Alveolar capillary dysplasia is a life-threading disease of newborns. Babies are born without symptoms, but immediately after birth will show symptoms of hypoxia and pulmonary hypertension. Mechanical ventilation and oxygenation in an intensive care unit will improve the clinical situation; however, immediately after withdrawal the symptoms will worse again [13]. There is no cure for this disease.

Histologically the number of capillaries is dramatically reduced or they might be almost absent. Larger arteries will show mild increase of vessel wall thickness. On step section AV anastomoses can be proven. In those cases where there is also misalignment of the veins, these run parallel with the arteries within alveolar septa, and they are anastomosing focally. Veins are closely attached to pulmonary arterioles and small arteries and are widened (Figs. 3.4. 3.5, 3.6, and 3.7). As a result the blood flow is shunted from the arterial bed to the veins without a significant flow into the capillaries resulting in severe hypoxia [14]. Recently microdeletions resulting in frameshift, nonsense, and stop mutations of the FOXF1 gene have been identified probably underlying this disease [15–17]. Another genetic abnormality possibly also leading to the same phenotype was identified as PTEN loss in mesodermal cells inhibiting the proliferation of angioblasts, and a relationship was identified with FOXF1 mutation [18]. So it is most likely that not just a single gene causes this disease but more than one, disrupting the cross talk between different cells involved in the correct alignment of the peripheral vascular bed. In a case report, trisomy 21 was described in a child with alveolar capillary dysplasia and misalignment of veins [19], but again cardiac malformations were also present, which makes it difficult to assign a chromosomal abnormality to one of the different organ abnormalities.

Pulmonary arteries and veins can be affected by different malformations, which are presently ill defined. Usually patients present with alveolar hemorrhage, which sometimes can be life threatening [20]. Pulmonary hypertension is usually present in diffuse non-tumor cases. All ages can be affected; however, diffuse AV anastomoses such as in Rendu-Osler disease usually present at an early age [21–23], whereas localized AV anastomoses (i.e., within one lobe) are seen at an older age (above 12 years; Fig. 3.8). The underlying pathology can be capillary or cavernous hemangiomas, arteriovenous malformations, or angiomas. Usually a careful examination is necessary to find the underlying cause of bleeding. In my experience one should select those areas where massive hemorrhage is present. Take many sections and start searching for malformations.

Morbus Rendu–Osler (hereditary hemorrhagic telangiectasia) is an autosomal dominant systemic vascular disorder presenting with vascular malformations including thin-walled ill-formed small blood vessels (telangiectasia) and diffuse AV anastomoses (Figs. 3.9, 3.10, and 3.11). Most often the small and large bowel are affected, but other organs might be involved too – the affection of the lung is rare [22, 23]. It can cause life-threatening bleeding, but also hypertension. A constant clinical finding is an impaired vascular flow, which can be visualized by tracers showing a time difference in the venous flow between the affected and the normal lung lobe (short turnover due to AV anastomoses). Treatment is still experimental; however, we significantly improved the symptoms in a young boy using a treatment protocol for arterial hypertension (bosentan) [24]. Recently mutations in the endoglin and activin receptor-like kinase genes were discovered, which might open a new line of treatment in this rare disease [25–29].

Ehlers–Danlos syndrome type IV as well as Marfan disease can affect the pulmonary blood vessels [30, 31]. The symptoms are usually life-threatening bleedings (alveolar hemorrhage). It might be necessary to resect a lung lobe or do even a pneumonectomy, to rescue the patient, although the disease will recur affecting other lung lobes and finally cause death. Histologically these diseases are most difficult to prove. Of diagnostic help is the young age of the patients. All other causes of alveolar hemorrhage have to be excluded, such as vasculitis, localized hemangioma, trauma, etc. A typical feature of both diseases is the thin wall of the large pulmonary arteries. In Marfan disease, an elastic stain will highlight the nearly absent or ill-formed elastic fibers (Fig. 3.12a); in Ehlers-Danlos disease type IV, collagen and elastic fibers are very thin and sometimes form an incomplete rim around the vascular smooth muscles, whereas the lamina elastic is normal (Figs. 3.12b and 3.13). The synthesis of type III procollagen is impaired in this latter disease [31].

Veno-occlusive disease is characterized by venous stenosis and/or occlusion. Most often also arteries will show thickened walls (Figs. 3.14 and 3.15). Veno-occlusive disease can present with pulmonary arterial hypertension and capillary hemangiomatosis in children and adults, but rarely is found as an isolated disease. In children it is most often found in complex malformations of the heart. Veno-occlusive disease will be covered in detail also in the chapter on vascular disorders.

