AIMS: Monoclonal antibody 34betaE12 (Ck34betaE12) recognizes a set of cytokeratins (1, 5, 10, 14) expressed in normal stratified squamous epithelium. We have recently reported its expression in squamous cell carcinoma and basaloid carcinoma, in contrast to large cell neuroendocrine carcinoma, an entity with overlapping morphological features with basaloid carcinoma. We have now examined the role of Ck34betaE12 in discriminating between neuroendocrine and non-neuroendocrine proliferations. METHODS AND RESULTS: We performed an immunohistochemical study of 228 cases, comprising the whole spectrum of lung neuroendocrine proliferations and tumours. All cases of neuroendocrine cell hyperplasia (n = 15), tumorlet (n = 23), typical carcinoid (n = 27) and atypical carcinoid (n = 23) were completely negative for Ck34betaE12. Although the neuroendocrine cells of small cell lung carcinoma and large cell neuroendocrine carcinoma were consistently negative, a strong and diffuse positive staining was found in the non-neuroendocrine components of combined small cell carcinoma (three of eight cases) and combined large cell neuroendocrine carcinoma (11 of 12 cases). In addition, scattered Ck34betaE12+ cells were noted in 11 of 64 (17%) large cell neuroendocrine carcinoma and in seven of 56 (12.5%) small cell carcinoma, which were not obviously histologically combined. This heterogeneity of high-grade neuroendocrine tumours was not observed in carcinoids which lack Ck34betaE12 clusters of reactive cells. There was mutual exclusion between expression of neuroendocrine markers and that of Ck34betaE12. CONCLUSION: We conclude that 34betaE12 expression excludes the neuroendocrine nature of tumour cells and uncovers the real frequency of combined forms in high-grade neuroendocrine tumours.

Pulmonary neuroendocrine carcinomas. A review of 234 cases and a statistical analysis of 50 cases treated at one institution using a simple clinicopathologic classification.Arch Pathol Lab Med. 2002 May;126(5):545-53.

CONTEXT: Primary pulmonary neuroendocrine tumors are traditionally classified into 3 major types: typical carcinoid (TC), atypical carcinoid (AC), and large cell neuroendocrine carcinoma (LC) or small cell neuroendocrine carcinoma (SC). Confusion arises frequently regarding the malignant nature of TC and the morphologic differentiation between AC and LC or SC. OBJECTIVE: To provide clinicopathologic evidence to streamline and clarify the histomorphologic criteria for this group of tumors, emphasizing the prognostic implications. PATIENTS: To minimize variability in diagnostic criteria and treatment plans, we analyzed a group of patients whose diagnosis and treatment occurred at a single institution. We reviewed 234 cases of primary pulmonary neuroendocrine tumors and thoroughly studied 50 cases of resected tumors from 1986 to 1995. RESULTS: On the basis of morphologic characteristics and biologic behaviors of the tumors, we agree with many previous investigators that these tumors are all malignant and potentially aggressive. Based on our accumulated data, we have modified Gould criteria and reclassified these tumors into 5 types: (1) well-differentiated neuroendocrine carcinoma (otherwise called TC) (14 cases, with less than 1 mitosis per 10 high-power fields [HPF] with or without minimal necrosis); (2) moderately differentiated neuroendocrine carcinoma (otherwise called low-grade AC) (6 cases, with less than 10 mitoses per 10 HPF and necrosis evident at high magnification); (3) poorly differentiated neuroendocrine carcinoma (otherwise called high-grade AC) (10 cases, with more than 10 mitoses per 10 HPF and necrosis evident at low-power magnification); (4) undifferentiated LC (5 cases, with more than 30 mitoses per 10 HPF and marked necrosis); and (5) undifferentiated SC (15 cases, with more than 30 mitoses per 10 HPF and marked necrosis). The 5-year survival rates were 93%, 83%, 70%, 60%, and 40% for well, moderately, and poorly differentiated, and undifferentiated large cell and small cell neuroendocrine carcinomas, respectively. We found nodal metastasis in 28% of TC in this retrospective review, a figure higher than previously recorded. CONCLUSION: Using a grading system and terms comparable to those used for many years and used for neuroendocrine tumors elsewhere in the body, we found that classification of pulmonary neuroendocrine carcinomas as well, moderately, poorly differentiated, or undifferentiated provides prognostic information and avoids misleading terms and concepts. This facilitates communication between pathologists and clinicians and thereby improves diagnosis and management of the patient.

