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J Thorac Cardiovasc Surg 2004;127:1840-1843
© 2004 The American Association for Thoracic Surgery
Brief communication |
a Department of Thoracic Surgery, University of Torino, Torino, Italy
b Division of General Surgery, University of Torino, Torino, Italy,
c Department of Human Oncology and Biomedical Sciences, University of Torino, Torino, Italy
Received for publication February 11, 2003; accepted for publication March 12, 2003.
* Address for reprints: Pier Luigi Filosso, MD, University of Torino, San Giovanni Battista Hospital, Via Genova, 3, Torino 10126, Italy
pierluigifilosso{at}tiscalinet.it
Bronchial carcinoids (BCs) are rare and constitute less than 2% of pulmonary tumors.1 They are characterized by slow, mainly endobronchial growth, with infrequent regional lymph node involvement or distant metastases.2
Atypical carcinoids are part of the spectrum of neuroendocrine bronchopulmonary tumors, according to the 1999 World Health Organization–International Association for the Study of Lung Cancer (WHO-IASLC) Lung Tumor classification.3 They present 2 low-grade (typical and atypical carcinoids) and 2 high-grade malignant varieties (large cell neuroendocrine carcinoma and small cell lung carcinoma), the latter characterized by a high tendency toward mediastinal and distant metastatic spread.
Among low-grade malignant tumors, atypical carcinoids show a more aggressive biologic behavior than typical carcinoids4: mediastinal lymph node metastases occur at presentation in about 15% of cases. Distant metastases are generally in the liver and in the bone.
We present a case of a woman in whom thyroid metastasis occurred 30 months after the resection of an atypical BC.
Clinical summary
A 53-year-old white woman was referred to us in June 1999 because of the presence of a large pulmonary mass (7 x 3 cm in size) in the right lower lobe. The lesion had been detected with chest radiography performed in July 1998, and it was 5 x 2 cm in size, but at that time, the patient refused the intervention. She eventually agreed to be operated on because of the progression of the lesion and the associated cough and dyspnea. A preoperative transthoracic fine-needle aspiration biopsy was performed, and neoplastic cells with neuroendocrine features were observed. 111In-DTPA-Pentetreotide scintigraphy (Octreoscan) was performed for a correct preoperative assessment, resulting in an elective uptake in correspondence of the pulmonary lesion with no other abnormal uptakes. Chromogranin A and neuron-specific enolase serum levels were performed and increased: 197 ng/mL (normal values, 20-100 ng/mL) and 62 ng/mL (normal values, <12.5 ng/mL), respectively.
The patient underwent a right pneumonectomy with systemic lymphadenectomy: a more conservative intervention was not possible because of the tumor size. A residual tumor was left on the inferior pulmonary vein stump.
Grossly, an 8-cm mass with poorly demarcated borders infiltrating the mediastinal pleura and the adipose mediastinal tissue was found. The cut surface was tan-yellow, and a brown lymph node was adherent and directly infiltrated by the tumor.
Microscopically, the tumor was not capsulated, and it had a uniform organoid growth pattern composed of nests and sheets of cuboidal and eosinophilic cells. Rosette-like structures were also evident. The nuclei had either finely granular or coarse chromatin, and nucleoli were occasionally present (Figure 1, A). The inferior pulmonary vein was infiltrated by neoplastic cells. Limited foci of necrosis were evident, and the mitotic count was 3 per 10 high-power fields. One peribronchial lymph node and the visceral pleura were directly infiltrated by the tumor.
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Pathologic diagnosis was pT4 N1 atypical carcinoid or well-differentiated neuroendocrine carcinoma. The postoperative course was uneventful.
Medical therapy with Octreotide (Sandostatina LAR 30 mg; Novartis Pharma SPA, Origgio, Italy) was started and followed by mediastinal adjuvant radiotherapy.
A strict follow-up was planned with thoracic and upper abdominal computed tomographic scanning, Octreoscan, serum chromogranin A, and neuron-specific enolase dosages.
In December 2001, Octreoscan showed an uptake in the right thyroid lobe (Figure 2); an ultrasonographic evaluation demonstrated the presence of a 2 x 1–cm nodule. A fine-needle aspiration biopsy was performed: the highly cellular smears contained medium-sized polygonal and eosinophilic neoplastic cells with finely granular chromatin and faint nucleoli. These cells were unreactive for thyroglobulin and calcitonin and positive for chromogranin A. Diagnosis of thyroid metastasis of neurendocrine carcinoma of the lung was thus made.
