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J Thorac Cardiovasc Surg 2004;127:1215-1219
© 2004 The American Association for Thoracic Surgery
Brief communication |
a Department of Thoracic Surgery, University of Torino Italy San Giovanni Battista Hospital, Torino, Italy
b Department of Cardiac Surgery, University of Torino Italy San Giovanni Battista Hospital, Torino, Italy
c Service of Medical Oncology, Civil Hospital, Ivrea, Torino, Italy
d Service of Radiation Therapy, Civil Hospital, Ivrea, Torino, Italy
Received for publication August 22, 2003; revisions received September 30, 2003; accepted for publication December 4, 2003.
* Address for reprints: Pier Luigi Filosso, MD, University of Torino Italy, Department of Thoracic Surgery, San Giovanni Battista Hospital, Via Genova, 3, 10126 Torino, Italy
pierluigifillosso{at}tiscalinet.it
Thymic carcinoid (TC) is a rare entity: since the first description by Rosai and Higa1 in 1972, approximately 150 cases have been reported in the literature. These tumors are frequently associated with endocrinopathies (Cushing syndrome or multiple endocrine neoplasia type 1; MEN-1) and carry a poor prognosis.2,3 TCs present an aggressive biological behavior with a tendency to invade adjacent structures (mediastinal fatty tissue, lung, pericardium, and great vessels) and with a tendency for local recurrences or distant hematogenous metastases.
Surgery, when feasible, represents the treatment of choice3-5 even if, in some cases, radical resection is not achieved. The role of neoadjuvant or adjuvant therapy has not yet been assessed. We describe the successful multidisciplinary management of a giant TC treated with neoadjuvant radiotherapy/chemotherapy, radical surgical resection, and preoperative, intraoperative, and postoperative therapy with a somatostatin analog. In addition, we provide a review of the recent literature about the management of these tumors.
Clinical summary
A 39-year-old man underwent a bioptic left anterior mediastinotomy for a large mediastinal mass, discovered after he presented with cough and dyspnea. Histology revealed grade 2 neuroendocrine carcinoma (atypical carcinoid) of the thymus. Neoplastic tissue strongly expressed somatostatin receptors (sst2), and chromogranin immunostaining was positive. Total body computed tomographic (CT) scan showed involvement of the anterior mediastinum, of the thoracic inlet, and of the left lung (Figure 1). No distant metastases were seen. Indium 111 diethylenetriamine pentaacetic acid pentetreotide scintigraphy (Octreoscan; Mallincrodt Medical BV, Zaltbommel, The Netherlands) confirmed an elective uptake only in correspondence of the tumor (Figure 2).
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Neoadjuvant chemotherapy/radiotherapy was started—4 courses of cisplatin (100 mg/m2 on day 1) and etoposide (100 mg/m2 on days 1-3 and 5) repeated every 3 weeks—followed by irradiation (42 Gy in 2-Gy daily fractions) with a 10-MeV linear accelerator. Because of the presence of sst2 in the biopsy specimen, Octreotide (Sandostatina Novartis Pharma, Milan, Italy) was administered at 1500 mg/d subcutaneously for 15 days, shifting to the long-acting form (20 mg every 28 days; Sandostatina LAR Novartis Pharma, Milan, Italy).
Radiologic and radionuclide restaging (CT scan, magnetic resonance imaging, and Octreoscan) showed a moderate reduction of the mediastinal lesion (Figure 3), without evidence of distant metastases. Blood chromogranin A and NSE levels were 109 and 20.7 ng/mL, respectively. Surgery was thus planned.
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A left lateral cervicotomy (medial to sternocleidomastoid muscle) and a median sternotomy were performed. The tumor was easily dissected free from the right hemithorax, but the involvement of the thoracic inlet necessitated the resection of the left brachiocephalic vein and some centimeters of the subclavian and internal jugular veins.
A large tract of the involved pericardium, from the superior vena cava to the left hilum, was resected, but no heart infiltration was observed (Figure 4). The left main pulmonary artery was involved by the tumor, and left pneumonectomy was necessary. A transverse left sternotomy prolonged in an anterior thoracotomy in the fourth intercostal space was performed, and en bloc resection of the mediastinum along with the left lung was performed (Figure 5). Sampling mediastinal lymphadenectomy was performed. A Prolene mesh (Ethicon, Inc, Somerville, NJ) was used to close the large pericardial defect.