The surgical spectrum of pulmonary neuroendocrine neoplasms.Chest. 2001 Jan;119(1):14-8.

OBJECTIVES: The purpose of this study is to review our experience with the spectrum of neuroendocrine neoplasms of the lung with emphasis on the histopathologic classification and surgical therapy of each class of neoplasm. DESIGN: This retrospective review covers the entire spectrum of neuroendocrine neoplasms of the lung over an 11-year period (January 1985 to December 1995) in a university hospital setting. Only patients who underwent surgical resection were included in this review. PATIENTS: During this period, a total of 77 patients underwent lung resection for the following neuroendocrine neoplasms: typical carcinoid (TC), 50 patients; atypical carcinoid (AC), 5 patients; large cell neuroendocrine carcinoma (LCNEC), 9 patients; mixed large-small cell neuroendocrine carcinoma (LSNEC), 4 patients; or small cell neuroendocrine carcinoma (SCC), 9 patients. There were 37 men (48.1%) and 40 women (51.9%) among the patients, with a mean age of 57.9 years (range, 14 to 87 years). INTERVENTIONS: Primary surgical resection consisted of the following procedures: 52 lobectomies (67.5%); 10 pneumonectomies (13%); 13 limited resections (16.9%); 1 left main bronchus sleeve resection; and 1 carinal resection. Six patients had the following concomitant procedures: pericardiectomy, 2 patients; mediastinoscopy, 1 patient; chest wall resection, 1 patient; stapling blebs, 1 patient; and transdiaphragmatic liver biopsy, 1 patient. Four patients underwent bilobectomies, and two patients underwent multiple wedge resections. RESULTS: The hospital mortality rate was 2.6% (2 of 77 patients), and both patients died of pulmonary failure. Follow-up was obtained in 62 of 77 patients (80.9%) for an average of 38.1 months (range, 2 to 132 months). There were a total of 13 deaths, and 8 were disease-related (LCNEC, 4 deaths; SCC, 2 deaths; LSNEC, 1 death; and AC tumor, 1 death. The mean disease-free intervals for patients with these neoplasms were the following: TC tumor, 41.3 months; AC tumor, 20 months; LCNEC, 20.4 months; LSNEC, 25 months; and SCC, 48 months. The overall 3-year survival rate was 45.2% (28 of 62 patients). CONCLUSION: This report will emphasize the classification, surgical management, and treatment considerations of pulmonary neuroendocrine neoplasms. Despite the poor overall prognosis in high-grade neuroendocrine tumors of the lung, surgery remains a viable adjunct in the early stages of this disease.

Differential distribution of the neuron-associated class III beta-tubulin in neuroendocrine lung tumors. Arch Pathol Lab Med 2000;124:535–544.

OBJECTIVE: To study the immunoreactivity profile of the neuron-associated class III beta-tubulin isotype (beta III) in epithelial lung tumors. DESIGN: One hundred four formalin-fixed, paraffin-embedded primary and metastatic lung cancer specimens were immunostained with an anti-beta III mouse monoclonal antibody (TuJ1) and an anti-beta III affinity-purified rabbit antiserum. Paraffin sections from fetal, infantile, and adult nonneoplastic lung tissues were also examined. RESULTS: In the fetal airway epithelium, beta III staining is detected transiently in rare Kulchitsky-like cells from lung tissues corresponding to the pseudoglandular and canalicular but not the saccular or alveolar stages of development. beta III is absent in healthy, hyperplastic, metaplastic, and dysplastic airway epithelium of the adult lung. In contrast, beta III is highly expressed in small cell lung cancer, large cell neuroendocrine carcinoma, and in some non-small cell lung cancers, particularly adenocarcinomas. There is no correlation between expression of beta III and generic neuroendocrine markers, such as chromogranin A and/or synaptophysin, in pulmonary adenocarcinomas. Also, focal beta III staining is present in primary and metastatic adenocarcinomas (to the lung) originating in the colon, prostate, and ovary. beta III is expressed to a much lesser extent in atypical carcinoids and is rarely detectable in typical carcinoids and squamous cell carcinomas of the lung. The distribution of beta III in small cell lung cancer and adenocarcinoma metastases to regional lymph nodes and brain approaches 100% of tumor cells, which is substantially greater than in the primary tumors. CONCLUSIONS: In the context of neuroendocrine lung tumors, beta III immunoreactivity is a molecular signature of high-grade malignant neoplasms (small cell lung cancer and large cell neuroendocrine carcinoma) although its importance in atypical carcinoids must be evaluated further. In addition, beta III may be a useful diagnostic marker in distinguishing between small cell lung cancers and certain non-small cell lung cancers (poorly differentiated squamous cell carcinomas), especially in small biopsy specimens. To our knowledge, beta III is the only tumor biomarker that exhibits a substantially more widespread distribution in poorly differentiated than in better differentiated pulmonary neuroendocrine tumors. However, the significance of beta III phenotypes in non-small cell lung cancer, particularly adenocarcinoma, with respect to neuroendocrine differentiation and prognostic value, requires further evaluation.

