Thymus

Anatomy

The thymus is a gray to pink bilobed organ found in the precardiac mediastinum [1]. It extends from just cranial to the first rib to the fifth rib in dogs or sixth rib in cats, although the size and shape are highly variable[2]. It is divided into right and left lobes. The left lobe extends more caudally than the right to between the left thoracic wall and left ventricle, but composes only 40% of the weight of the thymus [1]. The larger right lobe is more laterally expanded and extends to the pericardial sac. Dorsally, the thymus is associated with the phrenic nerves, the trachea, and the cranial vena cava. The thymus is derived from the endoderm and ectoderm of the third pharyngeal pouch and the third branchial cleft [3].

Nine arterial vessels have been identified that comprise the blood supply to the thymus [4]. The left lobe is supplied by several branches. Two branches of the brachiocephalic trunk supply the cranial and caudal poles of the left thymus. The left internal thoracic artery sends a large branch to the caudal pole, has three thymic arterial branches with two going to the cranial pole and one going to the caudal pole, and feeds the pericardiophrenic artery, which sends a thin branch to the cranial pole. The right lobe is supplied by a branch of the right internal thoracic artery, the pericardiophrenic artery, which forms one branch to each pole of the right lobe. Veins of the thymus are associated with the arteries. Four to six lymphatic vessels empty into the cranial mediastinal and sternal lymph nodes.1 Parasympathetic and sympathetic nerve fibers supply the thymus [1,2].

The thymus has a capsule of fibrous intralobular septae separating the two lobes. These are difficult to separate cranially, but caudally allow separation into the two distinct lobes. These septae allow passage for vessels, nerves, and lymphatics [3]. The septae end near the corticomedullary junction in a compartment called the perivascular space, where nutrient and waste exchange occurs between the lobules and the blood and lymphatic circulation [3]. B-cells, plasma cells, myeloid cells, eosinophils, and mast cells also accumulate within the perivascular space. The cortex, located peripherally, is made up of a large population of small, immature thymocytes, specialized cortical epithelial cells, and scattered macrophages. The centrally located medulla contains nearly mature and mature T-cells that are closely associated with medullary epithelial cells, dendritic cells, macrophages, and Hassall’s corpuscles. Hassall’s corpuscles appear onion like, with concentrically organized, highly keratinized epithelial cells. The medulla has a lower cell density than does the cortex. The cortex to medulla ratio is 1:1.2 The most peripheral part of the thymus is the thin subcapsular zone, which is lined with a thin perivascular epithelium extending along the internal capsule and along the intralobular septae [3].

Physiology

The thymus is responsible for seeding T-cells against foreign antigens while recognizing the tissues of the body as normal. T-cells begin formation in the bone marrow as common lymphoid precursor (CLP) cells, which may develop into T-cells, B- cells, or natural killer (NK) cells [5]. Some of the CLP cells enter the thymus and become immature thymocytes. These cells go through stages to become immature T- cells, making them positive for T-cell markers like CD4 and CD8 [3]. Nurse cells in the cortex are thought to form protective environments for thymocyte differentiation. Each nurse cell is responsible for up to 200 thymoctyes. Positive selection occurs in the cortex, exposing the thymocytes to foreign antigens, resulting in recognition [5]. In the medulla, negative selection occurs, with dendritic cells designed to stimulate apoptosis of the cells with excessive self reactivity [6]. A large number of macrophages are present to help remove the unwanted T-cells. Hassall’s corpuscles also contribute to removal of unwanted T cells [3]. Only 5% to 10% of T-cells survive positive and negative selection [3,5]. T-cells remain in the thymus for 4 to 5 days during this process [6].

The thymus enlarges until the animal is 4 to 5 months of age, and then begins a rapid but never complete involution process [2]. It has been thought that increased adrenal corticosteroids coupled with a decrease in growth hormone may influence the involution process [7]. The thymic tissue is replaced by fat.

Neonatal thymectomy results in a loss of the cell-mediated immune response [6]. The number of circulating lymphocytes decreases dramatically, as do the lymphocytes in T-dependent areas. The number of plasma cells in lymphoid tissues, the amount of serum immunoglobulin, and antibody formation also decrease. Adult thymectomy results in a gradual decrease in the numbers of lymphocytes, suggesting that a reservoir of thymus-derived cells exists and must be exhausted [6].

Pathophysiology

Although rare, some thymic-related diseases have been reported. In a review of thymic disease processes, 54 of the 66 cases reported in dogs and cats were thymoma or thymic lymphoma [8].

Thymomas

Thymomas are tumors that originate from the thymic epithelium [9]. In dogs, large breeds and females are overrepresented [10]. In cats, purebreds (especially Siamese) and domestic shorthairs are commonly affected [11,12]. They usually occupy the cranial mediastium but may extend from the neck to the posterior mediastinum [13]. Thymomas are often nodular and encapsulated, causing compression of nearby structures. Cystic thymomas, more common in cats than in dogs, occur with distention and fusion of the perivasulcar space [14]. Variable degrees of lymphocyte infiltration may be present; small or heterogenous lymphocytes are usually found, although large lymphocytes predominate in one third of thymomas [13]. The epithelial cells of a thymoma are usually elongated, but occasionally may be round to oval. Epithelial cells are arranged in solid, trabecular, cribriform, whorled, rosette, or angiocentric patterns [13]. Other cells found within thymomas include mast cells, eosinophils, macrophages, melanocytes, plasma cells, and neutrophils. The results of fine-needle aspiration of thymomas may contain any of these cells, along with large numbers of lymphocytes; the epithelial cells may be present in smaller numbers. Cystic thymomas often yield a nondiagnostic sample [9]. Staining for cytokeratin positively identifies the epithelial cells of a thymoma [13]. The majority of thymomas are benign, with few metastasizing; however, thymomas are better categorized as invasive or noninvasive. Noninvasive thymomas are typically easy to resect. Invasive thymomas are non resectable, and palliative partial resection can result in high morbidity. Approximately 70% of thymomas are resectable, and no diagnostic test has been proven to be predictive of resection preoperatively [9]. Most presenting clinical signs of thymoma involve the respiratory tract, with the most common presentation in the dog and cat being coughing and dyspnea, respectively [11,15,16]. Other clinical signs are often associated with general ill health and paraneoplastic syndromes.

