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Large cell neuroendocrine carcinoma (LCNEC) is part of the neuroendocrine spectrum of pulmonary tumours.

 

LCNEC of the lung displays morphologic and immunohistochemical characteristics common to neuroendocrine tumours and morphologic features of large-cell carcinomas.

 

Large cell neuroendocrine carcinoma is composed of cells with moderate amounts of cytoplasm and nuclei that show peripheral clumping of chromatin, a prominent nucleolus.

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Much mitotic activity and extensive necrosis, as seen in any large cell carcinoma. However, it is soon noticed that the tumour cells are arranged in well demarcated groups or cords with peripheral palisading.

 

This feature is reminiscent of a carcinoid pattern and the relationship to carcinoid is strengthened by shared immunocytochemical and ultrastructural features of neuroendocrine differentiation such as the presence neural cell adhesion molecule (CD56), chromogranin, synaptophysin and scanty dense-core granules.

 

Certain squamous cell carcinomas also show these neuroendocrine features -  these have been termed non-small cell carcinoma with neuroendocrine features.

 

Neuroendocrine differentiation can be demonstrated by electron microscopy or immunohistochemistry in 10-15% of non-small cell carcinomas of the lung despite an absence of morphological neuroendocrine features.

Differential diagnosis of large cell neuroendocrine carcinoma includes atypical carcinoid tumour but the organoid pattern of that tumour is not so well developed and the degree of atypia, mitotic activity and necrosis all far exceed those seen in an atypical carcinoid (which has between 2 and 10 mitoses per 2mm square [=10 high power fields] .

In general, large cell neuroendocrine carcinomas are tumours of middle-aged or elderly cigarette smokers that arise in central bronchi.

Despite the morphological evidence of neuroendocrine differentiation, ectopic hormone secretion is not a feature.

Patients with large cell neuroendocrine carcinomas have a significantly worse survival after resection than patients with large cell carcinomas, even in stage I disease.

Accurate differentiation of large cell neuroendocrine carcinoma from large cell carcinoma is important because it identifies those patients at highest risk for the development of recurrent lung cancer.

The clinical significance of these tumours has yet to be fully evaluated but their recognition is of potential therapeutic significance for their undoubted neuroendocrine nature links them to classic small cell carcinoma and it would be important if their metastases were similarly sensitive to chemotherapy. However, reports available to date regarding their chemosensitivity are contradictory and as yet there have been no large scale, prospective, controlled trials of small cell chemotherapy for this subgroup of large cell carcinomas or for other non-small cell carcinomas showing neuroendocrine differentiation. Furthermore, the clinical importance of neuroendocrine differentiation may diminish if a current trend towards treating all inoperable lung carcinomas with aggressive chemotherapy continues.

                       

Large-cell neuroendocrine carcinoma of the lung.Cancer Control. 2006 Oct;13(4):270-5.

BACKGROUND: Large-cell neuroendocrine carcinoma (LCNEC) of the lung displays morphologic and immunohistochemical characteristics common to neuroendocrine tumors and morphologic features of large-cell carcinomas. Because surgical resection of LCNEC in many series has been described with 5-year actuarial survival that is far worse than that reported for other histologic variants of non-small-cell lung cancer (NSCLC), considerable debate has emerged as to whether these tumors should be classified and treated as NSCLC or small-cell lung cancer. METHODS: The initial evaluation and diagnosis, tumor classification, surgical treatment, results of therapy, and long-term prognosis of patients with LCNEC based on our experience are discussed, and a review of the literature is presented. RESULTS: Patients with LCNEC are more likely to develop recurrent lung cancer and have shorter actuarial survival than patients with other histologic types of NSCLC, even in those with stage I disease. CONCLUSIONS: Accurate differentiation of LCNEC from other types of NSCLC is important because it identifies those patients at highest risk for developing recurrent disease. Efforts to identify effective adjuvant therapies are needed to improve treatment outcomes with this aggressive type of lung cancer.

Large cell neuroendocrine carcinoma: an aggressive form of non-small cell lung cancer.J Thorac Cardiovasc Surg. 2005 Jul;130(1):166-72.