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Definitive histology showed a T2 N2 grade 2 neuroendocrine carcinoma (atypical carcinoid) of the thymus with mediastinal lymph nodal metastases and invasion of the lung. The surgical margins were tumor free.
Because of the radicality of the intervention, oncologists decided that adjuvant chemotherapy or radiotherapy was not indicated and put the patient under hormonal therapy with long-acting Octreotide (20 mg). Follow-up was scheduled with blood marker tests (chromogranin A and NSE) every 3 months and total body CT scan and Octreoscan every 6 months.
At the 18-month follow-up, the patient was in good clinical condition and had returned to his previous job (brick layer). Total body CT scan and Octreoscan showed an absence of local recurrence or distant metastases. Serum chromogranin A and NSE levels were 33 ng/mL (reference range, 20-100 ng/mL) and 9.2 ng/mL (reference value, <12.5 ng/mL), respectively. Medical therapy was well tolerated, and no important side effects were reported.
Comment
TC is a distinct clinicopathologic entity that has been confused with thymoma since Rosai and Higa1 first described this tumor as a separate entity in 1972. TC represents only 4% of all anterior mediastinal tumors6 and is a rare entity: no more than 150 cases have been described in the literature.
TCs are 3 times more frequent in men than in women4,7; tumors have been described in patients from 8 years8 to 87 years old,9 but more frequently they occur between the fourth and the sixth decades of life. Most TCs present an aggressive biological behavior from the time of presentation. Symptoms are usually strictly related to the neoplastic mass effects: chest pain, cough, and dyspnea are frequently observed. Superior vena cava syndrome is described in approximately 20% of cases.3 A clinically apparent endocrinopathy develops in approximately half of patients: Cushing syndrome is the most frequent of these. de Perrot and associates10 reported that approximately 40 TCs associated with Cushing syndrome had been described in the literature since 1972 and that there was no difference in sex distribution in cases of TC and Cushing syndrome.
TC can occur in association with other endocrine neoplasms (eg, MEN-1), as Rosai and Higa11 first described in 1972. Since then, the association between TC and MEN-1 has been recognized in several cases: Teh and associates2 concluded that approximately 20% of patients with TC presented with MEN-1. Patients with TC and MEN-1 are predominantly men and tend to be younger than those without any endocrine disease.
The aggressive biological behavior is in contrast with that of generally benign carcinoids that arise elsewhere in the body, in particular, bronchial carcinoid (BC). In our recently published series,12 we observed lymph node metastases in only 6 (8%) of 75 typical BCs and in 14 (36%) of 38 atypical ones. The 10- and 15-year survival was 93% and 84% for typical BC and 52% and 52% for atypical BC, respectively.
TCs often present as locally invasive at the time of diagnosis7,13; Wang and colleagues14 described locally invasive TC in 7 of 8 patients. In the series of Fukai and colleagues,4 12 of 15 TCs had invasive features.
Metastatic spread occurs by the hematogenous and lymphatic route, as with thymic carcinomas. Mediastinal lymph node metastases are frequently observed at presentation: de Montpréville and associates3 and Fukai and colleagues4 reported metastatic TC in 7 of 14 and 9 of 15 patients, respectively.
Distant metastasis sites include lung, bone, adrenal glands, liver, and spleen, in order of frequency. Distant metastases are observed in approximately 20% of patients with TC with a protracted clinical course.3
To simplify the nomenclature and make it more uniform, TCs have been reclassified according to specific criteria (mitotic activity, presence of necrosis, and cytologic atypia) as grade 1 neuroendocrine carcinoma (previous typical carcinoid), grade 2 neuroendocrine carcinoma (previous atypical carcinoid), and grade 3 neuroendocrine carcinoma (previously large-cell neuroendocrine carcinoma and small-cell carcinoma).15,16 Histologic criteria of this classification are shown in Table 1. In Table 2, a proposed new TNM classification is shown.4
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Incomplete resections are frequent. In this case, the local recurrence rate is high and survival is poor. Incomplete resections and local recurrences are the factors that influence the outcome in TC.3,17 de Montpréville and associates,3 on the basis of follow-up of 13 patients, observed that the median survival for complete resections (n = 4), incomplete resections (n = 5), and biopsy alone (n = 4) was 71, 30, and 5 months, respectively.