Carcinoid tumors of the lung. An analysis of 65 operated cases.J Cardiovasc Surg (Torino). 1999 Aug;40(4):607-12.

BACKGROUND: The aim of this study was to analyse two groups of patients operated for bronchopulmonary neuroendocrine neoplasms (bronchial carcinoid and well-differentiated neuroendocrine carcinoma) and to investigate their clinico-pathological data and long-term survival. METHODS: From January 1978 to June 1996, 65 patients with bronchial carcinoids underwent operation at our Institution. There were 33 males and 32 females, whose mean age was 49.8 years. Forty-four neoplasms (67.7%) were considered to be central. Histology revealed 54 typical bronchial carcinoids (83%) and 11 well-differentiated neuroendocrine carcinomas (17%). Surgical resection of tumor and complete lymph node dissection was performed in all cases. RESULTS: All patients entered follow-up: 5-year survival was 91% for patients with bronchial carcinoid and 49% for those with well-differentiated neuroendocrine carcinoma (p<0.05). Univariate analysis found that there was a significant decrease in survival also for peripheral location of the tumor, advanced pathologic stage and histologically positive lymph nodes. CONCLUSIONS: These results point out that carcinoid tumors are malignant neoplasms, so they require a complete and radical surgical resection. Most tumors are only locally invasive and show a low aggressive behaviour; therefore, when possible, it is recommended to attempt a limited resection. Frozen sections of bronchial margins and complete lymphadenectomy should be routinely performed. The same criteria should apply to well differentiated neuroendocrine carcinomas, though their behaviour is more aggressive.

Typical and atypical carcinoid tumors of the lung are characterized by 11q deletions as detected by comparative genomic hybridization. Am J Pathol 1998;153:1089–1098.

Neuroendocrine tumors of the lung represent a wide spectrum of phenotypically distinct entities with different biological characteristics such as typical carcinoid tumor (TC), atypical carcinoid tumor (AC), large-cell neuroendocrine carcinoma (LCNEC), and small-cell lung carcinoma (SCLC). The histogenetic relationships between TC, AC, LCNEC, and SCLC are still unclear. This study was carried out to provide cytogenetic data about pulmonary neuroendocrine tumors and to evaluate their characteristic alterations and histogenetic relations for an improved understanding of the mechanisms of tumor development. Twenty-nine paraffin-embedded tumor samples of TC (n = 17), AC (n = 6), LCNEC (n = 3), and SCLC (n = 3) were selected for isolation of tumor DNA and subsequent comparative genomic hybridization (CGH) analysis. To confirm the comparative genomic hybridization results for characteristic chromosomal imbalances, selected cases were additionally investigated by loss of heterozygosity analysis. For statistical evaluation, we also used comparative genomic hybridization data from 45 published SCLC cases. DNA underrepresentations of 11q were the most frequent findings in TC (8 of 17) and AC (4 of 6), whereas these aberrations were rare in LCNEC (1 of 3) and SCLC (0 of 3). Furthermore, AC showed DNA underrepresentation of 10q (3 of 6) and 13q (3 of 6). In contrast, SCLC and LCNEC were characterized by a different pattern of DNA losses (3p-, 4q-, 5q-, 13q-, and 15q-) and gains (5p+, 17p+, and +20). Statistical analysis revealed significantly different occurrences of 11q deletions in TC/AC versus SCLC (45 published cases of SCLC and our 3 cases; P = 0.002; Fisher's exact test). Thus, TC and AC display frequent loss of 11q material including the MEN1 gene locus, which represents a characteristic genetic alteration in these tumors. Losses of 10q and 13q sequences allow a further cytogenetic differentiation between TC and AC. These additional changes might be responsible for the more aggressive behavior of AC. Three cases of LCNEC, the first to be analyzed by comparative genomic hybridization, exhibited similar complex abnormal patterns (4q-, 5q-, 10q-, 13q-, 15q-) to those of SCLC. Although neuroendocrine tumors of the lung share common phenotypic features, suggesting a genotypic relationship, they differ remarkably in their cytogenetic characteristics, highlighting an early fundamental molecular divergence during the development of these tumors.

