Neuroendocrine bronchial and thymic tumors: ESMO Clinical Recommendation for diagnosis, treatment and follow-up
2009; Elsevier BV; Volume: 20; Linguagem: Inglês
10.1093/annonc/mdp157
ISSN1569-8041
Autores Tópico(s)Myasthenia Gravis and Thymoma
ResumoincidenceThe annual incidence of typical and atypical bronchial carcinoid tumors has been reported to be 0.6/100 000 and the overall age adjusted incidence for thymic carcinoids 0.01/100 000/year. Of all carcinoid tumors, ∼25% are located in the respiratory tract. The pulmonary carcinoids comprise 1–2% of all lung tumors. Both bronchial and thymic carcinoids may be part of multiple endocrine neoplasia type I syndrome (MEN-I).diagnosisApproximately 70% of all carcinoids are located in the major bronchi, and one-third in the periphery of the lungs. They occur more frequently (61%) in the right than in the left lung, especially in the middle lobe. Up to 92% of patients are symptomatic, presenting with hemoptysis, cough, recurrent pulmonary infection, fever, chest discomfort and unilateral wheezing.The carcinoid syndrome is very rare in patients with pulmonary and thymic carcinoids, ranging to ∼2%. Serotonin is the most frequently detected peptide responsible for the carcinoid syndrome. Occasionally, a carcinoid crisis may occur in previously asymptomatic patients following bronchoscopic biopsy or surgical manipulation. Approximately 2% of patients with pulmonary and thymic carcinoids present with Cushing's syndrome caused by ectopic adrenocorticotropic hormone (ACTH) production.Diagnostic work-up includes chest X-rays followed by CT scan, bronchoscopy, somatostatin receptor scintigraphy in selected cases, while PET scan with FDG often shows false negative results and is not recommended.The diagnosis is made by histological examination of tumor tissue assisted by immunohistochemical detection of neuroendocrine markers. For diagnosis of thymic tumors thoracotomy may be required. For bronchial localization in patients with centrally localized carcinoids, tissue samples are taken during bronchoscopic examination. Using the rigid bronchoscope has the advantage of larger and more reliable biopsy samples. To reduce the risk of bleeding, epinephrine solution administered through the bronchoscope before biopsy is useful. Brush cytology is of no value for diagnosis of neuroendocrine tumors.The bronchial neuroendocrine tumors can be divided by histopathology into:•Typical carcinoid (TC) with highly organized carcinoid architecture and rare mitoses.•Atypical carcinoid (AC), which shows greater mitotic activity, 10/HPF and necroses are more widely spread and confluent.•Small-cell lung carcinoma (SCLC), which is the most poorly differentiated neuroendocrine tumor of the lung and is characterized by a classical 'oat-cell' histology. The mitotic activity is very high, >80/10HPF, and necrosis is widely spread. SCLC is dealt with in a separate chapter of the ESMO Clinical Recommendations.Both typical and atypical bronchial carcinoids may express neuroendocrine markers by immunohistochemistry (chromogranin A, synaptophysin and NSE) and somatostatin receptors. Thymic carcinoid follows the same pattern and stains for N-CAM in 73%, somatostatin in 36% and ACTH in 27% of cases. LCNEC and SCLC may express synaptophysin and neuron-specific enolase (NSE) only weakly and rarely express chromogranin A. The last two histological types also display mutations in the P53 gene.Thymic neuroendocrine tumors can show a continuous spectrum of differentiation from typical, well-differentiated carcinoid to small-cell neuroendocrine carcinoma type.staging and risk assessmentThere is no specific TNM staging for neuroendocrine bronchial tumors. The TNM staging should be carried out according to criteria for non-small-cell lung cancer. TNM classification and staging for thymic carcinoids follows general rules for tumors of the thymus, which are presented in Table 1.Table 1UICC pathological TNM and staging of malignant thymic tumorspT pT1Completely encapsulated tumor pT2Tumor breaking through capsule, invading thymus or fatty tissue pT3Tumor breaking through the mediastinal pleura or pericardium, or invading neighboring organs, such as great vessels and lung pT4Tumor with pleural or pericardial implantationpN pN0No lymph node metastasis pN1Metastasis in anterior mediastinal lymph nodes pN2Metastasis in intrathoracic lymph nodes excluding anterior mediastinal lymph nodes pN3Metastasis in extrathoracic lymph nodespM pM0No distant organ metastasis pM1With distant metastasisPathological stage groupingPrimary tumorLymph node statusDistant metastasisStage IT1, T2N0M0Stage IIT1, T2N1M0Stage IIIT3N0, N1M0Stage IVaT4N0, N1M0Stage IVbany TN2, N3M0Stage IVcany Tany NM1 Open table in a new tab Conventional X-ray of the chest may suggest the diagnosis but CT and bronchoscopy, eventually assisted by endoscopic ultrasonography