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J Thorac Cardiovasc Surg 2007;134:799-801
© 2007 The American Association for Thoracic Surgery
Brief Communication |
a Department of Thoracic Surgery, Hôtel-Dieu University Hospital, Paris, France
b Department of Thoracic Surgery, Hospital of Troyes, Troyes, France
c Department of Pathology, Hospital of Troyes, Troyes, France.
Received for publication February 24, 2007; accepted for publication March 29, 2007. * Address for reprints: Alessandro Stefani, MD, Department of Thoracic Surgery, Hôtel Dieu University Hospital, 1, Place du Parvis Notre Dame, 75001, Paris, France. (Email: stefani.alessandro{at}unimore.it).
Primary intrapulmonary thymomas (PITs) are very uncommon, with 28 cases reported to date.1-3
Because of the paucity of studies, the biologic behavior and pathologic features of these neoplasms are not well known. The C677T methylenetetrahydrofolate reductase (MTHFR) genotype is a congenital disorder leading to low folate levels; the resultant mild hyperhomocysteinemia is associated with increased risk of venous thromboembolism and malignancies.4,5
We present a case of PIT associated with hyperhomocysteinemia caused by the C677T variant of MTHFR.
A 73-year-old woman was admitted for acute dyspnea with bronchospasm in a chronic obstructive pulmonary disease pathologic substrate. Her medical history was marked by episodes of venous thrombosis caused by a mutation of the MTHFR gene that imposed a preventive anticoagulant therapy. Chest radiography revealed an 18-mm nodule in the right upper lobe, which was confirmed by a computed tomographic scan (Figure 1). A positron emission tomographic scan showed a moderate uptake in correspondence of the lesion (standardized uptake value, 2.2). The results of bronchoscopy and computed tomographic scanning of the brain were normal.
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Macroscopic examination showed a well-circumscribed and encapsulated nodule (Figure 2, a). Histologic evaluation revealed the presence of 2 cell populations: epithelioid and lymphocytic (Figure 2, b). The epithelioid component was predominant and admixed with scattered lymphocytes. No areas of necrosis and very few mitoses could be identified. Immunohistochemical analysis demonstrated strong staining for cytokeratin 5 and 6 and epithelial membrane antigen in the epithelioid component, with negative staining for cytokeratin 7, thyroid transcription factor 1, and calretinine. These histologic findings were consistent with mixed or type AB thymoma. All lymph nodes were free of tumor.
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To our knowledge, 29 cases of PIT have been described, including this one.1-3 Pathogenesis is still a subject of debate: the most supported theory is that these tumors derive from ectopic thymic tissue, resulting from an embryologic displacement, but a teratomatous origin has also been invoked.1
The number of tumors reported is too small to clearly predict their biologic behavior. PITs occurred usually from the sixth decade of life,1-3 and a slight female predominance has been found.3 The right side was more often affected,1 with no preference in hilar or peripheral location.2 Patients were more commonly asymptomatic.3
The histologic spectrum of these lesions ranges from lymphocyte-rich to predominantly epithelioid to spindle-cell thymoma.1 In most cases tumors appeared as well-circumscribed lesions, with low mitotic activity and minimal atypia. PIT might represent a serious diagnostic challenge for the pathologist; the differential diagnosis includes lymphoma and primary or metastatic carcinoma of the lung. Immunohistochemical stains might be of aid, but morphologic features are of basic importance.1
Most reported cases of PIT were slow-growing tumors with a good prognosis when surgically resected.1-3 Because preoperative diagnosis, either on biopsy specimens or frozen sections, is very difficult, PITs are usually diagnosed postoperatively. Therefore indications about the surgical management are difficult to define and to apply (eg, type of resection or need for mediastinal dissection).
Our case was classified as a type AB thymoma, an essentially nonaggressive lesion; it confirms the low grade of malignancy of PIT and its favorable outcome if completely resected.
The association between PITs and myasthenia gravis is less frequent than for mediastinal thymomas. As far as we know, 3 patients with PIT had symptoms of myasthenia gravis, whereas other syndromes associated with mediastinal thymomas have never been described for PITs.
The C677T variant of the MTHFR gene is an inherited congenital disorder altering the metabolism of folic acid.4 The resulting low folate levels influence the homocysteine remethylation pathway, and this results in mild hyperhomocysteinemia. Increased levels of homocysteine have been related to an increased risk of venous thromboembolism, pregnancy loss, anomalous progeny, cancer (eg, hematologic malignancies), and brain and colon tumors.4,5 Our patient had the heterozygous variant of the C677T MTHFR genotype, which induces intermittent moderate hyperhomocysteinemia and leads to recurrent venous thromboses. Although the vascular toxicity of hyperhomocysteinemia is well demonstrated, the association between altered levels of this thiol and cancer is a recent acquisition, and its clinical significance has yet to be defined. This is the first article reporting an association between MTHFR variant/hyperhomocysteinemia and thymoma, supporting the role of hyperhomocysteinemia as a risk factor for cancer.
References
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