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Brief Communication |
Correspondence: 1Corresponding Author: Roselene Ecco, Departamento de Clínica e Cirurgia Veterinária, Escola de Veterinária, Universidade Federal de Minas Gerais (UFMG), PO Box 567, 31270-901 Belo Horizonte, MG, Brazil
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Abstract |
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Key Words: Bovine • immunohistochemistry • mediastinum • neoplasia • thymoma
Thymomas are neoplasms of thymic epithelial cells, accompanied by variable infiltration of benign lymphocytes.6 In human medicine, several histologic classification schemes have been proposed for thymomas in an attempt to establish criteria of clinical and prognostic significance. Histologic and immunophenotypic resemblance to cortical or medullary thymic regions, and the relative number of epithelial cells and lymphocytes are the main features used to classify thymomas in humans.3,7,16 In veterinary medicine, classification of these neoplasms is generally made only on the basis of the density of lymphocytes within the neoplasm, with separation of thymomas into 3 histologic subtypes: lymphocyte predominant, epithelial predominant, or mixed.6
Thymic epithelial neoplasms seem to occur at a relatively high prevalence in cats,12 dairy goats,2,4,8 and the small laboratory rodent Praomys (Mastomys) natalensis,18 but in other animal species they are considered uncommon.6 The scarcity in the veterinary literature of a more detailed description of this neoplasm specifically in bovine1,5,8–11,13,17 prompted the publication of this case of thymoma of the mixed subtype in a 10-year-old Holstein cow.
The cow was submitted for necropsy to the veterinary pathology section at the Faculty União Pioneira da Integração Social (UPIS), Brasília, DF, Brazil, following a history of dystocia leading to death. A complete necropsy was performed. In the mediastinal region, on the right craniolateral side of the heart, was a 25 x 8 x 3 cm reniform neoplastic mass that extended from the vessels at the base of the heart to the apex (Fig. 1). The lateral aspect of the neoplasm was firmly adhered to the right cranial lung lobe and the ipsilateral region of the pericardial sac, with no apparent invasion of the pulmonary parenchyma and pericardium. The surface of this mass was smooth and nodular. On cut surface, the neoplastic parenchyma was composed of multiple lobules of homogeneous, soft, yellowish-white tissue demarcated by white fibrous septa. This mass had many thin-walled multilocular cystic cavities filled with yellow fluid (Fig. 2). One of the cavities also contained small mineralized concretions. In the ascending portion of the aorta, the vascular lumen was dilated over an extension of approximately 5 cm, forming a thin-walled sacculated structure (aneurysm). Additional gross findings included poor body condition, endometritis associated with retained fetal membranes, and acute abomasal ulcers.
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Histologically, the neoplasm was composed of a dual cell population: solid sheets of ovoid- to spindle-shaped neoplastic epithelial cells were variably intermingled with well-differentiated nonneoplastic lymphocytes. The neoplastic epithelial cells had indistinct cell borders, eosinophilic cytoplasm, and 10- to 15-µm, ovoid to elongated, often indented nuclei with finely stippled chromatin and 1 or multiple prominent nucleoli. Mitoses were rare. Rare deeply basophilic, round, lamellar bodies were intermixed with the neoplastic cells (Fig. 3). In a few areas, neoplastic cells with strong eosinophilic cytoplasm and either vesicular nuclei or nuclear debris formed concentric clusters suggestive of abortive Hassall's corpuscle formation (Fig. 4). Multifocally, there were areas of necrosis and fibrin exudate surrounded by hemorrhage and siderophages. The stroma was confined mainly to the perivascular spaces. The intratumoral cystic cavities were lined by a single layer of attenuated, finely vacuolated, nonciliated epithelium. Lymphocytes were present either as individualized cells or in small clusters. The neoplasm was surrounded by a thick, intact fibrous capsule. The grossly lobulated pattern of the tumor was induced by delicate bands of fibrovascular tissue. By immunohistochemical evaluation, the spindle cells and Hassall's corpuscle formations had strong reactivity for pancytokeratins and HMW cytokeratins (Fig. 5). Lymphocytes were CD3 positive (Fig. 6).
The gross and histologic morphology of the tumor in this case was similar to that described in other cases of bovine thymoma.1,5,8–11,13,17 The occurrence of this tumor is considered to be uncommon. However, in a histologic survey of all neoplasms in slaughtered cattle during 1 year in 100 abattoirs in the UK,17 thymomas comprised 5% of all neoplasms and more than one third of all thymic tumors. The authors indicate that thymomas appear to be relatively common in cattle, and that the tumor may have gone unrecognized owing to lack of associated clinical signs or failure to relate any presenting signs to an underlying thymic lesion. It is interesting to note that also in Italy the tumor was considered to be relatively common13 and in South Africa a frequency (4%) of thymoma in cattle similar to that reported in the British study series was found,5 whereas 1 survey in Canada2 and 1 in the United States14 showed a frequency of less than 1% of this tumor in cattle.
Multilocular cystic areas were a prominent gross feature of the tumor in this case. These cysts might represent cystic degeneration, a constant feature in thymomas.13,18 Another possibility is that they represent pseudocysts originating from invaginations of the surface-lining mesothelium.11,17,18 Finally, cysts within thymomas have also been considered to be dilated and fused lymph cavities9 or perivascular spaces in which the central vessels have disappeared.3,4,12,18 Cystic thymomas should be distinguished from branchial and multilocular thymic cysts and from thymic carcinomas undergoing cystic change. Multiple sections might be necessary for a correct diagnosis in such cases.