with biopsies are the best procedures to detect bronchial neuroendocrine tumors [III, B]. Since 80% of typical bronchial carcinoids express somatostatin receptors, somatostatin receptor scintigraphy may be informative [III, B], but its specificity is low. For thymic carcinoids contrast enhanced CT or MRI is recommended to detect the tumor and metastases. Somatostatin receptor scintigraphy is an additional option.The biochemical findings are dependent on the histological type of bronchial neuroendocrine tumors. The TC presents increased plasma levels of chromogranin A [III, B]. When hormone-related symptoms are present, plasma ACTH, growth hormone-releasing hormone (GHRH), insulin-like growth factor-1 (IGF-I), urine cortisol, 5-HIAA or histamine metabolites may be elevated [III, B]. The biochemical profile for thymic carcinoid is usually similar to that of bronchial carcinoid.TCs are indolent tumors with low rate of recurrence. Metastases after adequate resection are rare (7%). Five-year survival rates have been found to be 80%, whereas ACs show a 5-year survival rate of 60%. Both LCNEC and SCLC have poor prognosis with 5-year survival rates of <10%. Thymic carcinoids, although occasionally achieving extended survival, have a low cure rate averaging 10–15% and thus have a poorer overall prognosis than bronchial carcinoids.treatment planlocalized tumorsConservative surgery is the primary treatment for all localized TC and AC tumors, both of the lung and the thymus, when 5-year survival rates of 80–100% may be expected. This is not true for LCNEC and SCLS unless for very selected and very limited, i.e. T1–2 N0, tumors; excision in toto in these cases occurs mostly as part of histological verification of a small peripherally situated nodule.The surgical approach is dependent on size, location and tissue type. Excision of intraluminal typical bronchial carcinoid may be attempted with bronchoscopic removal of the tumor (whenever possible bronchoscopic visualization should be combined with high-resolution CT), which may lead to complete eradication in a significant proportion of patients. Tumors not meeting criteria for endobronchial resection may be treated with bronchial sleeve resection, segmentectomy, lobectomy or pneumonectomy. External radiotherapy is an option for symptomatic localized disease [III, B], especially if surgery can not be performed. Endobronchial laser treatment, although not curative, can be useful in selected cases to treat airway obstruction.metastatic and recurrent diseaseCytotoxic treatment, combined with surgical resections when indicated, has been the standard for metastatic lung and thymic carcinoids, although the available chemotherapy regimens show rather poor activity. Chemotherapy for SCLC, which is a chemosensitive but not chemocurable cancer, is discussed in the appropriate guidelines. For low-proliferating tumors, treatment with somatostatin analogues and α interferons might be an option for functional tumors with severe clinical symptoms [III, B]. In non-functional tumors the use of somatostatin analogues is still controversial. Tumor-targeted radioactive treatment is an option in patients with tumors that present a high content of somatostatin receptors [III, B]. Available chemotherapy regimens for TC, AC and LCNEC include combination of 5-FU and interferon α, streptozoocin-based combinations, the etoposide–cisplatin regimen or chemotherapy combining cyclophosphamide, doxorubicin and vincristine. In general, chemotherapy results are discouraging and survival data have to be interpreted with caution. Symptomatic metastatic disease may be treated with palliative intent by appropriate local options such as embolization for liver metastases and irradiation treatment for brain and bone deposits.follow-upAfter primary surgery patients with TC and AC should be followed at least yearly up to 10 years [III, C] in order to detect eventual surgically manageable recurrences. Biochemical markers, such as chromogranin A, should be determined every 3–6 months (in cases where they were elevated at baseline) and CT or MRI should be performed once a year.Patients with metastatic or recurrent disease should be followed during treatment with cytotoxic or biological agents more often, at 3-monthly intervals, with imaging evaluation (preferably by CT) and biological markers when evaluable, in order to assess eventual benefits of the treatment applied.noteLevels of evidence [I–V] and grades of recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO Faculty. incidenceThe annual incidence of typical and atypical bronchial carcinoid tumors has been reported to be 0.6/100 000 and the overall age adjusted incidence for thymic carcinoids 0.01/100 000/year. Of all carcinoid tumors, ∼25% are located in the respiratory tract. The pulmonary carcinoids comprise 1–2% of all lung tumors. Both bronchial and thymic