OBJECTIVE: Large cell neuroendocrine carcinomas of the lung display morphologic and immunohistochemical characteristics common to neuroendocrine tumors and the morphologic features of large cell carcinomas. Surgical resection of large cell neuroendocrine carcinomas in many series has been described, with 5-year actuarial survivals ranging from 13% to 57%. Considerable debate has emerged as to whether these tumors should be classified and treated as non-small cell lung cancers or small cell lung cancers. The objective of this study was to report the outcome of surgical resection in patients with large cell neuroendocrine carcinomas. METHODS: An analysis of our tumor registry was performed to identify all patients undergoing surgical resection of lung cancer between July 1, 1988, and December 31, 2002, for large cell tumors. Cases were then segregated into large cell neuroendocrine carcinomas, mixed large cell neuroendocrine carcinomas (in which at least one portion of the tumor was a large cell neuroendocrine carcinoma), or large cell carcinomas on the basis of morphology and differentiation. Follow-up was complete on all patients, with a mean follow-up of 48 months. Type of resection, mortality, and survival by stage were analyzed. Kaplan-Meier survival was determined for all patients from the date of surgical intervention. Cox proportional hazards model analysis incorporating the variables of age, sex, histology, and stage estimated the effect of large cell neuroendocrine carcinomas and mixed large cell neuroendocrine carcinomas on recurrence and death. The stage of disease in all patients was assessed according to the 1997 American Joint Committee on Cancer guidelines. RESULTS: Of the 2099 patients who underwent resection, 82 (3.9%) had large cell lung cancers. Perioperative mortality was 2.4%. Overall survival and freedom from recurrence at 5 years for the entire group was 47.1% and 58.4%, respectively. Overall survival by histologic subtype at 5 years was 30.2% for patients with large cell neuroendocrine carcinomas (n = 45), 30.3% for patients with mixed large cell neuroendocrine carcinomas (n = 11), and 71.3% for patients with large cell carcinomas (n = 21). Survival was significantly worse for patients with large cell neuroendocrine carcinomas than for patients with large cell carcinomas ( P = .013). The presence of large cell neuroendocrine carcinomas in the specimen (the large cell neuroendocrine carcinoma and mixed large cell neuroendocrine carcinoma groups combined) was significantly associated with decreased survival (relative risk, 2.44; 95% confidence interval 1.29-4.58; P = .003) and decreased freedom from recurrence (relative risk, 4.52; 95% confidence interval, 1.76-11.57; P < .001). CONCLUSION: Patients with large cell neuroendocrine carcinomas have a significantly worse survival after resection than patients with large cell carcinomas, even in stage I disease. Accurate differentiation of large cell neuroendocrine carcinoma from large cell carcinoma is important because it identifies those patients at highest risk for the development of recurrent lung cancer.

Large cell neuroendocrine carcinoma and large cell carcinomas with neuroendocrine morphology of the lung: prognosis after complete resection and systematic nodal dissection.Ann Thorac Surg. 2003 Feb;75(2):348-52.

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) and large cell carcinoma with neuroendocrine morphology of the lung are both currently classified as subtypes of large cell carcinomas according to the World Health Organization IASLC classification system for lung and pleural tumors. Prognosis is reported as similar to that of small cell carcinomas. There is no consensus on management of this subset and adjuvant chemotherapy is recommended by some for early stage LCNEC to impact long-term prognosis. We retrospectively reviewed a cohort of patients at our institution who had this type of tumor to determine factors that might influence survival. METHODS: Twenty-one cases of LCNEC and large cell carcinoma with neuroendocrine morphology were identified in the files of the Royal Brompton Hospital between 1986 and 1999. All patient data were reviewed, and complete follow-up was achieved with 20 of these patients. RESULTS: Of the 21 patients identified, 20 underwent resection with systematic nodal dissection in 18. There was no in-hospital mortality. Of those patients fully staged by systematic nodal dissection, 9 were stage I, 5 were stage II and 4 were stage III. Median follow-up was 25 months (range, 2 to 120 months). At the time of review, 11 patients were alive and free of disease. One patient was alive and free of disease when lost to follow-up. Nine patients had died, 7 related and 2 unrelated to disease. The 5-year actuarial survival for the entire group was 47%. The actuarial survival of accurately staged, stage I patients at 5 years was 88%. The actuarial survival of patients in stage II and III was 28% at 5 years. CONCLUSIONS: LCNEC and large cell carcinoma with neuroendocrine morphology are aggressive tumors, but patients with completely resected disease after systematic nodal dissection have a better prognosis than previously described. Patients with more advanced disease have a poor prognosis.

Large cell neuroendocrine carcinoma of the lung: a clinicopathologic study of eighty-seven cases.J Thorac Cardiovasc Surg. 2002 Aug;124 (2): 285-92.

