lymphangiogenesis in various stages of idiopathic diffuse alveolar damage
2009, Human Pathology
Citation Excerpt :
We demonstrated that the intra-alveolar fibrotic lesions of DAD included few CD34+ capillaries. In contrast, Masson's body—an organized fibrotic lesion that manifests in cryptogenic organizing pneumonia—was observed to contain many capillaries [34]. Cryptogenic organizing pneumonia is reversible; moreover, fibrosis of Masson's body is repairable.
In pulmonary fibrosis, an abnormal healing process, is believed to be involved in the damage to lung tissue. This process has not been correlated with lymphangiogenesis, which has garnered current interest in relation to wound healing. The aim of the present study was to clarify the characteristics of lymphangiogenesis in pulmonary fibrosis associated with idiopathic diffuse alveolar damage. Formalin-fixed and paraffin-embedded lung tissues from 13 autopsy cases with idiopathic diffuse alveolar damage were used. Antibodies specific to CD34 and D2-40 were used to detect blood vessels and lymphatics, respectively, and immunohistochemical examinations and morphometry analyses were performed. The standardized density of capillaries was increased significantly in the exudative stage of diffuse alveolar damage, whereas that of the lymphatics remained unchanged. In the proliferative stage, new lymphatics emerged, primarily in the intra-alveolar fibrotic lesions where capillaries were absent. In the fibrotic stage, in which the lung was shrunken, as revealed by the elevated density of pulmonary arteries, the standardized density of capillaries was reduced significantly. The standardized area density of the interstitium was elevated in the proliferative stage and subsequently reduced in the fibrotic stage. Three-dimensional reconstruction of images revealed that some new lymphatics lacked connection to existing lymphatics. During the progression of diffuse alveolar damage, lymphangiogenesis occurs independent of capillary angiogenesis.

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Original contributionIntraluminal fibromyxoid lesions in bronchiolitis obliterans organizing pneumonia are high capillarized

Abstract

Cryptogenic fibrosing alveolitis: Clinical features and their influence on survival

Thorax

Bronchiolitis obliterans organizing pneumonia

N Engl J Med

Katzenstein and Askin's Surgical Pathology of Non-Neoplastic Lung Disease

Katzenstein and Askin's Surgical Pathology of Non-Neoplastic Lung Disease

Intraluminal fibrosis in interstitial lung disorders

Am J Pathol

Bronchiolitis obliterans organizing pneumonia: Definition and clinical features

Chest

An immunohistochemical study of architectural remodeling and connective tissue synthesis in pulmonary fibrosis

Am Rev Respir Dis

Alveolitis and collapse in the pathogenesis of pulmonary fibrosis

Am Rev Respir Dis

Pathologic aspects of bronchiolitis obliterans organizing pneumonia

Chest

Morphological aspects of interstitial pulmonary fibrosis

Arch Pathol

Alveolar-capillary membrane in idiopathic interstitial pulmonary fibrosis

Am Rev Respir Dis

Interstitial pulmonary fibrosis

Chest

Precapillary systemic pulmonary anastomoses

Thorax

Intra-alveolar fibrosis of idiopathic bronchiolitis obliterans-organizing pneumonia: Cell-matrix patterns

Am J Pathol

Original contribution
Intraluminal fibromyxoid lesions in bronchiolitis obliterans organizing pneumonia are high capillarized