key: cord-0034964-4gbxlnbo
authors: Popper, Helmut
title: Vascular Lung Diseases
date: 2016-12-24
journal: Pathology of Lung Disease
DOI: 10.1007/978-3-662-50491-8_11
sha: 92ebcc4c85582ff806164fd6ceaa05d9222a4e2c
doc_id: 34964
cord_uid: 4gbxlnbo

Here we will discuss infarct and thromboembolic disease, vasculitis, vascular malformations, and pulmonary hypertension. Vascular tumors have already been discussed.

Thromboembolism is a frequent event in older patients. Often the underlying disease is chronic heart failure with venous congestion. Thrombi are formed in the lower extremities but also in the pelvic region and give rise to emboli. Large emboli will get stuck in the large pulmonary arteries and cause sudden death with the symptoms similar to cardiac infarct. Smaller emboli might be pressed into smaller arteries and get stuck there. These emboli will cause a hemorrhagic infarct by occlusion of a pulmonary artery and retrograde infl ux of blood from the venous side as well as from bronchial arteries. Since the lung has a double system of blood fl ow, bronchial and pulmonary system ischemic infarcts do not occur -there is one exception, ischemic infarct in vasculitis.

An infarct has a cuneiform appearance, the broad side is at the periphery, and the tip is where the artery is occluded. On cut surface the infarct is dark red with a hemorrhagic dark blue-red border. The consistency is fi rm. On histology, the center of the infarct has lost staining of the cells (no nuclei visible), and the cells appear like ghost cells; however, the alveolar structure is still visible (Fig. 11.1 ). If the infarct is older, an infl ammatory granulation tissue develops (usually a type of organizing pneumonia), which slowly will organize the infarct and replace it with scar tissue. Even as scar the cuneiform fi gure will remain. At the border of the infarct, numerous hemosiderin-laden macrophages will appear. Elastic stains can easily highlight obstructed arteries. Typically there are thick-walled arteries in the vicinity of the infarct, probably refl ecting increased vascular pressure.

According to the Chapel Hill classifi cation, there is primary systemic vasculitis and secondary (most often infection associated) vasculitis, and there is large medium and small vessel vasculitis [ 1 ] ; the affection of arteries and veins is not further acknowledged. In this last update of the primary 1994 classifi cation, changes were made such as granulomatosis with polyangiitis instead of Wegener's granulomatosis and eosinophilic granulomatosis with polyangiitis instead of Churg-Strauss vasculitis. In addition, categories for variable vessel vasculitis and secondary forms of vasculitis were added. The lung is affected by a few variants of primary systemic vasculitis, which are discussed here. Secondary vasculitis will not extensively be discussed.

Schema of the classifi cation of vasculitides according to the 1994 Chapel Hill classifi cation: Vasculitides are grouped according to the size of the affected vessels; this classifi cation was modifi ed in 2012; however, the involvement of vessels is still the basis of the updated classifi cation.

Granulomatosis with polyangiitis (GPA), formerly called Wegener's granulomatosis , affects medium to small arteries, arterioles, capillaries, venules, and small-to medium-sized veins. There are three main organ systems involved: mucosa of the upper airways, lungs, and kidneys. In some patients, only one organ system, in other patients two organ systems, and in some patients all three systems can be affected. The vasculitis will cause vascular obstruction followed by occlusion, which fi nally will cause ischemic infarct if the vessel is large enough.

Patients present with hemoptysis, fever may be seen, on serum examination antineutrophil cytoplasmic antibodies (ANCA) may be present; antibodies are a sign of the underlying vasculitis. Examination of ANCA antibodies will show more common anti-proteinase 3 (PR3) [ 2 ] . On X-ray and CT scan, classical GPA will show infarct with less dense center parts ( Fig. 11 .2 ). Several infarcts can be present. If only small vessels are affected, the CT scan is less characteristic with diffuse interstitial infi ltrates. Usually both lungs are involved. In these cases hemoptysis will be more pronounced, and on BAL alveolar hemorrhage will be diagnosed. For a clinical diagnosis, the following features are required: histopathological evidence of granulomatous infl ammation, upper airway involvement, laryngo-tracheo-bronchial involvement, pulmonary involvement (X-ray/CT), antineutrophilic cytoplasmic antibody positivity, and renal involvement [ 3 ] .

