[Pulmonary Langerhans cell histiocytosis]. / Die pulmonale Langerhans-Zell-Histiozytose.

Pulmonary Langerhans cell histiocytosis is regarded as a reactive proliferation of the dendritic Langerhans cell population stimulated by chronic tobacco-derived plant proteins due to incomplete combustion but can also occur in childhood as a tumor-like systemic disease. Currently, both these forms cannot be morphologically distinguished. In the lungs a nodular proliferation of Langerhans cells occurs in the bronchial mucosa and also peripherally in the alveolar septa with an accompanying infiltration by eosinophilic granulocytes and destruction of the bronchial wall. Langerhans cells can be selectively detected with antibodies against CD1a and langerin. In the reactive isolated pulmonary form, abstinence from tobacco smoking in most patients leads to regression of infiltration and improvement of symptoms. In high-resolution computed tomography (HRCT) the small star-like scars can still be detected even after complete cessation of tobacco smoking.

EGFR and PDGFR differentially promote growth in malignant epithelioid mesothelioma of short and long term survivors.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an asbestos related tumour difficult to detect early and treat effectively. Asbestos causes genetic modifications and cell signalling events that favour the resistance of MPM to apoptosis and chemotherapy. Only a small number of patients, approximately 10%, survive more than 3 years. The aim of our study was to assess possible differences within signalling pathways between short term survivors (survival <3 years; STS) and long term survivors (survival >3 years; LTS) of MPM. METHODS: 37 antibodies detecting proteins engaged in cell signalling pathways, enforcing proliferation, antiapoptosis, angiogenesis and other cellular activities were investigated by tissue microarray (TMA) technology. RESULTS: Epidermal growth factor receptor (EGFR) was expressed stronger in LTS whereas platelet derived growth factor receptor (PDGFR) signalling was more abundant in STS. Expression of TIE2/Tek, a receptor for tyrosine kinases involved in angiogenesis, was differentially regulated via PDGFR and thus is more important in STS. Antiapoptosis was upregulated in STS by signal transducer and activator of transcription 1 (STAT1)-survivin and related molecules, but not in LTS. Our study provides novel insights into the regulatory mechanisms of signalling pathways in MPM, which differentially promote tumour growth in LTS and STS. CONCLUSION: We have demonstrated that small scale proteomics can be carried out by powerful linkage of TMA, immunohistochemistry and statistical methods to identify proteins which might be relevant targets for therapeutic intervention.

Early-life pulmonary arterial hypertension with subsequent development of diffuse pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia type 1.

The case history is presented of a male infant who was thought to have idiopathic pulmonary arterial hypertension (PAH) at 3 months of age. Subsequently the PAH decreased unexpectedly and diffuse pulmonary arteriovenous malformations (PAVMs) were seen at 6.9 years of age for the first time. Hereditary haemorrhagic telangiectasia type 1 (HHT1) related to an endoglin mutation was diagnosed. At 10.3 years of age a lung biopsy showed diffuse PAVMs as well as pulmonary arteriopathy with medial hypertrophy. This is the first case of HHT1 presenting with PAH at such a young age. The subsequent decrease in pulmonary arterial pressure (PAP) was probably caused by the development of PAVMs. In the presence of PAVMs, measurement of the PAP may underestimate the extent of PAH-related vasculopathy.

Necrotizing sarcoid granulomatosis--is it different from nodular sarcoidosis?

BACKGROUND: Necrotizing sarcoid granulomatosis (NSG) was initially defined as a granulomatosis with features in between sarcoidosis and Wegener's granulomatosis (WG), but without extrapulmonary involvement. Subsequent reports have shown that extrapulmonary involvement does exist, and some have suggested NSG as a variant of sarcoidosis. MATERIAL AND METHODS: We studied 10 cases from 3 institutions, and compared clinical and histologic features with those of nodular sarcoidosis and WG. We have analyzed the 10 cases for mycobacterial chaperonin and for the insertion sequence 6110 by PCR. RESULTS AND CONCLUSIONS: Nodular aggregates of granulomas in NSG were similar to those seen in nodular sarcoidosis. Granulocytic vasculitis, a hallmark of WG was not seen in any of the NSG cases. Granulomatous vasculitis was a common feature in cases of NSG, and did not differ from that seen in sarcoidosis. The only unique feature of NSG is infarct-like necrosis, induced by the vasculitis, which might also be interpreted as a function of the duration of the vasculitis, leading ultimately to vascular obstruction. NSG based on our morphologic findings is best classified as a variant of nodular sarcoidosis. In contrast to our findings in sarcoidosis mycobacterial DNA was not found in any of the 10 cases.