Sequestration was originally regarded as a malformation of the lung blood system. During lung development an artery from the branchial arch of the primitive blood supply persists and therefore a segment or even a lung lobe gets it blood supply from an aortic branch (A. mammaria interna, AA. intercostales, etc.) or the aorta directly. Recent surveys have shown that associated with this condition are other malformations, such as stenosis or atresia of the segmental bronchus and congenital cystic adenomatoid malformation (type I or II) [32, 33]. Surgeons will usually cut the bronchus at the atresia site and thus this lesion is usually not present at the resected segment. Sequestration can be intralobar (within the lung) or extralobar (thoracic cavity) or even within the abdominal cavity (below the diaphragm). On macroscopic examination a thick-walled artery is found entering the lung from the pleura. Macroscopically as well as microscopically, there is most often hemorrhage overlaying the specific histologic features. A diagnostic feature is elastosis of the involved arteries (Fig. 3.16). There is multilayering of elastic laminae. The increase of the vessel wall thickness is quite characteristic and not seen in that severity in other diseases such as pulmonary hypertension. The arterial wall looks like that of a large systemic artery. Often there is considerable inflammation in the lung tissue, so resection will much improve the overall situation of these patients [34–39]. In more than 50 % of cases, sequestration is associated with cystic pulmonary malformation (discussed below).

A rare anomalous venous return to the right atrium or the inferior vena cava has been described as Scimitar syndrome (Fig. 3.17). It can be combined with other abnormalities, especially the heart [40–42]. Arteriovenous angiomas have been seen in congenital heart malformations (Fig. 3.18).

Different other variants of anomalous arterial and venous blood supplies have been reported as single cases. Following the description of these cases, they are most probably based on the same organogenesis pathway: branches of the bronchogenic pouch remain and get fused to the peripheral lung blood vessels [14], and formation of veins out of the left atrium and sinus venosus is impaired [37, 43].

Other vascular malformations either inborn or acquired such as capillary hemangiomatosis and lymphangiomatosis will be discussed in the chapter on tumor pathology, vascular tumors.

Congenital cystic/pulmonary adenomatoid malformation is a developmental disease, which predominantly occurs in children; however, it has been diagnosed also in young adults and occasionally in older patients. Originally three types have been described, types I–III. Type I is characterized by large cysts, >2 cm, often multilocular, and type II is more uniform with smaller cysts, less than 2 cm, whereas type III is microcystic and not visible macroscopically. Stocker has added types 0 and IV several years ago, because not all lesions fitted into one of the three categories [44]. In a recent review, Langston critically discussed CCAM/CPAM. First of all, the Stocker classification was primarily based on autopsy cases and primarily characterized macroscopically. Second, today more cases come in as resected specimen, because by clinical investigation these lesions are diagnosed even intrauterine. In her series of cases, Langston has nicely shown that CPAM quite often is associated with other developmental abnormalities, as bronchial atresia and sequestration (see above). She proposed a simplified classification into large cyst type (CPAM I) [1, 33]. The cysts are multilocular, larger than 2 cm in diameter, and covered by bronchial epithelium overlying fibromuscular stroma (Figs. 3.19, 3.20, and 3.21). In contrast to bronchial cysts, there is no cartilage. CPAM I communicate with the peripheral lung tissue, also in contrast to the situation of bronchial cysts (no alveolar tissue), which is the main differential diagnosis. Within CPAM I and II foci of atypical goblet cell, hyperplasia does exist, which might give rise to childhood adenocarcinoma (Fig. 3.22) [45–47].

The small cyst type (CPAM II) is usually associated with airway obstruction, such as atresia, but also frequently with sequestration or even both. Cysts are found in a regional distribution; the cysts are lined by bronchiolar epithelium. Between the cysts normal alveolar lobules can be found (Figs. 3.23, 3.24, and 3.25).

The solid form of CPAM type III (CCAM III) is completely different from types I and II, because it appears macroscopically solid not cystic. Histologically it presents as an immature lung with tubular bronchioles organized into lung lobules without an alveolar part. It resembles fetal lung at the tubular stage (Figs. 3.26 and 3.27). It can be found combined with laryngeal atresia, according to Langston [1]. Therefore, CPAM III should be taken as a different non-cystic lesion best under a different name and not subcategorized under CPAM. The only thing in common with CPAM I and II is that it is also a growth and differentiation abnormality related to developmental genes. In a recent report, trisomy 13 was identified in a child; however, there were also several other malformations as holoprosencephaly, arhinencephaly, cleft palate, ventricular septal defect, and bilateral clubfeet [48]. In another case CPAM was described combined with cardiac and renal abnormalities [49].