If infarcts are present, these will have a similar cuneiform appearance as in hemorrhagic infarct; however, the cut surface is yellowish white with a hemorrhagic border. If only small vessels are involved, the cut surface shows hemorrhage without any further characteristics ( Fig. 11 .3 ). 

The vasculitis is characterized by a destructive infi ltration of the vessel wall by neutrophils, rarely also by eosinophils ( Fig. 11.4 ) . The vasculitis causes fi brinoid necrosis of the endothelium and bleeding, which depending on the size of the vessels can be focal or massive. The necrosis of endothelia is the most important sign of vasculitis, because in the differential diagnosis, transmigration of neutrophils in infections can be very prominent and therefore cannot be regarded as the proof of vasculitis. More often vasculitis causes thrombosis and vascular occlusion, which consequently lead to infarction and necrosis of the parenchyma. Since most often there is arterial occlusion, the infarcts are ischemic.

Epithelioid cell granulomas should be present in this new classifi cation, as granulomatosis is now a requisite of the diagnosis (Fig. 11 .5 ). Cases which present exclusively with vasculitis including those with capillaritis are now included into microscopic polyangiitis (see below).

In later stages, and under therapy, the neutrophils might be replaced by lymphocytes. In these cases, one has to exclude an infectious, mainly viral-induced secondary vasculitis ( Fig. 11.6 ).

GPA usually presents with PR3 antibodies. ANCA testing nowadays is a routine in clinical practice. But be aware that ANCA can be negative in early stages of GPA, and ANCA can be positive in some infectious secondary vasculitis.

GPA can start with unspecifi c syndromes, even organizing pneumonia without vasculitis [ 4 ] ; in these cases the patients should be observed until specifi c features will be present.

GPA patients will be treated primarily with corticosteroids; if non-responding, an immunosuppressive treatment with drugs like cyclophosphamide is the second choice.

GPA can be regarded as an autoimmune disease. ANCA directed against proteinase 3 (PR3) are preferentially associated with GPA. Anti-PR3 antibodies can activate neutrophils in vitro. A signifi cant association of PR3-ANCA and HLA-DP and the genes encoding alpha-1 antitrypsin and PR3 have been found [ 2 ] . How these are associated with the production of autoantibodies is not understood. Lymphocytes are also involved in GPA, mainly lesional T cells, which exhibit pro-infl ammatory properties and promote granuloma formation. Apart from T cells, 

with Polyangiitis (EGPA, Formerly Called Churg-Strauss Vasculitis)

EGPA was fi rst described in 1951 as a small-and medium-sized vessel vasculitis, characterized by an almost constant association with asthma and eosinophilia. Vasculitis typically develops in a previously asthmatic middle-aged patient. Asthma is severe, associated with eosinophilia and extrapulmonary symptoms. Some patients report allergic rhinitis without asthma. Most frequently EGPA involves the peripheral nerves and skin (allergic superfi cial eosinophilic vasculitis). Other organs such as the heart, kidney, and gastrointestinal tract, if affected, confer a poorer prognosis. In about 30-40 % of the patients, anti-myeloperoxidase (MPO) antineutrophil cytoplasm antibodies (ANCA) are present [ 2 ] . EGPA patients with anti-MPO ANCA suffered more, albeit not exclusively, from vasculitis symptoms, such as glomerulonephritis, mononeuritis multiplex, and alveolar hemorrhage, whereas ANCA-negative patients more frequently develop heart involvement [ 6 , 7 ] . In recent time EGPA has been linked to new antiasthmatic drugs such as montelukast. However, new investigations have ruled out this as a possible cause of the disease [ 8 ] . Elevated IgG4 levels were found in active EGPA patients compared to controls. Serum IgG4 correlated with the number of eosinophils. During treatment and in disease remission, both IgG4 level and IgG4/IgG ratio dropped [ 9 ] .