Bronchiolitis obliterans. Organizing pneumonia.

Bronchiolitis obliterans combined organizing pneumonia (BOOP), now called organizing pneumonia, is a multi-etiologic disease. It can present as a solitary lesion, or as multinodular or diffuse interstitial lung disease. It is speculated if solitary BOOP may evolve into inflammatory pseudotumor of the lung. BOOP can be seen after non-resolving infectious bronchopneumonia as well as acute interstitial pneumonia with diffuse alveolar damage. BOOP can be the early morphologic pattern in toxic inhalation, especially water-soluble substances, but also in drug induced lung disease. BOOP can be the late stage of extrinsic allergic alveolitis, but also a morphologic sequel of collagen vascular disease. Even Wegener's granulomatosis can be preceded by a BOOP pattern. In many cases a careful analysis of BOOP, including changes of the pneumocytes, macrophages, myofibroblasts and endothelial cells, can establish the correct etiologic diagnosis. For example virus-induced pneumocyte proliferation can be seen months after the onset of interstitial pneumonia, and can be found within BOOP. A small percentage of BOOP, however, has to be labeled as idiopathic, which is important too, because of different modalities of therapy. Idiopathic BOOP also is different with respect to prognosis. In the overview different BOOP etiologies will be discussed, and the etiologic background will be analyzed. The pathogenesis will be discussed with respect to the understanding of the causing mechanisms. The role of bronchoalveolar lavage and the optimal tissue sample for establishing the diagnosis will be discussed and demonstrated by examples. A part of the presentation will deal with the differential diagnosis, such as usual interstitial pneumonia, non-specific interstitial pneumonia, constrictive, and respiratory bronchiolitis combined interstitial lung disease.

Chromosomal aberrations in a series of large-cell neuroendocrine carcinomas: unexpected divergence from small-cell carcinoma of the lung.

Large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC) are high-grade neuroendocrine tumors of the lung. Despite different morphologic appearances, loss of heterozygosity and oncogene studies on LCNEC to date suggest genetic similarities. We analyzed 13 LCNEC and 5 mixed SCLC/LCNEC tumors by comparative genomic hybridization and subsequently compared our results with previously published data on 32 SCLCs. Comparison with SCLC showed several shared chromosomal aberrations, specifically losses of 3p, 4q, 5q, and 13q and gains of 5p. However, these aberrations are no special feature of neuroendocrine lung tumors but can also be found in other high-grade lung carcinomas. From this point of view, genetic similarities of LCNEC and SCLC are less important than the nonrandom changes that differ between these 2 tumor types. A gain of 3q observed in 66% of all SCLCs was detected only once in the LCNEC group. In contrast to the pure LCNEC, all mixed types with a SCLC component had a gain of 3q. Gains of 6p occurred more frequently in LCNEC. Deletions of 10q, 16q, and 17p were less frequent in LCNEC than in SCLC.

Relationship between Epstein-Barr virus and lymphoepithelioma-like carcinoma of the lung: a clinicopathologic study of 6 cases and review of the literature.

Lymphoepithelioma-like carcinoma (LELC) is a rare form of lung cancer, usually encountered in Chinese patients. Similar to nasopharyngeal carcinoma, LELC of the lung is strongly associated with Epstein-Barr virus (EBV) infection in Asian patients, but there is controversy over whether an association exists in patients from Western countries. To determine whether such a relationship exists, we retrospectively studied 6 cases of primary LELC of the lung, all of which were in Western patients. There were 4 men and 2 women, ranging in age from 49 to 75 years. The tumors ranged from 1 to 4.5 cm in diameter. Four patients had stage I disease, 1 had stage IIb disease, and 1 had stage IIIa disease. All patients are alive without evidence of disease with a follow-up of 18 to 30 months. Formalin-fixed, paraffin-embedded tissue was stained with hematoxylin-eosin for routine evaluation and immunostained for keratin and leukocyte common antigen (LCA). LCA staining was performed to exclude large-cell lymphoma. Immunoperoxidase staining (1:500 clone CS1-4; Dako, Carpinteria, CA) and in situ hybridization were performed to detect EBV. Tumors consisted of solid nests of undifferentiated tumor cells in a syncytial arrangement surrounded by heavy lymphoplasmacytic infiltrate. Tumor cells stained positively for keratin but negative for LCA. All 6 cases were negative for EBV, suggesting no association between EBV and LELC in the Western population.

Comparative genomic hybridization and cytogenetic analysis in a bronchial adenoma: three clones with different chromosomal aberrations.

