Carcinoid tumors can produce vasoactive hormones, whose activity rarely conditions the appearance of carcinoid syndrome (8%) and its crises (3%) as reported by Savu et al, who described this presentation in 3 out of 98 patients, characterized by tachycardia, arterial hypertension, flushing, bronchospasm and accelerated digestive transit (5). Furthermore, these disappeared after resection, similar clinical outcome was with our patient with the absence of respiratory and hemodynamic symptoms in ambulatory controls. Differential diagnoses include asthma, airway obstruction by aspirated foreign body, metastases, bronchopulmonary carcinoma, benign pulmonary nodule, or endocrinological entities such as Cushing's syndrome, which can occur in up to 2% of AC and TC due to ectopic production of adrenocorticotropic hormone (ACTH) or acromegaly, due to ectopic production of growth hormone-releasing hormone (GHRH) or insulin-like growth factor 1 (IGF-1). ACTH, growth hormone (GH) testing is not routinely performed unless there are related symptoms. Also, the time of illness is usually prolonged, having been studied for different causes in the context of a carcinoid syndrome such as cardiovascular and digestive manifestations, yet elevated levels of vasoactive hormones in plasma or urine are rarely detected.
They are usually visualized as solitary pulmonary nodules predominantly in segmental or subsegmental bronchi (80%), in some cases with calcifications, and in up to 75% they are associated with endobronchial lesions as in the present case (4). Central carcinoids can present with an endobronchial component, being round tumors with an average size of 2–3 cm, with the bronchoscopic study being the best method for biopsy and aetiological study. Histopathology of TC and AC consist of a uniform organoid growth pattern with cytological features consisting of a moderate amount of eosinophilic cytoplasm with an eosinophilic matrix, with a variety of histological patterns in both, including spindle cell, trabecular, palisade, glandular, follicular, rosette, pink, clear cell, and papillary patterns. Identification and classification can be difficult with immunohistochemistry being important, which points towards a neuroendocrine nature by being positive for synaptophysin, chromogranin, and CD56. However, these can be positive in 30% of cases of lung adenocarcinoma and squamous cell carcinoma, as well as metastatic carcinomas of the breast, prostate, and other sites, and should therefore be considered as differential diagnoses. TTF-1 expression in TC and AC is varied. Most carcinoids stain for cytokeratins, but up to 20–25% may be keratin negative. Ki-67 staining shows a low proliferation rate in TC, usually less than 5% while in AC it is higher, usually between 5% and 20%. The proliferation rate may be more useful in small crushed biopsies to separate TC and AC from LCNEC or SCLC.24,25,40 respectively. Ki67 is of limited value in tumors of lung origin, however, it has been estimated that a value > 5% in AC and > 10%, in general, are associated with poor prognosis (6). The transcription factors TTF-1, CDX-2, and PDX-1 allow differentiation of primary lung origin, being site-specific for lung, gastrointestinal and pancreatic origins, respectively.
Approximately 80% of low-grade (typical) and 60% of intermediate-grade (atypical) pulmonary carcinoids express somatostatin receptors by immunohistochemistry and can be imaged using Positron Emission Tomography (PET) or somatostatin receptor scans (OctreoScan) (7). Typically, 90% are confined to the bronchi and 10% to regional lymph nodes; however, in our case, the nodal staging was negative. As with any neoplastic process, prognosis depends on histological type, stage, and metastatic involvement. Surgical management is of choice and even curative in some cases, there is no standardization, with complete anatomical resection plus mediastinal lymphadenectomy being the most commonly described, however, options range from wedge resection, lobectomy, pneumonectomy or sleeve resection together with mediastinal lymph node study. The latter is controversial, due to the low potential for nodal metastasis of non-active AC and TC described. However, in endocrinologically active tumors a high nodal metastatic potential is presumed, as demonstrated by Seastedt who after evaluating 68 cases of pulmonary carcinoids associated with Cushing's syndrome found mediastinal nodal involvement in 37%, with an overall incidence of persistence/recurrence of 16.2% and with a median time to recurrence of 55 months (Range, 18–152 months). He also reported a disease-free time of 12.7 years (8).
Girelli et al. analyzed 325 patients with pulmonary carcinoids undergoing complete resection (236 with lymph node involvement and 89 without lymph node involvement), of these 23.6% had TC, 39.3% AC, and 37.1% Large Cell Neuroendocrine Carcinoma (LCNC). 58.4% underwent lobectomy, and 21.3% pneumonectomy, with a mean tumor size of 11–130 mm. Mortality analyzed after 4.0 years of follow-up reached 5.1%. For TC and AC, the 5-year survival was 89% and 78% at 10 years, with a worse prognosis for LCNC, 47% at 5 years, and 41% at 10 years (9). Follow-up is carried out taking into account the high potential for recurrence, by clinical and radiological examination. At 3 and 6 months and depending on whether it is TC or AC, annually and semi-annually respectively. Bronchoscopic control may even be indicated in the case of endoscopic resections. These measures should be maintained even for life, with a 10-year survival rate of approximately 90%. The patient underwent follow-ups at 3, 6, and 9 months with no evidence of recurrence (10). Somatostatin receptor (SRS)-based therapies such as 177-Lu-DOTATATE is an effective and safe option in patients with somatostatin receptor (SRS)-positive (TC)- and (AC)-positive progression. Zidan et al. reported in 48 patients after 42 months of follow-up a 33% mortality, a progression-free survival of 23 months, and an overall survival of 59 months (7). In cases where surgical management is not possible, other therapies such as local radiotherapy should be considered and combined with surgery in cases of AC and LCNC.