The major fi ndings at X-ray and CT scan are diffuse interstitial infi ltrates; hemorrhage will be seen on CT scans ( Fig. 11 .7 ). If eosinophilic pneumonia is present, this will cause more density and focally also ground glass changes.

On cut surface, pneumonia (consolidations) and hemorrhage are the major, however, unspecifi c fi ndings.

The hallmark is an eosinophilic vasculitis, again with destruction of the vessel wall and fi brinoid necrosis of the endothelium. Besides numerous eosinophils, also macrophages and histiocytes can be seen within these infi ltrations. This causes focal bleeding if capillaries are affected and hemorrhage if larger vessels are involved. In older lesions or in patients under therapy, an eosinophilic infi ltrate can persist up to 1 month, and hemosiderin-laden macrophages tell the story about previous bleeding. In fl orid cases there might be also an eosinophilic pneumonia with parenchymal necrosis. Granulomas are not associated with the vasculitis. In areas with parenchymal necrosis, a foreign body giant cell granulomatous reaction can be seen around the necrosis ( Fig. 11 .8 ).

A strong association with IL10 promoter polymorphisms was detected in EGPA. Other associations, including CTLA4, CD226, and copy number polymorphisms of FCGR3B need to be validated in further investigations [ 10 ] .

In most cases patients will respond to corticosteroid treatment, rarely an immunosuppressive therapy might be necessary. Encouraging results have been reported for the treatment of EGPA with rituximab or with the eosinophil-targeted antiinterleukin-5 agent mepolizumab [ 11 ] .

The nomenclature remains a source of confusion: (1) Is vessel infl ammation or the presence of ANCAs essential for the diagnosis of EGPA? (2) Are granulomas required for the diagnosis, and what type of granulomas should be seen? (3) Is eosinophilic pneumonia in EGPA another disease or just a variant? (4) Is hypereosinophilic syndrome a variant of EGPA?

As the understanding of the relation between the vasculitis and the eosinophilic proliferation is profoundly lacking, these questions so far cannot be answered.

Microscopic polyangiitis (MPA) is a small vessel vasculitis, sometimes indistinguishable from GPA. Epithelioid cell granulomas and infarctlike necrosis are absent. In contrast to GPA, MPA is often limited to the lungs; however, it may Fig. 11 .8 EGPA illustrated with three cases. In ( a ) and ( b ) eosinophilic vasculitis is shown with a small necrotic focus and few scattered epithelioid and giant cells. In ( c ) a patient with EGPA was treated with corticosteroids for 2 weeks before the transbronchial biopsy was taken. This resulted that the vasculitis was no longer present (no endothelial necrosis, no infi ltration of the vascular wall), but the eosinophilia could still be evaluated. In ( de ) an eosinophilic vasculitis is present, here predominantly as capillaritis. But there is also organizing pneumonia as a sign of a long-standing process with repair. H&E, ×50 and 100 involve the kidneys. Diffuse alveolar hemorrhage is most commonly seen in small vessel vasculitides, specifi cally MPA [ 12 ] . There is a wide variation of possible underlying diseases, but some might also be coincidentally associated with MPA. The most common are chronic airway diseases (CAD), where MPO-ANCA tended to be lower than in the non-CAD group. None of the patients in the CAD group had pulmonary hemorrhage or interstitial pneumonia. Also the outcome in the CAD group was better than in the non-CAD group [ 13 ] .