Surgery, when feasible, is the treatment of choice. An aggressive approach often includes en-bloc resection of the tumor with the pericardium, lung, great vessels, or all of these.18 Median sternotomy is often indicated as a surgical approach, but occasionally, in case of large and invasive TC, the addition of an anterior (or posterolateral) thoracotomy should be considered to obtain better exposure of the involved hemithorax.
Sampling lymphadenectomy is mandatory for staging and oncologic planning. Economopoulos and colleagues7 and Fukai and associates4 concluded that long-term survival in TC can be achieved only by resection of both the primary tumor and the subsequent recurrences and metastases. Sakuragi and colleagues5 reported a successful radical resection of a recurrent TC in which cardiopulmonary bypass was used to control the massive bleeding caused by dense adhesions between the sternum and the great vessels due to 3 previous interventions (2 sternotomies and 1 lateral thoracotomy).
The role of neoadjuvant/adjuvant therapy (chemotherapy or radiotherapy alone or in combination) has not been adequately assessed because of the low number of cases. Fukai and associates4 and de Perrot and colleagues10 reported the utility of postoperative radiotherapy to prevent local recurrences of invasive TC; 45 to 60 Gy were administered. Sakuragi and colleagues5 reported that 1 patient who underwent 4 interventions received 39 Gy of adjuvant radiotherapy after the third operation. Spaggiari and Pastorino18 reported use of adjuvant radiotherapy in a patient they operated on for an invasive atypical TC; this patient was free of disease 10 months after the intervention.
There are no standard regimens of chemotherapy, and only occasional experiences have been reported in the literature. Spaggiari and Pastorino18 reported that their patient received 3 cycles of neoadjuvant chemotherapy with ifosfamide and etoposide, but no signs of response were observed. Single agents or combination drug therapies with 5-fluorouracil, streptozocin, etoposide, or cisplatin have been proposed by Wang and colleagues14 and Takayama and colleagues19: these had no significant effect on survival or recurrence rates. Gal and colleagues17 concluded that neither chemotherapy nor radiotherapy leads to differences in survival.
Our patient was a moderate responder to neoadjuvant chemotherapy/radiotherapy. This was enough to consider him for surgery and to start hormonal therapy with Octreotide. To our knowledge, this is the first case of successful multidisciplinary treatment of a TC with neoadjuvant chemoradiotherapy, radical resection, and hormonal therapy.
Neuroendocrine tumors, including thymic tumors, express sst2 at immunohistochemistry. In vivo sst2 expression is provided by indium 111 diethylenetriamine pentaacetic acid pentetreotide scintigraphy (Octreoscan).20,21
Recent generations of somatostatin analogs (Octreotide and lanreotide) bind with high affinity to sst2 receptors22,23; Octreotide has demonstrated good antiproliferative activity on neuroendocrine tumors, even if they are metastatic, without important side effects.24 Serum chromogranin A seems very useful for monitoring the disease, both with regard to recurrences and the efficacy of the Octreotide therapy. However, any suspicion of relapse has to be confirmed with CT scan and Octreoscan.
In conclusion, primary neuroendocrine thymic carcinomas are rare and aggressive tumors that are often characterized by local invasive behavior. An aggressive surgical approach remains the treatment of choice; preoperative chemotherapy/radiotherapy (cisplatin, etoposide, and 45 Gy of irradiation) and Octreotide therapy should improve the possibility of achieving a radical resection. Postoperative radiotherapy has been proposed to prevent local recurrences, with unpredictable results. Adjuvant therapy with Octreotide should be considered because of the well-recognized antiproliferative activity of this drug and its limited side effects. Because the in vivo sst2 expression is provided by Octreoscan, this procedure should be considered for follow-up along with CT scan.
References
This article has been cited by other articles:
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  D. Whitaker Thymic neuroendocrine carcinoma (carcinoid): What if octreotide scanning is negative? J. Thorac. Cardiovasc. Surg., November 1, 2004; 128(5): 801 - 801. [Full Text] [PDF]
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P. L. Filosso Reply J. Thorac. Cardiovasc. Surg., November 1, 2004; 128(5): 801 - 801. [Full Text] [PDF]
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