Paraneoplastic processes are common in conjunction with thymomas. Acquired myasthenia gravis is the most common thymoma-associated paraneoplastic condition, caused by the production of autoantibodies against acetylcholine receptors in muscular tissue, leading to generalized weakness and megaesophagus [2]. The presence of megaesophagus is an important prognostic indicator, because patients with megaesophagus prior to surgery are at a high risk for aspiration pneumonia postoperatively. Isolated reports of resolution of megaesophagus and decline in acetylcholine antibodies after thymectomy exist [10,17]. Polymyositis may be linked to myasthenia gravis as well, with 29% of dogs with myasthenia gravis having polymyositis [10]. The cardiac muscle may also be affected. Autoantibodies to acetylcholine have been proposed to cause myocarditis or to attack the conducting tissue directly, resulting in third-degree atrioventricular heart block [15,18]. Hypercalcemia has been reported, and in one case parathyroid-related protein (PTHrP) was increased. Resection of thymoma caused calcium and PTHrP to return to normal levels.

Cats may present with exfoliative dermatitis characterized by auricular and periauricular reddening progressing to marked exfoliation over the head, neck, trunk, and limbs, with skin ulceration in the axillae and inguinal regions [19,20]. Brown waxy exudate is found in the interdigital region and in the claw beds [21]. Skin histopathology shows an interface dermatitis with CD3+ lymphocytes, mast cells, and plasma cells, and folliculitis [22]. The presence of CD3+ lymphocytes may be related to abnormal immune regulation that could occur with thymic disease. One cat with a thymectomy made a full recovery; other cats included in the study were euthanized. Other non-thymic tumors commonly occur in approximately 10% of human patients, and this is seen in dogs and cats as well [23].

Prognosis with thymoma is varied, and few retrospective large-scale studies exist. If megaesophagus is not present, an 83% 1 year survival has been reported.15 In 11 dogs that were treated with chemotherapy and/or radiation therapy, a wide range of survival times has been found, ranging from 61 days to over 1657 days, with a median of 180 days.12 In a study of 12 cats, half of them survived after surgical excision for a median of 21 months.11

Thymic Lymphoma

Thymic lymphoma is the most common thymic disease in the cat. Siamese and feline leukemia-positive cats are overrepresented.8 It is frequently accompanied by other findings associated with lymphoma, such as enlarged lymph nodes or paraneoplastic hypercalcemia.9 Chemotherapy for lymphoma is the definitive treatment, and a rapid and complete response is common.9 If the response is partial or if no response to chemotherapy is seen, thymoma is suspected. Radiation therapy can be used along with induction chemotherapy to improve the likelihood of rapid remission; it can be used if there is a delay in beginning chemotherapy; or if the patient is resistant to chemotherapy.24

Thymic Hemorrhage

Fatal thymic hemorrhage usually occurs within 2 years of birth during the involution process [2]. The etiology is uncertain, but several theories have been proposed. The vessels of the thymus are not well supported during involution, and relatively minor trauma to the neck may cause the fragile vessels to rupture [25]. Ingestion of anticoagulant medication may be linked; in a case series of 10 dogs, half of them had consumed rodenticide [26]. Sudden increases in blood pressure owing to excitement have been hypothesized to result in hemorrhage [27]. Epileptiform seizure activity has been linked to thymic hemorrhage and death [28]. There is some debate over whether thymic hemorrhage is considered to be a true pathogenic entity or if it is always secondary to another cause [25]. German shepherds and cocker spaniels may be overrepresented, and two Shetland sheepdog littermates were affected [27,29]. The mediastinum does not contain sufficient tissue for a hematoma to form, so bleeding can go unchecked and spill into the thoracic cavity. The mortality rate with thymic hemorrhage is high, but aggressive medical treatment with fluid support, blood transfusion, and vitamin K therapy if rodenticide toxicity is suspected, or rapid thoracotomy for control of bleeding and thymectomy if medical treatment is unrewarding [27,30].

Thymic remnants in aberrant locations have also been implicated in thymic hemorrhage. Fatal hemopericardium has been reported secondary to bleeding from a heart base thymic remnant [28].

Other Thymic Disorders

Premature thymic atrophy can be seen with viral disease (canine distemper, parvovirus, feline leukemia, feline immunodeficiency virus, and panleukopenia), zinc deficiency, and growth hormone deficiency in Weimerainers [7]. The absence of a thymus may be associated with fading puppy syndrome [31]. Thymic hypoplasia is associated with lethal acrodermatitis in bull terriers with zinc deficiency, with a severe reduction of lymphocytes in T-lymphocyte rich areas of lymphoid tissue [32]. Thymic hyperplasia has been reported in cats with laryngeal lymphoma and skin disease [8]. Other neoplastic conditions of the thymus may include carcinoma in conjunction with thymoma, germ cell tumor, and thymolipoma [2].