There is also a geographic variance as MPA and MPO-ANCA were more common in Japan, whereas granulomatosis with polyangiitis and PR3-ANCA were more common in the UK [ 14 ] . This difference may at least in part derive from the difference in genetic background. In Japanese patients with MPA, HLA-DRB1*09:01 was increased as well as in MPO-ANCA-positive vasculitis. HLA-DRB1*09:01 is one of the most common HLA-DRB1 alleles in Asians but is rare in Caucasian populations [ 15 ] . In an attempt to identify autoantigens within the ANCAs, Regent et al. identifi ed antibodies targeting lamin A, vimentin, alpha-enolase, and FUBP2 in patients with MPA. IgG from patients with microscopic polyangiitis reacted stronger against culture endothelial cells and induced a strong ERK phosphorylation in these cells [ 16 ] .

In a European study on GPA and MPA patients, HLA-DP, SERPINA1, PRTN3, and HLA-DQ SNPs were more signifi cantly associated with ANCA specifi cities (PR3 vs. MPO) than with the clinical syndromes [ 17 ] . In the study by Rahmatulla, these genetic variants were tested in GPA and MPA: CD226, CTLA-4, FCGR2A, HLA-B, HLA-DP, HLA-DQ, HLA-DR, HSD17B8, IRF5, PTPN22, RING1/ RXRB, RXRB, STAT4, SERPINA1, and TLR9. Subdivision based on ANCA serotype matched better with these gene variants compared to clinical diagnosis. Within the identifi ed 33 genetic variants, alpha-1 antitrypsin, the major histocompatibility complex system, and several distinct infl ammatory processes play a major role [ 18 ] .

In a VATS biopsy, there is hemorrhage without any specifi c morphology other than bleeding. The specimen should be sectioned in a 90° angle to the axis of the blood vessels to get the best cross sections of the larger vessels.

In MPA small vessels are involved. There is a neutrophilic rarely eosinophilic granulocytic infi ltration within capillary walls, also arterioles and venules can be affected. Since necrosis of the endothelial cells will cause disruption of the vessel walls, focal bleeding (alveolar hemorrhage) will result. As this process recurs, macrophages are following and ingest the blood. The histological picture is not easy to interpret; however, a strictly to the capillary wall-associated granulocytic infi ltration, and no outside accumulation within alveoli, as well as the scattered hemosiderin-laden macrophages will guide to the correct diagnosis ( Fig. 11.9 ). Granulomas as well as infarct are absent.

A higher mortality is seen in patients with MPAassociated fi brosing interstitial lung disease (ILD) compared to those with peripheral nervous system involvement [ 19 ] . This was also confi rmed in the study by Katsumata et al [ 20 ] .

Panarteritis nodosa is a large, medium, and small vessel vasculitis, which very rarely affects the lungs. Within the Armed Forces Institute collection, there are only a few cases recorded involving the lungs. Organs most commonly affected are the gastrointestinal tract, arteries at the base of the brain, heart, liver, and spleen. To my knowledge only one defi nitely proven case has been published in the literature, which involved the lungs [ 12 ] . It is a neutrophilic granulocytic vasculitis, but during the course of the disease, also histiocytes are present too; the vasculitis is nodular and granulomatous, causing either stenosis with ischemic infarcts or dilation with aneurysm formation, rupture, and bleeding ( Fig. 11.10 ).

The relevance of the classifi cation system of vasculitides, relying on affected vessel size as the primary discriminator, is still questionable. Classifi cation on ANCA-positive and negative vasculitis is a fi rst step to get a better separation, and also the type of ANCA is clinically important. However, some entities remain ill defi ned: polyarteritis nodosa, microscopic polyangiitis, and adult immunoglobulin A vasculitis [ 21 ] (Table 11 .1 ). 

As a rule, infections should always be ruled out in cases with vasculitis before a systemic vasculitis is diagnosed.

