BACKGROUND: Pulmonary carcinoid tumors represent a group of malignant neoplasms comprised of neuroendocrine cells. In 1999, the World Health Organization (W.H.O.) proposed the definitive classification of neuroendocrine tumors based on the criteria from Travis and associates. The W.H.O. described two different groups of carcinoid tumors: typical carcinoids (TC) and atypical carcinoids (AC). Few reports have reviewed their data according to the current classification, and therefore, prognosis and standard therapy for TC and AC are still uncertain. METHODS: From 1980 to 2001, 98 pulmonary resections have been performed for primary bronchial carcinoid tumors in our Thoracic Department of the University of Milan. We reviewed original histology using the current W.H.O. criteria and identified 88 patients with TC and 10 with AC. We reviewed the outcomes in each group. RESULTS: The 5 year-overall survival rate was 91.9% for TC and 71% for AC. The 10-year overall survival rate was 89.7% for TC and 60% for AC. The 5-year TNM-related survival rates in the TC group were: IA-B, 100%; IIA-B, 75%; and IIIA, 50%. At 10 years, they were: IA-B, 100%; IIA-B, 75%; and IIIA, 0%. The 5-year survival rates in the AC group were: IA-B, 100%; IIA-B, 100%; and IIIA, 0%. At 10 years, they were: IA-B, 100%; IIA-B, 66%; and IIIA, 0%. CONCLUSIONS: Prognosis is favorable for both subtypes in the early stage. Advanced stages are related to better prognosis in TC. Recurrences rate is worse in the AC subtype. Our data suggest avoiding limited resections when feasible in AC. Parenchyma-sparing resections should be encouraged in TC.

Typical and atypical pulmonary carcinoids : outcome in patients presenting with regional lymph node involvement.Chest. 2001 Apr;119(4):1143-50.

STUDY OBJECTIVE: Typical pulmonary carcinoid tumors are well-differentiated neuroendocrine tumors that are associated with good patient survival rates, while atypical carcinoid tumors are more aggressive and have worse patient survival rates. Because these tumors rarely involve the thoracic lymph nodes at presentation, it is currently unknown to what extent the presence of thoracic lymph node metastases at the time of diagnosis influences patient survival. METHODS: A computerized search of the medical records for pulmonary carcinoid tumor at the Mayo Clinic from 1976 to 1997 revealed 517 patients, from which we identified 36 patients with pulmonary carcinoid tumors involving regional thoracic lymph nodes but without distant disease. For each patient, we reviewed the tumor histology, stage, and outcome. In addition, because the histologic criteria for the diagnosis of carcinoid tumors had changed significantly during the time of the study, we reexamined all of the histologic specimens using the current World Health Organization (WHO) criteria for classifying pulmonary neuroendocrine tumors. RESULTS: After reclassification with the WHO criteria for neuroendocrine tumors, 23 patients had typical carcinoid tumors with thoracic lymph node involvement. At the last follow-up, 19 patients had no evidence of disease (NED), 2 patients had developed systemic metastases (SM) and are still alive, and 2 patients had died. Eleven patients had atypical carcinoid tumors with thoracic lymph node involvement. At the last follow-up, four patients had NED, seven patients had developed SM within a median time of 17 months, and six patients with SM died shortly thereafter (median survival time, 25.5 months), while one is still alive. Two patients had been reclassified with large cell neuroendocrine carcinoma at the time of this review; both of these patients had developed SM (at 4 months and 21 months after diagnosis) and had died (at 15 months and 21 months after diagnosis, respectively). CONCLUSIONS: These data suggest that patients with atypical pulmonary carcinoid tumors with regional lymph node metastases have a high likelihood of developing recurrent disease if treated with surgical resection alone and have significantly worse outcome (p < 0.001) compared to those patients with typical carcinoid tumors with thoracic lymph node involvement.

Pulmonary atypical carcinoid: predictors of survival in 106 cases.Hum Pathol. 2000 Oct;31(10):1255-65.

