Microscopic thymoma
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《血管的通路杂志》
a Department of Pathology, Hopital Louis Pradel, 28 avenue Doyen Lépine, 69 677 Bron Cedex, France
b Department of Thoracic Surgery, Hopital Louis Pradel, 28 avenue Doyen Lépine, 69 677 Bron Cedex, France
c Department of Neurology, Hopital Pierre Wertheimer, 59 boulevard Pinel, 69 677 Bron Cedex, France
Abstract
Microscopic thymoma was first described in 1976 and remains in the latest WHO classification (2004). It defines an epithelial proliferation, with <1 mm in diameter, usually multifocal, that preferentially occurs in patients suffering from myasthenia gravis without a macroscopically evident tumour. A series of 87 thymectomies realised in myasthenic patients between 1992 and 2005 was reviewed. We describe three cases of microscopic thymoma: two male and one female with an average age of 41.6 years. All patients suffered from myasthenia gravis positive for acetylcholine receptor antibodies without any tumour detectable on chest tomodensitometric examination. Thymectomy was performed in all cases, enlarged to the mediastinal fat in one. Microscopic examination revealed three type-A microscopic thymoma, one multifocal, associated with lymphoid hyperplasia in two cases. After surgery, all patients had clinically improved. In summary, chest computed tomography is unable to detect microscopic thymoma. Histological examination of the entire specimen is indicated after thymectomy in myasthenic patients even if the thymus appears normal on radiographic examination. The role of microscopic thymoma as a predictor of clinical thymoma has not been proven.
Key Words: Thymoma; Myasthenia gravis; Thymectomy
1. Introduction
The term of microscopic thymoma (MT) was introduced in 1976 by Rosa [1] and is still recognised in the latest (2004) WHO classification published in 2004 [2]. It defines an epithelial proliferation with <1 mm in diameter usually multifocal, located in the cortex or medulla that preferentially occurs in patients suffering from myasthenia gravis (MG) without a macroscopical evident tumour. In this paper, we describe three cases of this rare entity.
2. Material
A serial of 87 thymectomies realised between 1992 and 2005 in myasthenic patients were reviewed at the Thoracic Pathology Department of the Louis Pradel Hospital (Lyon, France). Clinical symptoms, chest computed tomography, and therapeutic procedures were recorded.
3. Results
We identified three patients with a diagnosis of MT [3] (Table 1). Two patients were male. The mean age was 41.6 years. Diplopia, ptosis and dysphagia were the most common presenting symptoms. Antibodies against acetylcholine receptor were positive in all cases. Electromyogram confirmed in all cases the diagnosis of MG. All patients were treated by anticholinesterase agents. On chest tomodensitometric examination, the thymus was normal in one case, displayed calcifications in one case, and revealed an enlarged thymus in the last one. Thymectomy by sternotomy was performed in two patients, enlarged to the mediastinal fat in the third one. In the last case, thymectomy was obtained by manubriotomy. Surgery was performed two years, one year and six months, respectively, after the beginning of the symptoms. The resected thymus weighed between 10 and 25 g, with no macroscopic tumour. In two cases, histological examination revealed one microscopic thymoma <1 mm in diameter accompanied by lymphoid hyperplasia (case 2 and 3). The microscopic thymoma was uncapsulated and was composed of several nests of ovoid bland cells with vesicular nuclei (Fig. 1). There was no perivascular spaces nor lobulation. In one of these cases, the lesion was located in the mediastinal fat (case 2). In the latter one (case 1), microscopic examination revealed several uncapsulated foci of MT constituted by several uncapsulated epithelial nests of ovoid cells with oval nuclei. There was no lymphoid hyperplasia. After thymectomy, there was a progressive clinical improvement over a follow-up period of 10, 5 and 2 years, respectively. The remaining symptoms were an intermittent ptosis in one case and diplopia in two cases. In two patients, antibodies became negative whereas in one case antibodies remained positive at 64.7 nmol/l (case 2).
4. Comments
The term MT was first introduced by Rosa in 1976 for a microscopic lesion of 1 mm in diameter incidentally found in a thymus removed during cardiac surgery [1]. In the current WHO classification, MT is the term applied to an epithelial proliferation, <1 mm in diameter, usually multifocal, located in the cortex or medulla that preferentially occurs in patients suffering from MG without a macroscopically evident tumour. Since the initial description, five cases have been reported in the literature [1,4–6]. The prevalence of MT in autopsy specimens among myasthenic patients is 15% and 4% without clinical symptoms, according to some authors [4,5]. We describe in this paper three cases of MT, solitary in two of them. In the literature, only one solitary lesion was reported [6], the others being plurifocal [4,5]. Our three cases were type-A thymoma, as described previously [4–6]. The description of MT occurring in cortical or medullary compartments and multifocality suggest a multifocal origin of MT from distinct epithelial clones present in the different areas of the thymus [4].