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Microscopically, these nodules were composed of polygonal and eosinophilic cells arranged in cords and nests, having the typical organoid pattern of carcinoid tumors (Figure 1, E-G). Foci of necrosis were observed. No thyroglobulin immunostaining (polyclonal; BioGenex, San Ramon, Calif) was seen. The absence of calcitonin immunoreactivity (polyclonal, Dako) also ruled out the diagnosis of medullary thyroid carcinoma. Chromogranin A immunostaining (clone LK2H10, Dako) was strongly positive. The morphologic features and the similarity with the previously resected pulmonary neuroendocrine lesion confirmed the preoperative diagnosis of metastatic neuroendocrine carcinoma.
The postoperative course was also uneventful.
The patient is alive and well without recurrence 13 months after the second intervention, and no adjuvant chemotherapy or radiotherapy was planned; she is now only continuing medical therapy with Octreotide (Sandostatina LAR 30 mg; Novartis Pharma, Origgio, Italy), which is well tolerated without important side effects.
Discussion
BCs have raised important issues for thoracic surgeons, in particular whether to regard them as benign or malignant tumors. BCs are a part of the spectrum of the neuroendocrine tumors of the lung3: the WHO-IASLC classification considers BCs as different from large cell neuroendocrine carcinoma and small cell lung carcinoma on the basis of their histologic and biologic features. BCs are low-grade malignant tumors that can be locally invasive or spread to mediastinal lymph nodes, but distant metastases are rare.4 Martini and colleagues2 report that only 10% to 15% of patients present with regional lymph node metastases at diagnosis. Surgical intervention represents the treatment of choice, even if mediastinal nodal metastases are present: BCs are generally unresponsive to preoperative radiation or chemotherapy, and long-term prognosis is good for both the typical and atypical forms when treated with radical resection.5
Distant metastases are rare: we experienced liver metastases in 7 patients with radically resected atypical BCs,5,6 in whom carcinoid syndrome was the first symptom. Octreoscan was effective in diagnosis, and octreotide therapy allowed us to control symptoms and to reduce metastases in size in 2 cases.6
We point out the importance of 111In-DTPA-Pentetreotide scintigraphy (Octreoscan) in the early diagnosis of the thyroid metastasis and in general in the follow-up of neurorendocrine lung tumors.7,8 Neuroendocrine tumors in vitro express somatostatin receptor subtype 2, which can be imaged in vivo by using Octreoscan.
Octreoscan has demonstrated its effectiveness in diagnosis of the primary tumor but particularly in detecting early recurrences or distant metastases in asymptomatic patients earlier than with traditional radiologic procedures.9
A positive Octreoscan result should guide an effective medical therapy with somatostatin analogs (octreotide and lanreotide).6
Positron emission tomography scanning in the presence of BCs shows lower uptake than in non–small cell lung cancers; therefore positron emission tomography scanning is, at present, not indicated for the differential diagnosis of a solitary pulmonary nodule with neuroendocrine features from a benign process.10
Complete resection with radical mediastinal lymph node dissection provides excellent local control and long-term survival in BCs; the presence of mediastinal metastases does not preclude surgical intervention.2
Local recurrences are rare and generally associated with an inadequate (not anatomic) surgical treatment of the primary tumor. Distant metastases appear to be related to the histologic form of BCs (atypical carcinoid) more than to the nodal status.2,11 When possible, surgical intervention remains the treatment of choice for recurrences because there is no evidence that radiotherapy or chemotherapy are effective in local control or in long-term survival.
Our experience provides evidence that the use of somatostatin analogs (octreotide and lanreotide) is effective in cases of distant metastases discovered by means of Octreoscan6 in which surgical intervention is not feasible. Octreotide binds with high affinity to somatostatin receptor subtype 2, which is expressed in neuroendocrine tumoral cells. Octreotide has demonstrated a valid inhibitory growth effect on neoplastic cells, and it is well tolerated, without important side effects. The optimal dose of octreotide is generally 1500 mg/d subcutaneously, but a recent long-acting form (Octreotide LAR) appears more simple for patient management because only one dose every 28 days is necessary.
References
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