Extremely rare case of B 3 / thymic carcinoma borderline tumor of the middle mediastinum in a myasthenic patient

Thymomas and thymic carcinomas are rare mediastinal tumors. Ectopic middle mediastinal thymomas/thymic carcinomas are even more rare. We report the first case of B3/thymic carcinoma borderline tumor of the middle mediastinum in a 61-year-old myasthenic woman. Preoperative chest tomography and magnetic resonance imaging documented a 4.0 × 3.5 × 2.7 cm mass in the retroinnominate space. A resection of the tumor of the middle mediastinum, associated with an extended thymectomy, was carried out through a median sternotomy. Pathological diagnosis was ectopic B3/thymic carcinoma borderline tumor, stage IIa in the Masaoka clinical staging system; the thymic tissue showed normal fatty involution. Postoperative course was uneventful and, at 1 year follow-up, the patient showed an improvement of Myasthenia Gravis and no sign of tumor recurrence.


Introduction
Thymomas are rare mediastinal neoplasms and thymic carcinomas (TCs) represent only the 1% of all thymic tumors [1].
Embryologically, thymic epithelium arises from the third and probably fourth branchial pouches bilaterally and migrates into the antero-superior mediastinum.A mismigration of thymic gland tissue during embryogenesis is considered the cause of the possible finding of ectopic thymoma in the middle mediastinum [2].
Thymic neoplasms may be associated with a wide range of paraneopastic disorders; Myasthenia Gravis (MG) can be present in a third of cases.

Case report
A 61-year-old Caucasian female presented with right ptosis, diplopia and dysphagia.Her medical history was positive for Hashimoto thyroiditis and hypercholesterolemia.
She received a diagnosis of MG because of a positive intramuscular prostigmine test, with positive serum acetylcholine receptor (Ach-R) antibodies (11.9 nmol/L; normal range< 0.2nmol/L) and negative muscle-specific tyrosine kinase antibodies.the tumor and the right wall of the trachea and the posterior wall of right and left innominate veins at their confluence into the superior vena cava (SVC), that presented signs of extrinsic compression.The posterior side of the mass contacted the aberrant right subclavian artery (arteria lusoria) and the esophageal wall, however the fat plan between these structures was conserved.
Magnetic resonance imaging (MRI) showed a low intensity lesion both on T1-and on T2-weighted images, as for solid mass.
Several tumor markers were within the normal range.

Postoperative
histophatological specimen examination showed a normal fatty involution of thymic tissue, while the middle mediastinal tumor consisted of a multinodular, 4 cm in maximum size, neoplasia, yellowish in color on cut surface with brown necrotic area.
Histologically, it was a neoplasm with a solid growth pattern composed of epithelial cells with minimal atypia, separated by fibrous septa (Fig. 2A and B) and with perivascular spaces.Scattered and isolated thymic lymphocytes (immunohistochemistry positivity for TdT, CD5 and CD3) at the periphery of the lesion, rare mitosis and necrotic areas were found.Images of neoplastic infiltration of the surrounding adipose tissue were frequently observed.The neoplastic cells were positive for CK19 and negative for CD117 (Fig. 2D) and chromogranin.A focal positivity for CD5 was also reported in the neoplastic cells (Fig. 2C).Therefore, because of the absence of major atypia and intercellular bridges, the lack of TdT+ T cells (Fig. 2E) but the expression of CD5, according to ITMIG Consensus Statement on the Use of the WHO Histological Classification of Thymoma and Thymic Carcinoma [3], the diagnosis was B3/TC borderline tumor and stage IIa in the Masaoka clinical staging system [4].
The patient was referred to our department for surgical treatment of the mediastinal mass detected by radiological examinations, after a multidisciplinary discussion.
Surgical resection was proposed in order to clarify the pathological diagnosis of the tumor and try to improve the MG by removing thymic tissue.Therefore, she underwent an extended thymectomy associated with resection of the tumor in the middle mediastinum through a median sternotomy.This surgical access was chosen -instead of a right thoracotomy -in order to better manage the possible radiological suspicion of infiltration of the posterior wall of right and left innominate veins at their confluence into SVC and to perform an extended thymetomy.Intraoperatively, it was possible to dissect the tumor from the trachea, SVC, innominate veins and esophagus, without any sign of invasion of the adjacent mediastinal structures.The middle mediastinal tumor had no connection to the thymic tissue that was also resected together with the surrounding fat tissue (Fig. 1C and D).
The postoperative course was uneventful.The patient was discharged on postoperative day 5 and then was referred to adjuvant radiotherapy.At oneyear follow-up, the patient was alive without recurrence and had an improvement of MG.Indeed, her preoperative myasthenic symptoms (ptosis, diplopia and dysphagia) were well controlled by pyridostigmine (90 mg/day), deltacortene (62.5 mg/day) and azathioprine (100 mg/day) A year after surgery, the immunosuppressive therapy was reduced as follows: pyridostigmine 60mg/day, deltacortene 30 mg/every other day and azathioprine 75 mg/day.