carcinoids may be part of multiple endocrine neoplasia type I syndrome (MEN-I). The annual incidence of typical and atypical bronchial carcinoid tumors has been reported to be 0.6/100 000 and the overall age adjusted incidence for thymic carcinoids 0.01/100 000/year. Of all carcinoid tumors, ∼25% are located in the respiratory tract. The pulmonary carcinoids comprise 1–2% of all lung tumors. Both bronchial and thymic carcinoids may be part of multiple endocrine neoplasia type I syndrome (MEN-I). diagnosisApproximately 70% of all carcinoids are located in the major bronchi, and one-third in the periphery of the lungs. They occur more frequently (61%) in the right than in the left lung, especially in the middle lobe. Up to 92% of patients are symptomatic, presenting with hemoptysis, cough, recurrent pulmonary infection, fever, chest discomfort and unilateral wheezing.The carcinoid syndrome is very rare in patients with pulmonary and thymic carcinoids, ranging to ∼2%. Serotonin is the most frequently detected peptide responsible for the carcinoid syndrome. Occasionally, a carcinoid crisis may occur in previously asymptomatic patients following bronchoscopic biopsy or surgical manipulation. Approximately 2% of patients with pulmonary and thymic carcinoids present with Cushing's syndrome caused by ectopic adrenocorticotropic hormone (ACTH) production.Diagnostic work-up includes chest X-rays followed by CT scan, bronchoscopy, somatostatin receptor scintigraphy in selected cases, while PET scan with FDG often shows false negative results and is not recommended.The diagnosis is made by histological examination of tumor tissue assisted by immunohistochemical detection of neuroendocrine markers. For diagnosis of thymic tumors thoracotomy may be required. For bronchial localization in patients with centrally localized carcinoids, tissue samples are taken during bronchoscopic examination. Using the rigid bronchoscope has the advantage of larger and more reliable biopsy samples. To reduce the risk of bleeding, epinephrine solution administered through the bronchoscope before biopsy is useful. Brush cytology is of no value for diagnosis of neuroendocrine tumors.The bronchial neuroendocrine tumors can be divided by histopathology into:•Typical carcinoid (TC) with highly organized carcinoid architecture and rare mitoses.•Atypical carcinoid (AC), which shows greater mitotic activity, 10/HPF and necroses are more widely spread and confluent.•Small-cell lung carcinoma (SCLC), which is the most poorly differentiated neuroendocrine tumor of the lung and is characterized by a classical 'oat-cell' histology. The mitotic activity is very high, >80/10HPF, and necrosis is widely spread. SCLC is dealt with in a separate chapter of the ESMO Clinical Recommendations.Both typical and atypical bronchial carcinoids may express neuroendocrine markers by immunohistochemistry (chromogranin A, synaptophysin and NSE) and somatostatin receptors. Thymic carcinoid follows the same pattern and stains for N-CAM in 73%, somatostatin in 36% and ACTH in 27% of cases. LCNEC and SCLC may express synaptophysin and neuron-specific enolase (NSE) only weakly and rarely express chromogranin A. The last two histological types also display mutations in the P53 gene.Thymic neuroendocrine tumors can show a continuous spectrum of differentiation from typical, well-differentiated carcinoid to small-cell neuroendocrine carcinoma type. Approximately 70% of all carcinoids are located in the major bronchi, and one-third in the periphery of the lungs. They occur more frequently (61%) in the right than in the left lung, especially in the middle lobe. Up to 92% of patients are symptomatic, presenting with hemoptysis, cough, recurrent pulmonary infection, fever, chest discomfort and unilateral wheezing. The carcinoid syndrome is very rare in patients with pulmonary and thymic carcinoids, ranging to ∼2%. Serotonin is the most frequently detected peptide responsible for the carcinoid syndrome. Occasionally, a carcinoid crisis may occur in previously asymptomatic patients following bronchoscopic biopsy or surgical manipulation. Approximately 2% of patients with pulmonary and thymic carcinoids present with Cushing's syndrome caused by ectopic adrenocorticotropic hormone (ACTH) production. Diagnostic work-up includes chest X-rays followed by CT scan, bronchoscopy, somatostatin receptor scintigraphy in selected cases, while PET scan with FDG often shows false negative results and is not recommended. The diagnosis is made by histological examination of tumor tissue assisted by immunohistochemical detection of neuroendocrine markers. For diagnosis of thymic tumors thoracotomy may be required. For bronchial localization in patients with centrally localized carcinoids, tissue samples are taken during bronchoscopic examination. Using the rigid bronchoscope has the advantage of larger and more reliable biopsy samples. To reduce the risk of bleeding, epinephrine solution administered through the bronchoscope before biopsy is useful. Brush cytology is of no value for diagnosis of neuroendocrine tumors. The bronchial neuroendocrine tumors can be divided by histopathology into:•Typical carcinoid (TC) with highly organized carcinoid architecture and rare mitoses.