Classical chromosomal analysis and comparative genomic hybridization (CGH) were performed in a tubular bronchial gland adenoma. Trisomy of chromosomes 2, 11, 18 and 20 and clonal loss of Y were found in cultured cells derived from two different kryotubes; this was also confirmed by CGH from one of these tubes. Cells from two other tubes, investigated by CGH only, showed gains and losses of parts of chromosome 11q in one, and in the second additional gain of the distal portion of 9q and 17q, respectively. CGH analysis of tumor DNA extracted from paraffin-embedded sections showed no chromosomal imbalances. In cell culture growth the advantage of specific clones probably altered the clone distribution. This study highlights the risk of cytogenetic analysis based on cell cultures only.

Atypical adenomatous hyperplasia of the lung: a probable forerunner in the development of adenocarcinoma of the lung.

An increasingly large body of work suggests that atypical adenomatous hyperplasia (AAH) of the lung may be a forerunner of pulmonary adenocarcinoma. Recognizing this fact, the World Health Organization now acknowledges the existence of AAH while noting difficulties that may be encountered in distinguishing AAH from the nonmucinous variant of bronchioloalveolar carcinoma. Regrettably, a universally acceptable definition of morphologic criteria for the diagnosis of AAH has not been achieved. This review of the literature examines the epidemiology, gross appearance, light microscopic findings, morphometry, immunohistochemistry, and molecular features of AAH and suggests a set of histopathologic features that may help the practicing pathologist identify this intriguing lesion. These features include the following: irregularly bordered focal proliferations of atypical cells spreading along the preexisting alveolar framework; prominent cuboidal to low columnar alveolar epithelial cells with variable degree of atypia but less than that seen in adenocarcinoma; increased cell size and nuclear-cytoplasmic ratio with hyperchromasia and prominent nucleoli, generally intact intercellular attachment of atypical cells with occasional empty-looking spaces between them without high cellularity and without tufting or papillary structures; and slight thickening of the alveolar walls on which the AAH cells have spread, with some fibrosis but without scar formation or significant chronic inflammation of the surrounding lung tissue. Several lines of evidence indicate that AAH is a lesion closely associated with adenocarcinoma of the lung, suggesting AAH may be involved in the early stage of a complex multistep carcinogenesis of pulmonary adenocarcinoma.

Loss of heterozygosity on chromosome arm 11q in lung carcinoids.

Neuroendocrine lung tumors such as typical carcinoid, atypical carcinoid, small-cell lung carcinoma, and large-cell neuroendocrine carcinoma represent a variable group with different biologic characteristics and unclear genetical relationships. We investigated the pattern of allelic loss on chromosome arm 11q in 20 sporadic carcinoid tumors of the lung using 10 microsatellite markers. Loss of heterozygosity was found in 13 of 20 tumors. In 5 of 9 typical carcinoids, 3 distinct regions of allelic loss were identified: 11q13.1 (D11S1883), 11q14.3-11q21 (D11S906), and 11q25 (D11S910). Atypical carcinoids showed loss of heterozygosity at 4 different regions: the first, most proximal region at 11q13 between markers PYGM and D11S937; the second at 11q14.3-11q21 (D11S906); and the third and fourth defined by markers D11S939 (11q23.2-23.3) and D11S910 (11q25). However, the region 11q13 harboring the MEN1 gene was more frequently affected in atypical carcinoids (7 of 11) than in typical carcinoids (2 of 9). The high rate of allelic losses within chromosomal region 11q13 in atypical carcinoids emphasizes the importance of this region for tumor development. We also recognized that more aggressive atypical carcinoids defined by high mitotic counts, vascular invasion, and/or organ metastasis are combined with increased allelic losses. HUM PATHOL 32:333-338.

Which biopsies in diffuse infiltrative lung diseases and when are these necessary?

Different biopsy techniques are used to obtain appropriate tissue for diagnostic pulmonary pathology. Traditionally open lung biopsies were more often used in the USA, whereas transbronchial biopsies prevailed in many European countries. However, the type of biopsy especially in interstitial lung diseases (ILD) should be selected not on traditional grounds, but on a scientific rationale. In progressive ILD where the pathologic diagnosis is based on the recognition of different patterns at different process stages, an open or video-assisted thoracoscopic lung biopsy is preferred, whereas in most granulomatous pneumonias transbronchial or even bronchial biopsies may suffice. For many other ILDs no recommendations exist, but will be tentatively given. In addition comprehensive clinical information should be provided for the pathologist, because this is the prerequisite for a qualitative diagnosis, which means not only a descriptive answer, but also an etiologically based one.