Nevertheless, the role of MT as an incipient thymoma or precursor of thymoma has not been proven [7]. For several authors, MT shoud be renamed ‘nodular hyperplasia of the thymic epithelium’ [7], based on the morphological differences between MT and conventional thymoma with lack of lobulation, immature T cells, perivascular spaces, medullary differentiation and capsule [7]. In opposition to this, multifocality of MT and description of MT adjacent to conventional thymoma argues for a precursor lesion [4].
MT is a diagnosis of exclusion, eliminating purely epithelial clusters which are smaller, uncapsulated, plurifocal and described in involuted thymuses or in congenital immunodeficiency conditions. Furthermore, two cases of a new entity called microthymoma have been described [7]. It differs from conventional thymoma only by its size, <1 cm in diameter, but exhibits the typical histological features of conventional thymoma.
MG is often associated with pathological changes of the thymus, either lymphoid hyperplasia (65–85%) or thymoma (10–15%) [1]. In the remaining cases, the thymus is normal or involuted. MG is due to abnormal activation of thymic B lymphocytes in lymphoid hyperplasia or in contact with epithelial cells thymoma. In one of our cases and in three cases of the five reported in the literature, MT was not associated with lymphoid hyperplasia of the thymus. This suggests a relationship between MT and myasthenia [4]. Moreover, our patients showed durable improvement after thymectomy.
Thymus was normal in tomodensitometric examination in one of our cases and in two cases reported [5,6]. Computed tomography of the chest is unable to detect MT [5]. Surgery is indicated in myasthenic patients, even when the thymus is normal in a tomodensitometric examination because it may contain MT and surgical thymectomy has desmontrated its efficacy in disease [8]. Different surgical approaches have been recommended including transcervical, transsternal and recently a transthoracoscopic thymectomy [9]. All procedures allow extracapsular resection of the thymus and vary somewhat in the extent of mediastinal fat removal, which may contain foci of thymic tissue. This was the case in one of our patients with MT located in the mediastinal fat. This argues for extended thymectomy by sternotomy. On the other hand, minimally invasive approaches such as manubriotomy allows a better preservation of lung function perioperatively than median sternotomy [10].
Our findings indicate the usefulness of complete histological examination of all macroscopic non-neoplastic thymuses from myasthenic patients, in order to increase the detection of microscopically-sized foci of thymoma. This would allow us to assess the overall incidence of MT in patients with MG and would help to elucidate the possible role of such lesions in the pathogenesis of MG, in particular in those cases without lymphoid hyperplasia.
References
Rosa J, Levine GD. Atlas of tumour pathology. Second series. Fascicle 13. Tumours of the thymus. 1976;Washington DC: Armed Forces Institute of Pathology In:.
Rosa J, Sobin LH. Histological typing of tumors of the thymus: WHO international histological classification of tumors. 1999;Berlin: Springer-Verlag.
Chalabreysse L, Roy P, Cordier JF, Loire R, Gamondes JP, Thivolet-Bejui F. Correlation of the WHO schema for the classification of thymic epithelial neoplasms with prognosis: a retrospective study of 90 tumors. Am J Surg Pathol 2002; 26:1605–1611.
Pescarmona E, Rosati S, Pisacane A, Rendina EA, Venuta F, Baroni CD. Microscopic thymoma: histological evidence of multifocal cortical and medullary origin. Histopathology 1992; 20:263–266.
Puglisi F, Finato N, Mariuzzi L, Marchini C, Floretti G, Beltrami CA. Microscopic thymoma and myasthenia gravis. J Clin Pathol 1995; 48:682–683.
Poulard G, Mosnier JF, Dumollard JM, Prades JM, Convers Ph, Boucheron S. Thymome microscopique et myasthénie grave. Ann Pathol 1994; 14:203–204.
Cheuk W, Tsang WYW, Chan JKC. Microthymoma. Definition of the entity and distinction from nodular hyperplasia of the thymic epithelium (so-called microscopic thymoma). Am J Surg Pathol 2005; 29:415–419.
Roth T, Ackermann R, Stein R, Inderbitzi R, Rosler K, Schmid RA. Thirteen years follow-up after radical transsternal thymectomy for myasthenia gravis. Do short-term results predict long-term outcome Eur J Cardiothorac Surg 2002; 21:664–670.
de Perrot M, Bril V, McRae K, Keshavjee S. Impact of minimally invasive trans-cervical thymectomy on outcome in patients with myasthenia gravis. Eur J Cardiothorac Surg 2003; 24:677–683.