Most infections can cause a secondary vasculitis; in case of bacterial and fungal infections, these are usually granulocytic (neutrophilic) vasculitis, whereas viral infections cause lymphocytic vasculitis (Figs. 11.11 and 11.12 ). Parasitic infections come as eosinophilic vasculitis, similar to allergic reaction. Most common secondary infectious vasculitides occur in tuberculosis, mycobacteriosis, almost all forms of fungal infections, and many viral infections. Of note some infectious vasculitides can also be ANCA positive, as we have seen in a case of infectious vasculitis caused by Treponema pallidum .

In children mycotic infections are seen in patients treated for leukemia and in bone marrow transplant (Fig. 11.13 ). In these cases processing of the tissue and diagnosis by the pathologist should be done as quick as possible, because these children are on a high risk of developing sepsis: all fungi grow toward high oxygen tension and therefore can invade the pulmonary vascular system within hours, resulting in bacteremia and sepsis.

These forms of vasculitis have been discussed in other chapters. Examples are vasculitis in sarcoidosis, necrotizing sarcoid granulomatosis, and hypersensitivity pneumonia. An unusual form of eosinophilic vasculitis has been described in a newborn with congenital chylothorax [ 22 ] . The vasculitis vanished after correction of the ductus thoracicus within a week (Fig. 11.14 ) . Other forms of noninfectious vasculitis can occur in drug abuse, for example, in methadone abuse, where the fi lling material from the drugs is injected together with the drug into a vein. The fi lling material often contains talcum, which will cause a granulomatous vasculitis with foreign body giant cells. Another vasculitis can be induced by material from dialysis membranes. If used several times, polyhydrocarbon fragments Fig. 11 .13 Secondary vasculitis due to sepsis with an Aspergillus species in a child after chemotherapy for leukemia. Inset : a fruiting body of the fungus allowed a more specifi c diagnosis. H&E, Grocott, ×100 and 400 Fig. 11 .14 Eosinophilic vasculitis due to chylothorax in a 2-day-old child. Note the dense eosinophilic infi ltration confi ned to the blood vessels, whereas the alveolar tissue is normal. H&E and Movat stain, ×200 and 50

can be dissolved and will circulate via the venous system, reaching the lung and will cause a macrophage vasculitis (Fig. 11.15 ).

Pulmonary arteries and veins can be affected by different malformations, which are at present ill defi ned. Usually patients present with alveolar hemorrhage, which sometimes can be life threatening. The underlying pathology can be capillary or cavernous hemangiomas, arteriovenous malformations, or angiomas but also rare diseases such as Marfan syndrome and Ehlers-Danlos disease type IV. Usually a careful exam-ination is necessary to fi nd the underlying cause of bleeding. This requires extensive sectioning.

In my experience one should select those areas, where massive hemorrhage is present. Take many sections and start searching for malformations. In Marfan disease clinical information, if provided, might help a lot, so one can immediately focus on the large arteries and investigate the elastic laminae ( Fig. 11.16 ). The formation of elastin is disabled, causing thin-walled large blood vessels, which easily rupture; in the lung mainly the large pulmonary arteries are affected; however, in these patients the symptoms are mainly due to aortic problems (rupture). In Ehlers -Danlos disease IV , the most important fi nding is thin-walled large arteries and illdeveloped collagen in the adventitia. The synthesis of different types of collagen is blocked. In the lungs large pulmonary arteries are affected. Most important both diseases will manifest in a young-aged population. Clinical symptoms are massive hemorrhage in young patients, which tend to be fatal. As this is a systemic disease, there is no option for treatment.

On low power examination, no abnormalities are seen. The bronchovascular bundles are well structured; within the lung parenchyma, massive hemorrhage is the only fi nding. The abnormality, which will lead to further chemical investigation, is the thin wall of large pulmonary arteries seen on mesenchymal tissue stains such as Movat pentachrome. The intima is normal and the elastic laminae are normal, but the collagen is abnormally thin (Figs. 11.17 and 11.18 ). This combination together with the age of the patient and the rapid deterioration should cause chemical investigation for the underlying enzyme defect.