•Atypical carcinoid (AC), which shows greater mitotic activity, 10/HPF and necroses are more widely spread and confluent.•Small-cell lung carcinoma (SCLC), which is the most poorly differentiated neuroendocrine tumor of the lung and is characterized by a classical 'oat-cell' histology. The mitotic activity is very high, >80/10HPF, and necrosis is widely spread. SCLC is dealt with in a separate chapter of the ESMO Clinical Recommendations. Both typical and atypical bronchial carcinoids may express neuroendocrine markers by immunohistochemistry (chromogranin A, synaptophysin and NSE) and somatostatin receptors. Thymic carcinoid follows the same pattern and stains for N-CAM in 73%, somatostatin in 36% and ACTH in 27% of cases. LCNEC and SCLC may express synaptophysin and neuron-specific enolase (NSE) only weakly and rarely express chromogranin A. The last two histological types also display mutations in the P53 gene. Thymic neuroendocrine tumors can show a continuous spectrum of differentiation from typical, well-differentiated carcinoid to small-cell neuroendocrine carcinoma type. staging and risk assessmentThere is no specific TNM staging for neuroendocrine bronchial tumors. The TNM staging should be carried out according to criteria for non-small-cell lung cancer. TNM classification and staging for thymic carcinoids follows general rules for tumors of the thymus, which are presented in Table 1.Table 1UICC pathological TNM and staging of malignant thymic tumorspT pT1Completely encapsulated tumor pT2Tumor breaking through capsule, invading thymus or fatty tissue pT3Tumor breaking through the mediastinal pleura or pericardium, or invading neighboring organs, such as great vessels and lung pT4Tumor with pleural or pericardial implantationpN pN0No lymph node metastasis pN1Metastasis in anterior mediastinal lymph nodes pN2Metastasis in intrathoracic lymph nodes excluding anterior mediastinal lymph nodes pN3Metastasis in extrathoracic lymph nodespM pM0No distant organ metastasis pM1With distant metastasisPathological stage groupingPrimary tumorLymph node statusDistant metastasisStage IT1, T2N0M0Stage IIT1, T2N1M0Stage IIIT3N0, N1M0Stage IVaT4N0, N1M0Stage IVbany TN2, N3M0Stage IVcany Tany NM1 Open table in a new tab Conventional X-ray of the chest may suggest the diagnosis but CT and bronchoscopy, eventually assisted by endoscopic ultrasonography with biopsies are the best procedures to detect bronchial neuroendocrine tumors [III, B]. Since 80% of typical bronchial carcinoids express somatostatin receptors, somatostatin receptor scintigraphy may be informative [III, B], but its specificity is low. For thymic carcinoids contrast enhanced CT or MRI is recommended to detect the tumor and metastases. Somatostatin receptor scintigraphy is an additional option.The biochemical findings are dependent on the histological type of bronchial neuroendocrine tumors. The TC presents increased plasma levels of chromogranin A [III, B]. When hormone-related symptoms are present, plasma ACTH, growth hormone-releasing hormone (GHRH), insulin-like growth factor-1 (IGF-I), urine cortisol, 5-HIAA or histamine metabolites may be elevated [III, B]. The biochemical profile for thymic carcinoid is usually similar to that of bronchial carcinoid.TCs are indolent tumors with low rate of recurrence. Metastases after adequate resection are rare (7%). Five-year survival rates have been found to be 80%, whereas ACs show a 5-year survival rate of 60%. Both LCNEC and SCLC have poor prognosis with 5-year survival rates of <10%. Thymic carcinoids, although occasionally achieving extended survival, have a low cure rate averaging 10–15% and thus have a poorer overall prognosis than bronchial carcinoids. There is no specific TNM staging for neuroendocrine bronchial tumors. The TNM staging should be carried out according to criteria for non-small-cell lung cancer. TNM classification and staging for thymic carcinoids follows general rules for tumors of the thymus, which are presented in Table 1. Conventional X-ray of the chest may suggest the diagnosis but CT and bronchoscopy, eventually assisted by endoscopic ultrasonography with biopsies are the best procedures to detect bronchial neuroendocrine tumors [III, B]. Since 80% of typical bronchial carcinoids express somatostatin receptors, somatostatin receptor scintigraphy may be informative [III, B], but its specificity is low. For thymic carcinoids contrast enhanced CT or MRI is recommended to detect the tumor and metastases. Somatostatin receptor