Granetzny A, Hatem A, Shalaby A, Boseila A. Manubriotomy versus median sternotomy in thymectomy for myasthenia gravis. Evaluation of the pulmonary status. Eur J Cardiothorac Surg 2005; 27:361–366.(Lara Chalabreyssea,, Alessandro Orsinib,)
b Department of Thoracic Surgery, Hopital Louis Pradel, 28 avenue Doyen Lépine, 69 677 Bron Cedex, France
c Department of Neurology, Hopital Pierre Wertheimer, 59 boulevard Pinel, 69 677 Bron Cedex, France
Abstract
Microscopic thymoma was first described in 1976 and remains in the latest WHO classification (2004). It defines an epithelial proliferation, with <1 mm in diameter, usually multifocal, that preferentially occurs in patients suffering from myasthenia gravis without a macroscopically evident tumour. A series of 87 thymectomies realised in myasthenic patients between 1992 and 2005 was reviewed. We describe three cases of microscopic thymoma: two male and one female with an average age of 41.6 years. All patients suffered from myasthenia gravis positive for acetylcholine receptor antibodies without any tumour detectable on chest tomodensitometric examination. Thymectomy was performed in all cases, enlarged to the mediastinal fat in one. Microscopic examination revealed three type-A microscopic thymoma, one multifocal, associated with lymphoid hyperplasia in two cases. After surgery, all patients had clinically improved. In summary, chest computed tomography is unable to detect microscopic thymoma. Histological examination of the entire specimen is indicated after thymectomy in myasthenic patients even if the thymus appears normal on radiographic examination. The role of microscopic thymoma as a predictor of clinical thymoma has not been proven.
Key Words: Thymoma; Myasthenia gravis; Thymectomy
1. Introduction
The term of microscopic thymoma (MT) was introduced in 1976 by Rosa [1] and is still recognised in the latest (2004) WHO classification published in 2004 [2]. It defines an epithelial proliferation with <1 mm in diameter usually multifocal, located in the cortex or medulla that preferentially occurs in patients suffering from myasthenia gravis (MG) without a macroscopical evident tumour. In this paper, we describe three cases of this rare entity.
2. Material
A serial of 87 thymectomies realised between 1992 and 2005 in myasthenic patients were reviewed at the Thoracic Pathology Department of the Louis Pradel Hospital (Lyon, France). Clinical symptoms, chest computed tomography, and therapeutic procedures were recorded.
3. Results
We identified three patients with a diagnosis of MT [3] (Table 1). Two patients were male. The mean age was 41.6 years. Diplopia, ptosis and dysphagia were the most common presenting symptoms. Antibodies against acetylcholine receptor were positive in all cases. Electromyogram confirmed in all cases the diagnosis of MG. All patients were treated by anticholinesterase agents. On chest tomodensitometric examination, the thymus was normal in one case, displayed calcifications in one case, and revealed an enlarged thymus in the last one. Thymectomy by sternotomy was performed in two patients, enlarged to the mediastinal fat in the third one. In the last case, thymectomy was obtained by manubriotomy. Surgery was performed two years, one year and six months, respectively, after the beginning of the symptoms. The resected thymus weighed between 10 and 25 g, with no macroscopic tumour. In two cases, histological examination revealed one microscopic thymoma <1 mm in diameter accompanied by lymphoid hyperplasia (case 2 and 3). The microscopic thymoma was uncapsulated and was composed of several nests of ovoid bland cells with vesicular nuclei (Fig. 1). There was no perivascular spaces nor lobulation. In one of these cases, the lesion was located in the mediastinal fat (case 2). In the latter one (case 1), microscopic examination revealed several uncapsulated foci of MT constituted by several uncapsulated epithelial nests of ovoid cells with oval nuclei. There was no lymphoid hyperplasia. After thymectomy, there was a progressive clinical improvement over a follow-up period of 10, 5 and 2 years, respectively. The remaining symptoms were an intermittent ptosis in one case and diplopia in two cases. In two patients, antibodies became negative whereas in one case antibodies remained positive at 64.7 nmol/l (case 2).
4. Comments
The term MT was first introduced by Rosa in 1976 for a microscopic lesion of 1 mm in diameter incidentally found in a thymus removed during cardiac surgery [1]. In the current WHO classification, MT is the term applied to an epithelial proliferation, <1 mm in diameter, usually multifocal, located in the cortex or medulla that preferentially occurs in patients suffering from MG without a macroscopically evident tumour. Since the initial description, five cases have been reported in the literature [1,4–6]. The prevalence of MT in autopsy specimens among myasthenic patients is 15% and 4% without clinical symptoms, according to some authors [4,5]. We describe in this paper three cases of MT, solitary in two of them. In the literature, only one solitary lesion was reported [6], the others being plurifocal [4,5]. Our three cases were type-A thymoma, as described previously [4–6]. The description of MT occurring in cortical or medullary compartments and multifocality suggest a multifocal origin of MT from distinct epithelial clones present in the different areas of the thymus [4].