Mutation within the COL3AI gene results in the disorder of type III procollagen. The diagnosis is confi rmed by demonstrating the synthesis of abnormal type III procollagen molecules from cultured dermal fi broblasts or by identifying the mutation in the COL3A1 gene [ 23 ] . Biallelic sequence variants have a signifi cantly worse outcome than heterozygous variants for either null mutations or missense mutations, and frontoparietal polymicrogyria may be an added phenotype feature. This genetic constellation provides a very rare explanation for marked intrafamilial clinical variation due to sequence variants in COL3A1 [ 24 ] .

This has been already discussed in the chapter on childhood and will not further be treated here.

Pulmonary hypertensive diseases will not often be subjected to pathological analysis; however, the pathologist might be questioned in autopsy cases or in rare diseases with hypertension. Therefore we will describe the morphological changes to be seen in histological specimen to enable the pathologist to make the diagnosis of pulmonary hypertension and some variants. In some cases such as in systemic diseases or in autopsy cases with heart diseases, the pathologist can arrive at a diagnosis, which includes also the etiology of hypertension, but in biopsies the fi nal diagnosis has to be established by a multidisciplinary team led by the clinician. Pulmonary hypertension is defi ned as an arterial pressure of ≥25 mmHg under resting condition. There are also defi nitions for pre-and postcapillary hypertension, where >15 mmHg defi nes a postcapillary hypertension whereas precapillary hypertension is defi ned by ≤15 mmHg.

The severity of changes within the walls of pulmonary arteries can be graded, and to my experience the grading system by Heath and Edwards is most useful (Table 11 .2 ). [ 25 ] Grade 1: medial hypertrophy and muscularization of arterioles Grade 2: medial hypertrophy and intimal proliferation in small arteries Grade 3: medial hypertrophy, intimal proliferation, and concentric laminar fi brosis Grade 4: medial hypertrophy, intimal proliferation, and concentric laminar fi brosis and plexiform lesions Grade 5: prominent plexiform and angiomatoid lesions, + hemosiderin deposition Grade 6: as grade 5, + necrotizing arteritis Primary pulmonary hypertension, venoocclusive syndrome (diseases), and pulmonary capillary hemangiomatosis were originally considered separate diseases, although D. Dail many years ago pointed to a connection of these three in his thesis work. Primary pulmonary hypertension is caused by a vascular obstruction of medium to small blood vessels. As a reaction a secondary proliferation of small capillaries with a glomerulum-like appearance is started -the so-called plexiform lesion (Fig. 11.19 ). The driving forces are vascular factors such as VEGF, endothelin, endostatin, and their receptors (Fig. 11.19d ). Small areas of necrosis can occur, and a hemangioma-like dilation of veins is typically found around these proliferations ( Fig. 11.19e ). Small areas of necrosis can occur. Larger arteries will show vessel wall thickening and stenosis. Bleeding and hemosiderin deposits can be found; however, no large hemorrhage will be seen.

Veno-occlusive disease is characterized by an occlusion of pulmonary veins, which are found along interlobular septa. Sometimes an elastic stain is necessary, to highlight remnants of these vessels (Fig. 11.20 ) . Pulmonary capillary hemangiomatosis often can be found associated with the former two diseases. PCH is characterized by a proliferation of pulmonary capillaries typically in septa. There are at least doubled capillary beds (Fig. 11.21 ) . The disease occurs in children and young adults and causes alveolar hemorrhage syndrome. To my experience and according to case reports in the literature, there are two probably separated forms: PCH associated with PAH ± VOD and PCH as an isolated tumorlike form.

PAH in collagen vascular disease, most often systemic sclerosis, is characterized by vessel wall thickening (grades 2-4). In some cases this thickening resembles sclerosis as in chronic vascular transplant rejection due to antigen-antibody complex deposition. Also vasculitis can occur.

