During the embryogenesis, a small bud or diverticulum of the foregut may be separated and become mediastinal cysts that are referred to as foregut cysts. They are surrounded by lining epithelial cells of endodermal and wall of mesodermal origin that normally would have developed into trachea, bronchi, esophagus, stomach, or intestine. These cysts usually do not communicate with tracheobronchial tract or the esophageal lumens. Malignancy may occur in a background of foregut cysts, though very rare, usually in the form of adenocarcinoma [2]. While most patients with bronchogenic, esophageal and enteric cysts are asymptomatic, gastric, and gastroenteric cysts may cause severe symptoms in the affected patients due to peptic ulcer or even present with a life-threatening complication associated with perforation.

Bronchogenic or bronchial cysts can occur anywhere along the tracheobronchial tree. They are most frequently found in the location posterior to the carina but rarely in the lower portion of the visceral mediastinum, just above the diaphragm [3]. Barium study or CT scan should be helpful in finding the lesion that could be missed by plain chest X-ray. Bronchogenic cysts are usually unilocular and contain clear or gelatinous fluid. Average diameter of the cysts is 3–4 cm and the lining epithelium is respiratory type (i.e., ciliated columnar epithelium) with variable degree of squamous metaplasia (Fig. 9.1). The cyst wall also may contain cartilage, smooth muscle, bronchial glands, and nerve fibers, as in the normal bronchial wall.

Most esophageal cysts are found within the wall of the lower half of the esophagus. The lining epithelium is diverse and may be squamous, ciliated columnar, or mixed (showing both types). Distinction from bronchogenic cysts can be difficult and even impossible, but the presence of two layers of smooth muscle helps to confirm the diagnosis of esophageal cysts.

The paravertebral area in the paravertebral mediastinum is the most common location for these cysts that are often attached to or embedded within the esophageal wall [1]. Nearly all cases are associated with vertebral malformations. The gastric variety is made up of the same coats as the stomach, whereas the enteric type simulates the normal small intestinal wall. Nerve fibers and ganglia are often found in the wall. Gastroenteric cyst refers to the combined form of gastric and enteric cysts.

Most pericardial cysts (also known as coelomic cysts) are located at the right cardiophrenic angle but also can be seen in the left heart border and the prevascular and paravertebral mediastinum. Pericardial cysts are lined by mesothelial cells that should be positive for keratins as well as mesothelial markers. The cyst wall may show sparse inflammatory infiltrates and mild fibrosis. Xanthomatous changes and reactive mesothelial hyperplasia may occur. Differential diagnosis includes lymphangioma, bronchogenic cysts, and pseudocysts. If a core biopsy of the cyst shows the mesothelial lining cells, the diagnosis of pericardial cyst can be made.

There are two types of thymic cysts: unilocular and multilocular. Unilocular thymic cysts are thought to be developmental origin and likely arise from remnants of the third branchial pouch [4]. They tend to be small and can be found anywhere along a line extending from the angle of the mandible to the manubrium sternum (i.e., along the migration route of the thymus during the development), though present more often in the neck than in the mediastinum. The cyst wall is thin and translucent without inflammation. The epithelial lining is flattened, cuboidal, columnar, or rarely squamous. In contrast to the developmental nature of unilocular thymic cysts, multilocular thymic cysts are thought to be an acquired process, likely representing a reactive or secondary change due to other lesions within the thymus or other adjacent organs, given the inflammation and fibrosis present in nearly all cases [5]. Multilocular thymic cysts might be identified as an incidental microscopic finding. However, they can also present as a large tumor-like mass with adhesion to other mediastinal structures, mistaken as a malignant process at the time of surgery. The lining cells of multilocular thymic cysts may be also flat, cuboidal, ciliated columnar, or squamous as in unilocular thymic cysts. Multilocular thymic cysts may also show denuded areas lacking the lining cells or a highly proliferative appearance with the features of pseudoepitheliomatous hyperplasia. Nonspecific reactive changes are very common including cholesterol granulomas, mixed inflammatory infiltrates, and numerous lymphoid follicles. A multilocular thymic cyst is postulated to be formed by acquired cystic dilation of medullary epithelial structures, which is probably induced by an inflammatory reaction within the thymic parenchyma (Fig. 9.2). The initial thymic inflammation could be idiopathic without any cause, but there might be a specific etiology (e.g., HIV infection, autoimmune disease, etc.) [6]. Also, one should remember that the histopathologic features of multilocular thymic cysts are often seen in the thymuses harboring nodular sclerosis Hodgkin lymphoma or seminoma. Other tumors such as thymoma, non-Hodgkin lymphoma, mature teratoma, and yolk sac tumor may be also associated with multilocular thymic cysts, though less common. Therefore, a thorough clinical and radiologic correlation is needed to rule out the neoplastic process in the vicinity when a diagnosis of multilocular thymic cysts is made. Main histopathologic differential diagnosis of multilocular thymic cysts include cystic degeneration of thymus and cystic lymphangioma [7]. Rarely, squamous cells carcinomas, basaloid carcinomas, and neuroendocrine carcinomas may be seen in a background of multilocular thymic cysts with the intimate connection between the lining and the carcinoma, suggesting their causal relationship [8–11]. A core biopsy can provide with the diagnosis of multilocular thymic cysts. However, sampling is always an issue and one has to be always mindful about the adjacent cancer.