scintigraphy is an additional option. The biochemical findings are dependent on the histological type of bronchial neuroendocrine tumors. The TC presents increased plasma levels of chromogranin A [III, B]. When hormone-related symptoms are present, plasma ACTH, growth hormone-releasing hormone (GHRH), insulin-like growth factor-1 (IGF-I), urine cortisol, 5-HIAA or histamine metabolites may be elevated [III, B]. The biochemical profile for thymic carcinoid is usually similar to that of bronchial carcinoid. TCs are indolent tumors with low rate of recurrence. Metastases after adequate resection are rare (7%). Five-year survival rates have been found to be 80%, whereas ACs show a 5-year survival rate of 60%. Both LCNEC and SCLC have poor prognosis with 5-year survival rates of <10%. Thymic carcinoids, although occasionally achieving extended survival, have a low cure rate averaging 10–15% and thus have a poorer overall prognosis than bronchial carcinoids. treatment planlocalized tumorsConservative surgery is the primary treatment for all localized TC and AC tumors, both of the lung and the thymus, when 5-year survival rates of 80–100% may be expected. This is not true for LCNEC and SCLS unless for very selected and very limited, i.e. T1–2 N0, tumors; excision in toto in these cases occurs mostly as part of histological verification of a small peripherally situated nodule.The surgical approach is dependent on size, location and tissue type. Excision of intraluminal typical bronchial carcinoid may be attempted with bronchoscopic removal of the tumor (whenever possible bronchoscopic visualization should be combined with high-resolution CT), which may lead to complete eradication in a significant proportion of patients. Tumors not meeting criteria for endobronchial resection may be treated with bronchial sleeve resection, segmentectomy, lobectomy or pneumonectomy. External radiotherapy is an option for symptomatic localized disease [III, B], especially if surgery can not be performed. Endobronchial laser treatment, although not curative, can be useful in selected cases to treat airway obstruction.metastatic and recurrent diseaseCytotoxic treatment, combined with surgical resections when indicated, has been the standard for metastatic lung and thymic carcinoids, although the available chemotherapy regimens show rather poor activity. Chemotherapy for SCLC, which is a chemosensitive but not chemocurable cancer, is discussed in the appropriate guidelines. For low-proliferating tumors, treatment with somatostatin analogues and α interferons might be an option for functional tumors with severe clinical symptoms [III, B]. In non-functional tumors the use of somatostatin analogues is still controversial. Tumor-targeted radioactive treatment is an option in patients with tumors that present a high content of somatostatin receptors [III, B]. Available chemotherapy regimens for TC, AC and LCNEC include combination of 5-FU and interferon α, streptozoocin-based combinations, the etoposide–cisplatin regimen or chemotherapy combining cyclophosphamide, doxorubicin and vincristine. In general, chemotherapy results are discouraging and survival data have to be interpreted with caution. Symptomatic metastatic disease may be treated with palliative intent by appropriate local options such as embolization for liver metastases and irradiation treatment for brain and bone deposits. localized tumorsConservative surgery is the primary treatment for all localized TC and AC tumors, both of the lung and the thymus, when 5-year survival rates of 80–100% may be expected. This is not true for LCNEC and SCLS unless for very selected and very limited, i.e. T1–2 N0, tumors; excision in toto in these cases occurs mostly as part of histological verification of a small peripherally situated nodule.The surgical approach is dependent on size, location and tissue type. Excision of intraluminal typical bronchial carcinoid may be attempted with bronchoscopic removal of the tumor (whenever possible bronchoscopic visualization should be combined with high-resolution CT), which may lead to complete eradication in a significant proportion of patients. Tumors not meeting criteria for endobronchial resection may be treated with bronchial sleeve resection, segmentectomy, lobectomy or pneumonectomy. External radiotherapy is an option for symptomatic localized disease [III, B], especially if surgery can not be performed. Endobronchial laser treatment, although not curative, can be useful in selected cases to treat airway obstruction. Conservative surgery is the primary treatment for all localized TC and AC tumors, both of the lung and the thymus, when 5-year survival rates of 80–100% may be expected. This is not true for LCNEC and SCLS unless for very selected and very limited, i.e. T1–2 N0, tumors; excision in toto in these cases occurs mostly as part of histological