The epithelial cells in thymomas can be arranged in different patterns including solid, trabecular, cribriform, whorled, or rosette-like.6 In the present case, neoplastic epithelial cells formed solid sheets, interspersed by a few abortive Hassall's corpuscles. Despite their rare occurrence in thymomas, Hassall's corpuscles are usually considered to be helpful diagnostic features of the tumor because they recapitulate the medullary portion of the normal thymus. However, it must noted that when present in large numbers, Hassall's corpuscles usually are an indication of pre-existing structures surrounded by a tumor other than thymoma.16 The occurrence of mineralized lamellar bodies, also known as calcispherites, was described previously in other bovine thymomas.11,17 Infiltration of the neoplasm by eosinophils and their precursors, considered by some to be typical of thymomas,5 was absent in this case.
The proportion of neoplastic epithelial cells and nonneoplastic lymphocytes in thymomas varies widely between tumors and between different lobules of the same tumor. Based on this finding, thymomas may be categorized in veterinary medicine as lymphocyte predominant, epithelial predominant, or mixed.6 When lymphocytes predominate, the neoplasm must be differentiated from thymic lymphoma. Immunohistochemistry for cytokeratin is helpful in these cases, since the presence of rare epithelial cells in serial sections is suggestive of thymoma.6 Cytokeratin profiles have been established in human medicine for the thymus and thymomas, and have been shown to be clinically useful in determining the invasive potential of these neoplasms.7 Since a cytomorphologic and histologic classification of thymomas seems not to be a useful prognosticator in animals, the use of a pan-specific cocktail of antibodies for cytokeratins is sufficient for the diagnosis of these tumors in veterinary medicine. The HMW cytokeratins 10 and 14 (included among the antigens identified by the antibody anti-HMW cytokeratins used in this case) were shown to be expressed by subcapsular, medullary, and Hassall's corpuscle epithelial cells, but not by cortical cells of the thymus in humans.7 These cytokeratin expression patterns suggest that the epithelial cells of the thymoma in this cow were derived from the medullary region.
The age of the affected animal is another factor to be taken into consideration to distinguish thymoma from thymic lymphoma, the latter occurring in younger animals, whereas the majority of bovine thymomas occurs in animals over 3 years of age.5,8–10,13,17 Another differentiating factor includes the likelihood of lymph node involvement in thymic lymphoma.17 Other neoplasms to be considered in the differential diagnosis of thymoma are metastatic carcinoma and tumors of the aortic body.6
In the present case, the affected animal was relatively old, and immunohistochemistry indicated a predominantly pancytokeratin and HMW cytokeratin positive cell population forming the bulk of the neoplasm, consistent with the diagnosis of thymoma. The neoplastic epithelial cells were variably intermixed with numerous lymphocytes that stained strongly positive with CD3, indicating T-cell differentiation. Based on these results, the tumor was categorized as "mixed." In the human medical literature, thymic neoplasms are classified by different schemes, using various criteria.3,16 When using the World Health Organization (WHO) or Müller-Hermelink classification schemes, the tumor falls into the "mixed" (type AB thymoma) category. This category incorporates tumors in which foci having type A thymoma (composed of neoplastic thymic epithelial cells with spindle- or oval-shaped nuclei) are admixed with foci rich in lymphocytes (a characteristic of type B thymomas). The segregation of the 2 patterns can be either sharp or, as in this case, indistinct.
Thymomas have been described in different sites of the body. The anterior mediastinum or thoracic inlet is their usual site of occurrence, but these neoplasms can also be seen elsewhere, including the cervical region and posterior mediastinum, with variable compression of adjacent structures such as trachea, esophagus, and mediastinal vessels.4–6,9,10,12,13,17 The majority of the thymomas are benign. Local invasion and metastasis are considered by most authors to be uncommon, with metastases being reported in the pulmonary and pericardial pleura,5 lung,9,10,12,13 mediastinal lymph node,8,12 cervical portion of the thymus,13 kidney,9 and uterus.9 In the absence of any features of malignancy in this case, the tumor was considered to be benign in nature.
Clinical signs associated with thymomas are highly dependent of the location of the neoplasm. Reported signs in bovine include edema of the ventral head and neck region,9 clinically detectable mass in the thoracic inlet,11 respiratory distress,6,10 dysphagia,5 dull heart sounds,9 ruminal tympany,10 anorexia, emaciation, and drop of milk yield.9 In other cases (including the present one, where the emaciated state of the cow was attributed to inadequate nutrition during gestation), the tumors are incidental findings at necropsy or at slaughter.1,13 An additional finding in this animal was an aneurysm in the ascending aorta. This was likely a result of compression by the neoplasm onto the artery with poststenotic vascular dilation. Acute death as a result of rupture of the thoracic aortic aneurysm might have occurred eventually. Evidence of significant compression of the regional major vasculature by the neoplasm further indicates that thymomas should be included in the differential diagnosis for chronic congestive heart failure.
In summary, this case report describes the gross, histologic, and immunohistochemical characteristics of a mixed thymoma in an aged dairy cow. The neoplasm in this case was too large to be overlooked at necropsy, but smaller thymic epithelial neoplasms can easily go unrecognized at gross inspection. In order to establish the true prevalence of thymic epithelial neoplasms in bovine, which, as previously indicated,5,13,17 is likely higher than the number of reports in the veterinary literature, the thymus should always be examined carefully when older cattle are submitted for necropsy or slaughter.
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Acknowledgments |
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a. Pancytokeratins (cytokeratins AE1/AE3), Dako (M3515), Carpinteria, CA.
b. High molecular weight cytokeratins, Dako (M0630), Carpinteria, CA.
c. CD3, Dako (A0452), Carpinteria, CA.
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