Mycobacterial DNA in recurrent sarcoidosis in the transplanted lung--a PCR-based study on four cases.

Sarcoidosis is a systemic granulomatous inflammation, which may be caused by mycobacteria other than M. tuberculosis complex (MOTT) in one-third of cases. A few cases of recurrent sarcoidosis in the transplanted lung have been reported. However, mycobacteria have been excluded by acid-fast stains only. We investigated four cases of recurrent sarcoidosis in lung transplant patients. Using PCR for the insertion sequence 6110 of Mycobacterium tuberculosis complex and a second PCR for the mycobacterial chaperonin (65-kDa antigen coding sequence), we looked for mycobacterial DNA. In three cases sequence analysis was also performed. One patient was negative for mycobacterial DNA in explanted, but positive for M. tuberculosis DNA in transplanted lung, qualifying this case as M. tuberculosis infection in the transplant. Three patients were negative for M. tuberculosis DNA, but were positive for MOTT-DNA in both explanted and transplanted lungs. In these three patients sequence identity of the amplified sequences before and after transplantation was proven, which rules out mycobacteriosis. Recurrent sarcoidosis does occur, but can only be proven by the exclusion of mycobacterial DNA. In cases of recurrent MOTT-DNA-positive sarcoidosis the diagnosis cannot be confirmed except by proof of sequence identity. Probably MOTT-DNA-positive sarcoidosis is more likely to recur in a transplanted lung.

Bronchiolitis, an update.

Besides the classical forms of acute and chronic bronchiolitis, different special forms, such as obliterative, respiratory, and follicular bronchiolitis are recognized. In addition, even new entities emerge, such as Sauropus-induced bronchiolitis. Despite this progress in pathology, pulmonologists still prefer the diagnostic term 'small airways disease', instead of the more specific and even etiology-directed diagnoses provided by the morphologic examination. In this overview, an updated classification will be presented, which includes all forms of bronchiolitis described so far. This classification is structured along morphologic features of bronchiolitis. Different forms of acute and chronic bronchiolitis are described, so that a given reaction pattern can be associated with specific causes, such as eosinophilic bronchiolitis in asthma, or necrotizing bronchiolitis in viral infection. However, there exist more than just one morphologic reaction for a given etiologic agent, resulting in an overlap of morphologic appearances for a given disease.

[Differential diagnosis and etiology of epitheloid cell granulomatosis of the lung]. / Differentialdiagnose und Atiologie der epitheloidzelligen Granulomatosen der Lunge.

Our knowledge on epithelioid cell granulomatosis of the lung has been extended in recent years. New entities have been added, like zirconiosis, others like tuberculosis, mycobacteriosis and sarcoidosis have gained new interest, because molecular techniques allowed new insight into their pathogenesis and a more rapid and species-specific diagnosis. Experimental work in addition has added a lot of information about the network of cytokines and other inflammatory mediators responsible for granuloma formation, however, our knowledge of this network is still incomplete. Three types of agents are now known to cause epitheloid cell granulomas: infectious organisms (bacteria, fungi, and parasites), products of plants and animals (pollen, sporangia, proteins), and metallic compounds. In addition there is still a group of epithelioid cell granulomatoses with unknown etiology. Sarcoidosis, one of these granulomatosis, has recently elicited an old controversy: By molecular techniques Mycobacteria and Corynebacterium acnes have been identified in sarcoid granulomas and a link to the aetiology of sarcoidosis has been proposed. If these bacteria induce some cases of sarcoidosis by an allergic mechanism, has still to be proven.

Epithelioid cell granulomatosis of the lung: new insights and concepts.

Our knowledge on epithelioid cell granulomatosis of the lung has been extended in recent years. New entities have been added, like zirconiosis; others like tuberculosis, mycobacteriosis and sarcoidosis have gained new interest, because molecular techniques allowed new insight into their pathogenesis and a more rapid and species-specific diagnosis. Experimental work in addition has added a lot of information about the network of cytokines and other inflammatory mediators responsible for granuloma formation. However, our knowledge of this network is still incomplete. Three types of agents are now known to cause epithelioid cell granulomas: infectious organisms (bacteria and fungi), products of plants and animals (pollen, sporangia, proteins), and metallic compounds. In addition, there is still a group of epithelioid cell granulomatoses with unknown etiology. Sarcoidosis, one of these granulomatoses has recently elicited an old controversy; by molecular techniques atypical Mycobacteria and Corynebacterium acne have been identified in sarcoid granulomas and a link to the etiology of sarcoidosis has been proposed. Whether these bacteria induce some cases of sarcoidosis by an allergic mechanism, has still to be proven.