verification of a small peripherally situated nodule. The surgical approach is dependent on size, location and tissue type. Excision of intraluminal typical bronchial carcinoid may be attempted with bronchoscopic removal of the tumor (whenever possible bronchoscopic visualization should be combined with high-resolution CT), which may lead to complete eradication in a significant proportion of patients. Tumors not meeting criteria for endobronchial resection may be treated with bronchial sleeve resection, segmentectomy, lobectomy or pneumonectomy. External radiotherapy is an option for symptomatic localized disease [III, B], especially if surgery can not be performed. Endobronchial laser treatment, although not curative, can be useful in selected cases to treat airway obstruction. metastatic and recurrent diseaseCytotoxic treatment, combined with surgical resections when indicated, has been the standard for metastatic lung and thymic carcinoids, although the available chemotherapy regimens show rather poor activity. Chemotherapy for SCLC, which is a chemosensitive but not chemocurable cancer, is discussed in the appropriate guidelines. For low-proliferating tumors, treatment with somatostatin analogues and α interferons might be an option for functional tumors with severe clinical symptoms [III, B]. In non-functional tumors the use of somatostatin analogues is still controversial. Tumor-targeted radioactive treatment is an option in patients with tumors that present a high content of somatostatin receptors [III, B]. Available chemotherapy regimens for TC, AC and LCNEC include combination of 5-FU and interferon α, streptozoocin-based combinations, the etoposide–cisplatin regimen or chemotherapy combining cyclophosphamide, doxorubicin and vincristine. In general, chemotherapy results are discouraging and survival data have to be interpreted with caution. Symptomatic metastatic disease may be treated with palliative intent by appropriate local options such as embolization for liver metastases and irradiation treatment for brain and bone deposits. Cytotoxic treatment, combined with surgical resections when indicated, has been the standard for metastatic lung and thymic carcinoids, although the available chemotherapy regimens show rather poor activity. Chemotherapy for SCLC, which is a chemosensitive but not chemocurable cancer, is discussed in the appropriate guidelines. For low-proliferating tumors, treatment with somatostatin analogues and α interferons might be an option for functional tumors with severe clinical symptoms [III, B]. In non-functional tumors the use of somatostatin analogues is still controversial. Tumor-targeted radioactive treatment is an option in patients with tumors that present a high content of somatostatin receptors [III, B]. Available chemotherapy regimens for TC, AC and LCNEC include combination of 5-FU and interferon α, streptozoocin-based combinations, the etoposide–cisplatin regimen or chemotherapy combining cyclophosphamide, doxorubicin and vincristine. In general, chemotherapy results are discouraging and survival data have to be interpreted with caution. Symptomatic metastatic disease may be treated with palliative intent by appropriate local options such as embolization for liver metastases and irradiation treatment for brain and bone deposits. follow-upAfter primary surgery patients with TC and AC should be followed at least yearly up to 10 years [III, C] in order to detect eventual surgically manageable recurrences. Biochemical markers, such as chromogranin A, should be determined every 3–6 months (in cases where they were elevated at baseline) and CT or MRI should be performed once a year.Patients with metastatic or recurrent disease should be followed during treatment with cytotoxic or biological agents more often, at 3-monthly intervals, with imaging evaluation (preferably by CT) and biological markers when evaluable, in order to assess eventual benefits of the treatment applied. After primary surgery patients with TC and AC should be followed at least yearly up to 10 years [III, C] in order to detect eventual surgically manageable recurrences. Biochemical markers, such as chromogranin A, should be determined every 3–6 months (in cases where they were elevated at baseline) and CT or MRI should be performed once a year. Patients with metastatic or recurrent disease should be followed during treatment with cytotoxic or biological agents more often, at 3-monthly intervals, with imaging evaluation (preferably by CT) and biological markers when evaluable, in order to assess eventual benefits of the treatment applied. noteLevels of evidence [I–V] and grades of recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO Faculty. Levels of evidence [I–V] and grades of recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO Faculty.
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