Pulmonary neuroendocrine tumors (NE) include a spectrum of tumors from typical carcinoid (TC) to atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCLC). Little is known about prognostic predictors for AC because of its rarity. Survival analysis was performed on 106 ACs with clinical follow-up from the AFIP and the Pathology Panel of the International Association for the Study of Lung Cancer (IASLC). The tumors fulfilled the 1999 WHO/IASLC criteria for AC of a NE tumor with a mitotic rate of 2 to 10 per 2 mm(2) of viable tumor or coagulative necrosis. Multiple clinical and histologic features were analyzed by Kaplan-Meier and Cox regression analysis. Of the clinical features, higher stage (P = .003) and a tumor size of 3.5 cm or greater (P = .003) were associated with a worse prognosis. Features that were histologically unfavorable by univariate analysis were mitotic rate (P =.002), pleomorphism (P = .018), and aerogenous spread (P =.007). Histologically favorable features by univariate analysis were the presence of palisading (P = .008), papillary (P = .039), pseudoglandular (P =.026), and rosette (P = .022) patterns. Female gender showed a trend toward a poorer prognosis (P =.085) and was included in the multivariate model. Multivariate analysis stratified for stage showed mitoses (P<.001), a tumor size of 3.5 cm or greater (P =.017), and female gender (P =.012) to be the only negative independent predictors of prognosis and the presence of rosettes (P = .016) to be the only independent positive predictor. We further divided the AC into subgroups of low (2 to 5 mitoses/2 mm(2)) and high (6 to 10 mitoses/2 mm(2)) mitotic rate and compared the survival with TC and with LCNEC. Within the category of AC, the patients with a higher mitotic rate had a significantly worse survival than those with a lower mitotic rate (P<.001) stratified for stage. Five- and 10-year survival rates for AC (61% and 35%, respectively) stratified for stage were significantly worse than for TC and better than that for LCNEC and SCLC. Chemotherapy or radiation therapy was given in 12 of 52 and 14 of 52 cases, respectively, but the data were insufficient to evaluate tumor response. We conclude that AC is an aggressive neuroendocrine neoplasm with survival intermediate between TC and LCNEC and SCLC. Higher mitotic rate, tumor size of 3.5 cm or greater, female gender, and presence of rosettes are the only independent predictors of survival. Surgical resection remains the treatment of choice, and the role of chemotherapy and radiation therapy remains to be proven.

Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol. 1998 Aug;22(8):934-44.

Neuroendocrine tumors of the lung embrace a spectrum from low-grade typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), and high-grade categories of large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCLC). We studied 200 neuroendocrine lung tumors to critically evaluate the Arrigoni histologic criteria for AC using statistical analysis to delimit more rigorously an intermediate survival for AC between TC and the high-grade tumors of LCNEC and SCLC. Histologic features that might predict prognosis were used for Kaplan-Meier and Cox proportional hazards survival analysis, and an optimal mitotic range for AC was calculated. The optimal mitotic range for AC was 2 to 10 mitoses per 2 mm2 of viable tumor (10 high-power fields). Based on this finding, we collapsed mitoses into three categories (< 2; 2-10; > or = 11) and performed Cox multivariate analysis for all 200 neuroendocrine tumors. Mitotic counts were the only independent predictor of prognosis. Based on this analysis, we propose that AC be defined as a tumor with neuroendocrine morphology, mitotic counts between 2-10 per 2 mm2 of viable tumor (10 high-power fields), or coagulative necrosis. Using these criteria, the 200 neuroendocrine tumors were classified as 51 TC, 62 AC, 37 LCNEC, and 50 SCLC. The 5- and 10-year survival was 87% and 87% for TC, 56% and 35% for AC, 27% and 9% for LCNEC, and 9% and 5% for SCLC, respectively. After stratification for stage, survival for AC was significantly worse than for TC (p < 0.001); for LCNEC and SCLC it was significantly worse than for AC; but the survival for LCNEC was no different than that for SCLC.

Typical and atypical pulmonary carcinoids--pathologic and clinical analysis of 77 cases.Pneumonol Alergol Pol. 1998;66(5-6):297-303.

Neuroendocrine tumors of the lung represent a group of controversial pulmonary neoplasms regarding their classification, criteria for diagnosis, predictors of future behavior, and therapy. The histologic criteria for their classification rest heavily on the proposed by Arrigoni et al. in 1972, for atypical carcinoid (AC). According to these authors AC has mitoses between 5 and 10 per 10 high power fields (HPF), necrosis, hypercellularity and disorganized architecture. The survival analysis performed by Flieder et al. (1997) for a variety of clinical and histologic features revised the histologic criteria for separating AC from typical carcinoid (TC) and proposed a range of mitotic counts between 2 and 20 per HPF for AC. From 1978 until 1997, 77 resected pulmonary carcinoids were reclassified for TCs and ACs according to Flieder's et al. histologic criteria. The clinical and pathological various features were studied for the group of 62 TCs and 15 ACs. 77 patients (pts) entered the study: 29(38%) males and 48(62%)females; mean age 43 years, range 18-75 years, 46 pts underwent lobectomies, 16 bilobectomies, 12 pneumonectomies and 3 wedge resections. The patients with TC were younger than those with AC (males: 40 vs 50 years and females 42 vs 49 years). TCs were significantly smaller than ACs (mean diameter respectively: 24 mm vs 33 mm). Fifty four (87%) of TCs and all ACs had central localization. The time of patients observation ranged from 2 months to 18 and half years; 2 patients with TC died due to tumours progression; 3 due to other diseases. Regional lymph node metastases occurred in 10% TCs and 33% ACs (p = 0.032). The heterotopic bone formation appeared in 11(18%) TCs and 2(13%) ACs. The mitotic counts for AC range between 2 and 6 per 10 HPF, accompanied by small foci of necrosis in 2 cases. Peripheral carcinoids showed a spindle-cell morphology. The performed study has highlighted the new concept of the carcinoids classification and the importance of the mitotic counts as histologic criteria for AC diagnosis. The data based on the largest in Polish literature lung carcinoids collection.

Carcinoid tumors of the lung: do atypical features require aggressive management?. Ann Thorac Surg 1995;59:78–83.