Ectopic parathyroid or thyroid tissue can be seen in the mediastinum (Fig. 9.3) and gives rise to a benign or malignant process. Sebaceous glands or salivary gland tissue may be seen in the mediastinum, though extremely rare. Accordingly, these tissues can be encountered in a needle biopsy or fine needle aspiration that can provide with a definite diagnosis.

Chronic mediastinitis refers to chronic inflammation with granulomas and/or severe fibrosis, typically affecting the anterior mediastinum (Fig. 9.4). This term is often used interchangeably with fibrosing mediastinitis (also known as sclerosing mediastinitis), a rare condition characterized by an aggressive fibroinflammatory process involving the mediastinum [12–17]. Fibrosing mediastinitis affects predominantly young adults with a slight male predominance [17]. It frequently causes compression of airways or blood vessels in the mediastinum, which may result in superior vena cava syndrome. Pulmonary edema or pulmonary venous infarct may occur due to the obstruction of pulmonary veins. Clinical and radiologic features of fibrosing mediastinitis may mimic a malignancy. Treatment for fibrosing mediastinitis is somewhat controversial, and may include steroids or surgical decompression of affected vessels or other vital structures.

A specific etiology cannot be demonstrated in many instances of fibrosing mediastinitis. However, it has been postulated that some cases might be an abnormal immunologic response to various infection, such as histoplasmosis, especially in the endemic areas of such infection [18–24]. A study of 38 fibrosing mediastinitis cases reported that histoplasmosis and mycobacterial infection were implicated in 26 and 12 cases, respectively [25]. Fibrosing mediastinitis cases due to nocardiosis or radiation therapy have been also reported [26].

Morphologic heterogeneity of fibrosing mediastinitis was addressed in a study of 30 cases with idiopathic fibrosing mediastinitis [24]. Three distinct groups (stages) were described: Stage I, edematous fibromyxoid tissue with numerous spindle cells, eosinophils, mast cells, lymphocytes, plasma cells, and thin-walled blood vessels; stage II, thick glassy bands of haphazardly arranged collagen with focal interstitial spindle cells, lymphocytes, and plasma cells; stage III, dense acellular collagen with scattered lymphoid follicles and occasional dystrophic calcification. These findings suggested that “sclerosing mediastinitis” may represent the final stage of an evolving, dynamic process with different morphologic appearances akin to abnormal wound healing [24]. Fibrosing mediastinitis can be seen in association with one or more of idiopathic fibroinflammatory conditions, such as retroperitoneal fibrosis, sclerosing cholangitis, Riedel’s struma, and inflammatory pseudotumor of the orbit [24]. Importantly, one should always keep in mind that any given biopsy with only fibrosis and chronic inflammation may represent a nonspecific reactive change to some neoplastic disorders in the vicinity, especially nodular sclerosis type of Hodgkin lymphoma. Thus, a careful clinical and radiologic correlation is required whenever a diagnosis of fibrosing mediastinitis is made.

Immunoglobulin(Ig)G4-related disease (IgG4-RD) is a chronic fibroinflammatory condition of unknown etiology characterized by tumefactive/infiltrative fibrosis and lymphoplasmacytic infiltrates involving a single or several anatomic sites and often with an elevated IgG4 serum level [27]. Autoimmune pancreatitis is the originally described organ manifestation of IgG4-RD [28]. Many other anatomic sites have been reported since, including mediastinum, as well as salivary and lacrimal glands, lymph nodes, spleen, lung, pleura, breast, liver, bile ducts, gallbladder, retroperitoneum, kidney, prostate, paravertebral space, meninges, and peripheral nerves and arteries [15].