Discussion:
Ectopic middle mediastinal thymomas are extremely rare and to date only one case of TC of the middle mediastinum, in subcarinal area, was reported in English literature (Table 1).Our report is the first case of ectopic B3/TC borderline tumor in middle mediastinum (retro-innominate space) in a mysthenic patient.Only three cases of myasthenic patients with a middle mediastial thymoma were already described in literature but all pathological diagnoses were thymomas AB or B1 according to the WHO histological criteria (Details of these previous cases and the present one are shown in Table 1).Very few reports have described MG associated with thymic carcinoma [5][6][7] but never with ectopic borderline tumor.In fact, according to those reports, all such cases involved type B2 or B3 thymoma in thymic carcinoma, that developed from thymoma after a long period, probably in the necrotic tissue of the same thymoma.Furthermore, the association of an ectopic thymic tumor in the middle mediastinum with no connection to the normal thymus in a patient with an aberrant right subclavian artery has never been reported previously in the literature.Differential diagnosis of middle mediastinal masses includes lymphadenopathy (malignant lymphoma, sarcoidosis, Castleman's disease and metastasis), duplication cysts (bronchogenic and esophageal), aortic arch aneurysm, enlarged pulmonary artery, pericardial cyst and tracheal lesions.Neurogenic tumors and mediastinal goiters can also occur in the middle mediastinum.
Although extremely rare, thymomas and TCs should be considered in the differential diagnosis of middle mediastinal tumors and a complete resection should be attempted at the time of the operation, because of their malignant potential and relatively good longterm survival after complete macroscopic resection.
In patients with raised preoperative Ach-R antibody with or without clinically apparent myasthenic symptoms, additional extended thymectomy should be considered for ectopic thymomas, as is usual for MG associated with non-ectopic thymomas.
In patients without raised ACh-R antibody and no myasthenic symptoms, simple resection of ectopic thymomas should be sufficient [2].
Despite TCs have a worse prognosis compared to thymomas, complete surgical excision with negative margins is the treatment of choice when feasible, in order to decrease the risk of local recurrence and improve prognosis [8,9].Adjuvant treatmentwhether or not combined -should also be taken in account, depending on the pathological stage of the tumor.Although the optimal adjuvant therapy after surgical resection has not been well established and remains controversial, because of the rarity of this disease and limited available data, radiotherapy seems to show a better progression-free survival after R0 resection [10].

Fig. 1 :
Fig.1: Axial (A) and coronal (B) CT scans of the chest showing the ectopic thymoma in the middle mediastinum.Intraoperative findings: before (C: I: Visible portion of the ectopic thymic tumor partially covered by SVC and right innominate vein; II: Left innominate vein; III: SVC; IV: Right innominate vein) and after (D) dissecting the tumor from surrounding structures.

Table 1 :
Report of ectopic thymomas/thymic carcinomas in the middle mediastinum