PAH in intravenous drug abuse comes usually as foreign body giant cell vasculitis with obstruction of small arteries and capillaries. Plexiform lesions can be present in rare cases. The reason is embolization of tablet fi lling substances such as talcum. Another drug Sauropus androgynus inducing PAH was reported in Korea and Japan. This starts with myxoid changes in arteries and bronchioles, followed by eosinophilic vasculitis and bronchiolitis, and fi nally occlusion of bronchioles and blood vessels.

Signs of pulmonary hypertension including elastosis of the arteries are characteristically found in lung sequestration with and without CPAM. Elastosis (multiplicity of elastic layers), which is also present in other types of pulmonary hypertension, is most severe in sequestration and can be used as another aid in making the correct diagnosis.

PAH is also found in thromboembolic disease, even with plexiform lesions, but venous dilations associated with these lesions do not occur (Fig. 11.22 ) (Table 11 .3 ). There are many capillaries within an alveolar septum, best seen at cross sections in the middle of the picture. H&E, ×200   Fig. 11 .20 Veno-occlusive disease: the overview in top panel shows an almost normal peripheral lung; however, the thickened and obstructed veins stick out. In the middle one artery with thickened wall is shown and two veins, which are occluded and therefore lost to circulation. In the lower panel , another vein is shown, which is severely obstructed. H&E, Movat, ×12, 50, 100 11.7 Pulmonary Hypertension

Chronic thromboembolic disease and thickened arteries are seen and within the vessel wall some primitive endothelial proliferations, which will give raise to plexiform lesion later on.

Note that there are no dilated veins. H&E, ×200 

Some reports have shed light to the mechanisms, but a fi nal cause has not been discovered. Mutations in bone morphogenic protein receptor type II (BMPR2) have been discovered, and it has been shown that BMPR2 mutations in different exons result in altered function. However, BMPR2 mutations are found in only a minority of PAH patients [ 30 , 31 ] . So it is speculated that disease modifi er genes might exist. Activin-like kinase type I (ALK1) was found altered in hereditary hemorrhagic telangiectasia. Since both genes belong to the TGFβ family, this pathway might be most probably affected [ 31 ] . BMP receptors 1 and 2 associate to form homo-or heterodimers. BMP4, a ligand for BMPR2, inhibits the proliferation of arterial muscle cells from proximal pulmonary arteries but stimulates proliferation of peripheral arteries. In iPAH hypoxia induces production of endothelium-derived BMP4, associated with increased proliferation and migration of vascular smooth muscle cells. The serotonin transporter (5-HTT) was found to be overexpressed in PAH [ 32 ] . Functional polymorphism of the 5-HTT gene promoter has been demonstrated in some patients, an increase of the expression of the 5-HT transporter (5-HTT) in others. This all result in an abnormally strong proliferative response to serotonin. Interestingly appetitesuppressant drugs are potent inhibitors of neuronal 5-HT uptake and inhibit 5-HTT.

In the downstream pathway, VEGF and VEGF receptors play an essential role in PAH. Also an increase of TXA 2 synthesis was shown in patients with iPAH, pointing to the involvement of thrombotic and infl ammatory mechanisms [ 33 ] .

PAH caused by antiphospholipid autoantibodies most likely is caused by fi brin thrombi causing widespread obstruction of small pulmonary arteries with concentric cellular and fi brous intimal hyperplasia (Fig. 11.24 ) [ 34 ] .

In children the group of Fukushima studied the mechanisms of PAH with PVOD in left-to-right shunt of the heart. There was a predominant biosynthesis of TXA 2 over PGI 2 , which might cause vasoconstriction in these infants [ 33 ] . Finally in a study on PCH, the authors reported on mutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene. EIF2AK4 potentially connects with BMPR2 to cause PCH. Mutant EIF2AK4 could promote proliferation of small pulmonary arteries by cross talk with mammalian targets of the rapamycin signaling pathway [ 35 ] (Table 11 .4 ). 