Nevertheless, the role of MT as an incipient thymoma or precursor of thymoma has not been proven [7]. For several authors, MT shoud be renamed ‘nodular hyperplasia of the thymic epithelium’ [7], based on the morphological differences between MT and conventional thymoma with lack of lobulation, immature T cells, perivascular spaces, medullary differentiation and capsule [7]. In opposition to this, multifocality of MT and description of MT adjacent to conventional thymoma argues for a precursor lesion [4].
MT is a diagnosis of exclusion, eliminating purely epithelial clusters which are smaller, uncapsulated, plurifocal and described in involuted thymuses or in congenital immunodeficiency conditions. Furthermore, two cases of a new entity called microthymoma have been described [7]. It differs from conventional thymoma only by its size, <1 cm in diameter, but exhibits the typical histological features of conventional thymoma.
MG is often associated with pathological changes of the thymus, either lymphoid hyperplasia (65–85%) or thymoma (10–15%) [1]. In the remaining cases, the thymus is normal or involuted. MG is due to abnormal activation of thymic B lymphocytes in lymphoid hyperplasia or in contact with epithelial cells thymoma. In one of our cases and in three cases of the five reported in the literature, MT was not associated with lymphoid hyperplasia of the thymus. This suggests a relationship between MT and myasthenia [4]. Moreover, our patients showed durable improvement after thymectomy.
Thymus was normal in tomodensitometric examination in one of our cases and in two cases reported [5,6]. Computed tomography of the chest is unable to detect MT [5]. Surgery is indicated in myasthenic patients, even when the thymus is normal in a tomodensitometric examination because it may contain MT and surgical thymectomy has desmontrated its efficacy in disease [8]. Different surgical approaches have been recommended including transcervical, transsternal and recently a transthoracoscopic thymectomy [9]. All procedures allow extracapsular resection of the thymus and vary somewhat in the extent of mediastinal fat removal, which may contain foci of thymic tissue. This was the case in one of our patients with MT located in the mediastinal fat. This argues for extended thymectomy by sternotomy. On the other hand, minimally invasive approaches such as manubriotomy allows a better preservation of lung function perioperatively than median sternotomy [10].
Our findings indicate the usefulness of complete histological examination of all macroscopic non-neoplastic thymuses from myasthenic patients, in order to increase the detection of microscopically-sized foci of thymoma. This would allow us to assess the overall incidence of MT in patients with MG and would help to elucidate the possible role of such lesions in the pathogenesis of MG, in particular in those cases without lymphoid hyperplasia.
References
Rosa J, Levine GD. Atlas of tumour pathology. Second series. Fascicle 13. Tumours of the thymus. 1976;Washington DC: Armed Forces Institute of Pathology In:.
Rosa J, Sobin LH. Histological typing of tumors of the thymus: WHO international histological classification of tumors. 1999;Berlin: Springer-Verlag.
Chalabreysse L, Roy P, Cordier JF, Loire R, Gamondes JP, Thivolet-Bejui F. Correlation of the WHO schema for the classification of thymic epithelial neoplasms with prognosis: a retrospective study of 90 tumors. Am J Surg Pathol 2002; 26:1605–1611.
Pescarmona E, Rosati S, Pisacane A, Rendina EA, Venuta F, Baroni CD. Microscopic thymoma: histological evidence of multifocal cortical and medullary origin. Histopathology 1992; 20:263–266.
Puglisi F, Finato N, Mariuzzi L, Marchini C, Floretti G, Beltrami CA. Microscopic thymoma and myasthenia gravis. J Clin Pathol 1995; 48:682–683.
Poulard G, Mosnier JF, Dumollard JM, Prades JM, Convers Ph, Boucheron S. Thymome microscopique et myasthénie grave. Ann Pathol 1994; 14:203–204.
Cheuk W, Tsang WYW, Chan JKC. Microthymoma. Definition of the entity and distinction from nodular hyperplasia of the thymic epithelium (so-called microscopic thymoma). Am J Surg Pathol 2005; 29:415–419.
Roth T, Ackermann R, Stein R, Inderbitzi R, Rosler K, Schmid RA. Thirteen years follow-up after radical transsternal thymectomy for myasthenia gravis. Do short-term results predict long-term outcome Eur J Cardiothorac Surg 2002; 21:664–670.
de Perrot M, Bril V, McRae K, Keshavjee S. Impact of minimally invasive trans-cervical thymectomy on outcome in patients with myasthenia gravis. Eur J Cardiothorac Surg 2003; 24:677–683.
Granetzny A, Hatem A, Shalaby A, Boseila A. Manubriotomy versus median sternotomy in thymectomy for myasthenia gravis. Evaluation of the pulmonary status. Eur J Cardiothorac Surg 2005; 27:361–366.(Lara Chalabreyssea,, Alessandro Orsinib,)