Atypical carcinoids are an intermediate form of tumor between low-grade malignant typical carcinoid and high-grade malignant small cell carcinoma, which represent the two ends of the spectrum of neuroendocrine bronchopulmonary tumors. Between 1983 and 1993, 27 patients with atypical carcinoids underwent surgical treatment. The histologic diagnosis of an atypical carcinoid was established if the criteria proposed by Arrigoni and associates were fulfilled. Seven pneumonectomies, 16 lobectomies, 2 segmentectomies, and 2 wedge resections were performed. Thirteen patients (48.1%) had regional nodal metastases and 6 patients (22%) had N2 disease at the time of surgical therapy. Distant metastases developed in 5 patients (18.5%) after initial treatment. The 10-year survival in patients with an atypical carcinoid was 49%, versus the 84% 10-year survival rate observed in patients with a typical carcinoid. We conclude that the aggressive behavior of atypical carcinoids precludes the use of limited surgical resection and requires a more aggressive approach, with lobectomy and mediastinal lymph node dissection constituting a minimal procedure. The same criteria used for well-differentiated lung carcinoma should apply to this form of neuroendocrine lung tumor. Adjuvant chemotherapy is recommended for patients with stage III or distant metastases.

Atypical carcinoid tumour of the lung: a study of 33 cases with prognostic features. Histopathology 1994;24:363–369.

Atypical carcinoids of the lung (well-differentiated neuroendocrine carcinomas) are rare tumours of uncertain prognosis. We have studied 33 cases--male to female ratio 2:1, age range 22-75 years, mean 55 years, 80% smokers, 15 peripheral and 18 central, tumour size 1.2-9.5 cm. Microscopically they had a nesting/insular, trabecular or lobular pattern. Nuclear morphology was variable, round cells, large cells and spindle cells being identified with small cell areas in five tumours. Mitotic activity varied from 4 to 80 per 1.52 mm2. Areas of necrosis were seen in all tumours. All 33 tumours were cytokeratin positive (AE1/AE3 and CAM5.2), 32 were positive for neuron-specific enolase, synaptophysin and chromogranin A. Electron microscopy showed dense core granules in 29 available cases. Nineteen cases were stage I, nine stage II, four stage III and one stage IV. Follow-up information was available for 22 cases. Size, location, stage and large cell/small cell morphology were important prognostic indicators. Large tumour size, large cell or mixed large cell/small cell morphology, peripheral localization and advanced stage were adverse prognostic indicators. Mitotic activity and the presence of necrosis did not appear to influence stage or behaviour.

Bronchopulmonary carcinoids: An analysis of 1,875 reported cases with special reference to a comparison between typical carcinoids and atypical varieties.Ann Thorac Cardiovasc Surg. 1999 Aug;5(4):211-9.

This study was undertaken to provide investigators working in this particular research field with extensive and useful basic information based on an analysis of a large reliable series of cases regarding tracheal and bronchopulmonary carcinoids and their atypical varieties. A statistical evaluation was carried out which included a total of 1,875 patients with tracheal and bronchopulmonary carcinoids; these were divided into two series, one of 1,595 patients with typical carcinoids and the other of 280 with atypical varieties. These two series were compared regarding various aspects, which included the male to female ratio, age distribution, clinical manifestations, successful preoperative diagnosis, diagnostic accuracy of representative procedures, sites of involvement, tumor size distribution, metastases, carcinoid syndrome, serotonin activity in patients with or without the syndrome, immunohistochemistry, electron microscopy, and postoperative prognosis of the patients. The comparative analyses between the two series disclosed statistically significant differences (p<0.01) regarding various viewpoints; among others, such a difference was proved in the average age, sites of involvement in the lung (central or peripheral), rates and sites of metastases, adrenocorticotrophic hormone (ACTH) production, the association rate of the carcinoid syndrome, and postoperative 5-year and 10-year survival rates (93.3% and 82.1% for the typical carcinoid series versus 68.8% and 58.6% for the atypical variety series: p<0.0001). The postoperative 5-year and 10-year survival rates in the other two groups of patients with or without metastases were likewise calculated and showed a statistically significant difference (72.8% and 52.8% for the former versus 98.3% and 95.4% for the latter: p<0.0001).

Atypical carcinoid of the lung. A distinct clinicopathologic entity.Chest. 1988 Feb;93(2):370-5.

Eleven cases of atypical carcinoid (AC) of the lung were identified during an eight-year period. Their clinical features and treatment responses were contrasted with our experience at Vanderbilt with small cell lung cancer (SCLC) and a literature review of typical bronchial carcinoids (TC). Clinically, there were no features to distinguish AC from TC except for age at diagnosis (59 vs 49 years). Atypical carcinoid was similar to SCLC with respect to many clinical features, although female sex, absence of smoking history and localized disease at presentation were more common in AC. Pathologically, these tumors were distinguished by cellular atypia, necrosis, architectural disorder, or increased mitotic rate in the presence of a recognizable carcinoid pattern. Immunoperoxidase staining revealed no difference between AC and TC or SCLC. Atypical carcinoid of the lung represents a distinct clinicopathologic disease.

Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg 1972;64: 413–421.

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