Alveolar hemorrhage syndrome (AHS) presents with bleeding in the lung parenchyma. In some patients, AHS will cause hemoptysis; in other patients, there is only sometimes blood found in expectorations. In BAL specimen there are red blood cells as well as hemosiderin-laden macrophages -this is essential to differentiate AHS from artifi cial bleeding induced by bronchoscopy or biopsy, as well as from aspiration from the upper respiratory tract. There are several underlying diseases, which can present with AHS. Within the differential diagnosis, they are vasculitis, primary systemic as well as secondary; pulmonary hypertension; autoimmune diseases including collagen vascular diseases; Goodpasture syndrome; antiphospolipid autoantibody syndrome (Fig. 11.24 ); infections such as tuberculosis, infl uenza virus, Hantavirus , SARS, dengue fever, and Nile virus fever; inhalation of herbicides and pesticides; and drug reactions, especially cytostatics.

Tumors of the lymphatic system have been covered in tumors. Here we have to discuss malformation, obstruction, and infl ammation.

Malformation of the ductus thoracicus will cause obstruction of the lymphatic fl ow resulting in leakage of the fl uid into the alveoli. The histological picture will resemble edema; however red blood cells are missing, whereas scattered leukocytes are encountered. The septa are widened by this fl uid. Leakage can also affect the pleura causing chylothorax. This malformation can be focal, involving the lung and mediastinum, but exists also as a systemic form, Gorham-Stout syndrome [ 36 , 37 ] . In this case also the bones and many other organs are affected too (Fig. 11.25 ). These patients present with symptoms related to loss of electrolytes and small peptides/proteins. Most prominent is albuminemia. Patients are of young age or children. The diagnosis can be made by CT scan, because the multitude of cystic-dilated lymphatics within the mediastinum will simulate a cystic tumor. The local form will present as lymphangiosis, with the characteristic proliferation of lymphatic vessels ( Fig. 11.26 ). As an aid in the diagnosis, antibodies against podoplanin and VEGFR can highlight the lymphatics 3 .

Several diseases can cause lymphatic obstruction. Here we will give a list of common and rare causes. Lymphangioleiomyomatosis: The obstruction is caused by the proliferation of smooth muscle cells.

Tumors: Central tumors might directly compress lymphatics, or tumor cell clusters might obstruct lymphatics.

Parasites: Larvae as well as eggs can obstruct lymphatics. This is very common in tropical parasitic infection such as fi lariasis.

Lymphatics are always involved in any kind of infection. However, in common bacterial and viral infections lymphatics are usually not seen 11.12 Infl ammation Diffuse capillary lymphangiomatosis with many proliferating lymphatic vessels within a fi brotic tissue. The diagnosis will require immunohistochemical positivity for podoplanin and/or VEGF-C or VEGFR3. H&E, ×200 due to their small size. An exception is granulomatous pneumonias such as tuberculosis and sarcoidosis, where the granulomas can be more easily seen centered on lymphatics.

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Genetics of ANCA-associated vasculitides: HLA and beyond

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Circulating collagen biomarkers as indicators of disease severity in pulmonary arterial hypertension

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Secondary mutations at I1171 in the ALK gene confer resistance to both Crizotinib and Alectinib

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IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants infl uences granulomatosis with polyangiitis

Mixed connective tissue disease associated with MPO-ANCA-positive polyangiitis

Pulmonary eosinophilic vasculitis in a neonate with congenital chylothorax

Ehlers-Danlos syndrome type IV with few extrathoracic fi ndings: a newly recognized point mutation in the COL3A1 gene

Vascular Ehlers-Danlos Syndrome in siblings with biallelic COL3A1 sequence variants and marked clinical variability in the extended family

KITENIN increases invasion and migration of mouse squamous cancer cells and promotes pulmonary metastasis in a mouse squamous tumor model

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BMPR2 germline mutation in chronic thromboembolic pulmonary hypertension

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Spectrum of vascular pathology affecting patients with the antiphospholipid syndrome

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