CPAM 0 and IV are ill defined, and Stocker’s classification could not be reproduced in our experience (European Rare disease group). According to Stocker CPAM 0 is a malformation at the level of the tracheal bud and corresponds most likely to alveolar dysgenesis, which is discussed above, whereas CPAM IV in our experience is indistinguishable from congenital lobar emphysema. Both are not correctly placed into cystic malformations: CPAM 0 is not cystic and CPAM IV is emphysematous, so we will discuss these lesions under the appropriate term of alveolar dysgenesis and congenital emphysema, although at present we do not have enough data about pathogenesis and the genetic background.

In contrast, CPAM types I–III represent examples of growth and differentiation arrest, which could be highlighted by some recent molecular genetic studies. In the study by Wagner et al., fatty acid-binding protein-7 was found underexpressed in CPAM [50]; in the study by Jancelewicz, a fourfold expression of FGF9 was found in fetal epithelia of CPAM compared to normal fetal lung. By immunohistochemistry a decreased FGF7 expression was detected in CPAM mesenchyme [51]. However, both studies failed to classify the subtypes of CPAM, which they analyzed in their respective investigations. This might have contributed to understand better the pathogenesis and would have improved the present day classification (different time points of developmental stops/defects).

Bronchial cysts do occur usually extrapulmonary (most often within mediastinum), rarely within the lung. They are characterized by a cystic space covered by bronchial epithelium, usually with well-formed muscular layer. Cartilage most often is present. There is no peripheral lung tissue present (Fig. 3.28). It might be assumed that bronchial cysts represent supernumerary bronchi of the ontogenesis of the lung, not having been abolished by apoptosis during bronchial budding. In several mammals but also birds (sheep, goat, etc.), there exist a mediastinal lung lobe, the bronchus arising directly from the trachea. Since the lung development is recapitulated during morphogenesis, it might be that this bronchus persists, looses its communication with the trachea, and finally transforms into a cyst.

Congenital lobar emphysema (corresponding to Stocker’s CPAM type IV) is inborn or acquired emphysema for which no cause has been defined. It is similar to panacinar emphysema in adults, showing an even distension of alveoli. However, it affects only lung lobes or segments, not the whole lung (Fig. 3.29). Symptoms are caused by compression of the adjacent lung lobes. Newborn will present with hypoxia. A resection usually cures the patient, because the other lobes will expand and later on grow, and thus replaces what was resected.

William–Campbell syndrome is characterized by the absence or malformation of cartilages in peripheral bronchi. The cartilages in the trachea and main bronchi are normally developed; however, below the segmental bronchi, the cartilages are either totally absent or ill developed. This causes bronchial collapse during expiration and symptoms of bronchial obstruction in a very young-aged population. The diagnosis even on VATS biopsies is not easy, because VATS take usually peripheral lung tissue below the order of segmental or subsegmental bronchi (see schema below). Therefore, in these tissues, only small bronchi, which normally have ill-formed cartilage or none at all, are seen. Therefore, before the biopsy is taken, the thoracic surgeon needs to be advised, to take a tissue fragment, which contains at least one subsegmental bronchus. Also the largest bronchus should be marked, so that the tissue can be cut vertically to get cross sections of the bronchus.

Schema: Normally VATS biopsies are shallow and therefore only small bronchi and bronchioles are included as in schema A; for WC syndrome a steep section is required to get larger bronchi into the specimen as in B; in addition the tip containing the largest bronchus should be marked.

Histologically there might be no cartilage in a medium-sized bronchus or ill-developed immature cartilage islands (Fig. 3.30). These immature cartilage islands are most helpful in establishing the correct diagnosis.

Mounier–Kuhn syndrome (tracheobronchopulmonary megaly) is characterized by large dilated central bronchi and trachea. There is usually a degeneration of elastic fibers within the bronchial mucosa. All other elements are normal. From the subsegmental bronchi downward, the structure of the lung is normal. The clinician will report about an unusual wideness of the main bronchial system (Fig. 3.31). The patients will suffer from obstructive symptoms. In some cases a functional stenosis of the esophagus can be the dominant symptom. The disease is found in a young-aged population. Insertions of a stent might help in preventing airflow impairment.

Birt–Hogg–Dube (BHD) syndrome is a rare inherited genodermatosis characterized by distinctive cutaneous lesions, an increased risk of renal and colonic neoplasia, and the development of pleuropulmonary blebs and cysts. Within the lung with a predominant basal location, cysts are seen surrounded by normal lung parenchyma. These cysts present with thin fibrous walls and are a source of pneumothorax. Other cystic lesions may radiologically mimic BHD [52].