Unbalanced chromosomal aberrations in neuroendocrine lung tumors as detected by comparative genomic hybridization.

Typical and atypical carcinoids (TC, ATC) and small (SCLC) and large cell neuroendocrine carcinomas (LCNEC) constitute the spectrum of neuroendocrine lung tumors. Chromosomal aberrations have not been studied in LCNEC and only rarely in carcinoids. Only SCLCs have been investigated frequently for chromosomal aberrations. We compared three typical and four atypical carcinoids, one atypical carcinoid/SCLC mixed type, three SCLC, and three LCNEC for chromosomal gains and losses using comparative genomic hybridization. Typical carcinoids showed either no changes or only few chromosomal gains. Atypical carcinoids appeared genetically heterogeneous: One case had no aberrations, and three cases had few aberrations; two of them showed a deletion of 11q. SCLC and LCNEC were characterized by many gains and losses, especially similar changes of 3p, 5q, 5p, and 13q. Although ATC resemble LCNEC morphologically, there were no similarities at the genetic level. We have found a reciprocal relationship of prognosis and the amount of aberrations. TCs and ATCs with few chromosomal changes have the best prognosis, whereas SCLCs and LCNECs were generally characterized by a great amount of aberrations and worst prognosis. There was no unbalanced aberration common in all types of neuroendocrine tumors of the lung.

Multiplex polymerase chain reaction for rapid detection of atypical mycobacteria and Mycobacterium tuberculosis complex.

A three-step polymerase chain reaction (PCR) method was developed for the detection and typing of mycobacterial DNA in clinical samples and fixed tissue specimens. The first step was to rule out or prove the presence of DNA of Mycobacterium tuberculosis complex. An amplified fragment from the insertion sequence (IS) 6110 was used for this purpose. Patients negative for IS 6110 were evaluated for a fragment of the 65 kDa-antigen, present in all mycobacteria. In positive patients, a multiplex PCR was performed for M. gordonae, M. avium, M. kansasii, M. fortuitum, and M. malmoense, combined in one PCR run. As another control, to prove mycobacterial DNA, PCR was used for the gene coding for the 16S ribosomal RNA also found in all mycobacteria. Appropriate negative controls were included. Different clinical samples were compared for an efficient amplification of these different mycobacterial DNA fragments. Different mycobacteria can be identified within one day in either unfixed cytologic and bacteriologic samples, or formalin-fixed paraffin-embedded tissue samples. Therefore, this method is a quick, cost efficient, and reliable tool to identify mycobacteria other than the tuberculosis complex.

Presence of mycobacterial DNA in sarcoidosis.

In 11 of 35 clinically proven cases of sarcoidosis, we detected DNA sequences coding for the mycobacterial 65-kDa antigen. In four cases, the sequences were homologous to Mycobacterium avium; seven sequences were related to other nontuberculous Mycobacteria. The insertion sequence 1110, characteristic for Mycobacterium avium, was present in three cases. The insertion sequence 6110 of the Mycobacterium tuberculosis complex (M tuberculosis, africanum, bovis, BCG) was not detectable in any of the 11 cases, ruling out the presence of members of the Mycobacterium tuberculosis complex. Therefore, it seems reasonable to speculate about a mycobacterial cause in some cases of sarcoidosis.

[Lymphoepithelioma-like lung carcinomas]. / Lymphoepitheliomartige Lungenkarzinome.

Having observed 2 cases of lymphoepithelioma-like carcinoma of the lung in a 49-year-old female and in a 66-year-old male patient, we present a review on this entity, which was described for the first time in 1987. Essentially this neoplasm has the same histological appearance as a Schmincke-Regaud tumor, but it is possible that a certain morphological variety exists. In the differential diagnosis, a metastasis of a Schmincke-Regaud tumor and a malignant lymphoma should be considered. Including our 2 cases, a total of 30 cases have been reported: 14 male patients aged between 33 and 73 years and 12 female patients between 38 and 70 years; in 4 cases there was no reference to sex or age. Most of the patients were Asians, mainly Chinese. These tumors presented with nearly the same frequency in both lungs. They mostly appeared as peripheral coin lesions in the chest X-ray study. Lymph node metastases were found in approximately 25% of the cases. Hematogenous metastases seldom occurred and were observed almost only in the skeletal system. In most cases a lobectomy was performed. At present, no exact assertion is possible regarding the prognosis. An association with an Epstein-Barr virus infection was observed in the Asian patients, but not in the Caucasian patients.