OBJECTIVE: Large cell neuroendocrine carcinoma of the lung is a newly recognized clinicopathologic entity. The clinical characteristics and optimal treatment of patients with large cell carcinomas are not yet established. The aim of this study was to define the clinicopathologic characteristics of large cell neuroendocrine carcinoma. METHODS: The histologic characteristics of the patients receiving an initial diagnosis of poorly differentiated non-small cell lung carcinoma (n = 484), small cell carcinoma (n = 55), carcinoid (n = 31), and large cell neuroendocrine carcinoma (n = 12) were retrospectively reviewed according to World Health Organization criteria. Immunohistochemistry was performed to confirm the neuroendocrine phenotype. The outcomes and other clinical characteristics of those patients with large cell neuroendocrine carcinoma were retrospectively analyzed and compared with those of patients with poorly differentiated carcinoma of other histologic types. RESULTS: A total of 87 patients were given a diagnosis of large cell neuroendocrine carcinoma after the histologic review. These patients comprised 3.1% of all patients undergoing resection for primary lung cancer during the same period. The overall 5-year survival was 57%. The 5-year survivals of patients with stage I, II, III, and IV disease were 67%, 75%, 45%, and 0%, respectively. There was no statistically significant difference between the overall survival of patients with large cell neuroendocrine carcinoma and those with other non-small cell lung cancers. There was a significant difference between the survival of patients with stage I large cell neuroendocrine carcinoma and that of patients with the same stage of other non-small cell lung carcinomas. The site of the first documented recurrence was locoregional in 12 patients (34%), distant metastases in 20 patients (57%), and both simultaneously in 3 patients. Locoregional lymph node recurrences were observed frequently. More than 80% of recurrences were found within 1 year after the operation. CONCLUSION: In terms of prognosis, large cell neuroendocrine carcinoma is distinctly different from other non-small cell lung cancers. The prognosis of large cell neuroendocrine carcinoma was poor, even for early stage disease; the prognosis of the stage I disease of large cell neuroendocrine carcinoma was poorer than that of the same stage of other non-small cell lung cancers. Because of its aggressive clinical behavior and poor prognosis, large cell neuroendocrine carcinoma should be recognized as one of the poorest prognostic subgroups among primary lung cancers, and therefore novel therapeutic approaches should be established.

Large cell neuroendocrine carcinoma of the lung: a histologic and immunohistochemical study of 22 cases.Am J Surg Pathol. 1998 May;22(5):526-37.

Large cell neuroendocrine carcinoma (LCNEC) of the lung is defined as a poorly differentiated and high-grade neuroendocrine tumor that is morphologically and biologically between atypical carcinoid and small cell lung carcinoma (SCLC). During a survey concerning bcl-2 protein expression in the subtypes of lung cancer, we noticed that two previously diagnosed non-SCLCs met the criteria for LCNEC. Because LCNEC is a newly recognized clinicopathologic entity and because all reported cases have been retrieved from the so-called "neuroendocrine tumor file," we suspected that LCNEC had been underdiagnosed. In the present study, we histologically reviewed 766 surgically resected lung cancers and were able to diagnose 22 (2.87%) LCNECs with the neuroendocrine features subsequently confirmed by immunostaining for multiple neuroendocrine markers. Each case stained positively for at least three general neuroendocrine markers, and 12 (54.5%) also were positive for neuroendocrine hormones. Histologically, most LCNECs showed a marked decrease in or a loss of organoid architecture and could be mistaken for poorly differentiated adenocarcinoma or squamous cell carcinoma. Because our LCNECs are the first to be identified by retrospective review of routinely diagnosed lung cancers, and 18 had been classified as non-SCLC, they may represent cases relatively difficult to diagnose. The present study shows that the most difficult diagnostic factor of LCNEC is the recognition of its light microscopic neuroendocrine features, and LCNEC must be distinguished not only from atypical carcinoid or SCLC, but also from common non-SCLC. Histologically, when an organoid architecture is subtle or absent, the rosettelike structure becomes the best marker for the recognition of neuroendocrine differentiation. Clinically, the prognosis for our LCNECs was significantly worse than that for stage-comparable non-SCLCs (p = 0.046).

 
Pulmonary Lymphoproliferative Disease; Lymphomatoid Granulomatosis; Post-Transplant Lymphoproliferative Disease ; Biphasic Epithelial/ Mesenchymal Lung Tumours; Pulmonary Carcino sarcoma; Pulmonary Blastoma;
Abstracts:

Large-cell neuroendocrine carcinoma of the lung: an aggressive neuroendocrine lung cancer.Semin Thorac Cardiovasc Surg. 2006 Autumn;18(3):206-10. 

Prognostic impact of large cell neuroendocrine histology in patients with pathologic stage Ia pulmonary non-small cell carcinoma.J Thorac Cardiovasc Surg. 2006 Aug;132(2):312-5

November  2009
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