Analysis of p53, K-ras, and c-raf-1 in pulmonary neuroendocrine tumors: correlation with histological subtype and clinical outcome. Am J Pathol 1996;148:1531–1541.

Neuroendocrine tumors of lung, including typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC) constitute a spectrum of malignancies in which the pathologist at times has difficulty in discerning tumor subtype and aggressiveness in a reproducible fashion. Therefore, 59 primary neuroendocrine lung tumors including 10 TCs, 26 ACs, 15 LCNECs, and 8 SCLCs were selected from cases collected from 1976 to 1988 and immunostained for p53 protein. All of these tumors were also genotyped for specific point mutational damage affecting p53 (exons 5, 7, and 8; with ACs additionally sequenced for p53 exon 6); 13 tumors for K-ras-2 (exon 1); and 31 tumors for c-raf-1 (exon 15) growth-regulatory genes. Genotyping was performed on topographically selected, minute tumor samples removed from unstained formalin-fixed, paraffin-embedded tissue sections (topographic genotyping) using polymerase chain reaction and direct sequencing. The distribution of p53 immunohistochemical staining had four patterns: negative in TCs, one-half of ACs, 3 of 15 LCNECs, and 1 of 8 SCLCs; less than 10% but more than five tumor cells per 10 high power fields (focal) in a subset (7 of 26) of aggressive ACs; 10 to 49% of tumor cells (patchy) in a subset (6 of 26) of ACs with a higher grade of aggressiveness; and 50 to 100% of tumor cells (diffuse), exclusively seen in LCNECs (12 of 15) and SCLCs (7 of 8). Three patterns of immunohistochemical staining intensity of p53 protein were seen: negative, weak or mild, and moderate to marked. SCLCs and LCNECs accounted for cases of moderate to marked staining and were the only ones to have mutations in p53 exons 5, 7, or 8. No mutations were found in AC and TC, showing absent to weak staining and no staining, respectively. The difference in distribution and staining intensities between LCNEC and SCLC compared with AC and TC was statistically significant (P < 0.001). Patients having AC with patchy p53 immunostaining usually had survival limited to 3 years, whereas those having AC with focal p53 immunostaining subsequently developed metastatic or recurrence of AC disease (P < 0.05). The absence of point mutations in cases with patchy or focal immunostaining suggests increased expression of wild-type p53 tumor suppressor protein likely in response to growth deregulation in a more aggressive subtype of AC. A novel hypothesis is presented in regard to these findings. K-ras-2 and c-raf-1 gene sequence analysis showed no evidence of point mutational change in any of the tumors studied. The TC and AC categories are therefore genetically distinct from the higher grade neuroendocrine SCLC and LCNEC. Immunohistochemistry for p53 on AC lung tumors may be helpful to delineate cases at higher risk for aggressive behavior. Additionally, although LCNEC is categorized as a non-small-cell carcinoma, it is more akin genetically and immunohistochemically to SCLC.

Apoptosis-related factors p53, Bcl-2, and Bax in neuroendocrine lung tumors. Am J Pathol 1996;149:1941–1952.

Neuroendocrine (NE) lung tumors comprise four classes of progressive aggressiveness for which proliferation and apoptosis rates could both contribute to their distinctive behavior. As p53 mutations may favor escape from apoptosis through changes in Bcl2-Bax expression balance, which are survival and apoptotic genes, respectively, we studied 121 NE lung tumors (16 typical carcinoids (TC), 5 atypical carcinoids (AC), 29 large-cell NE carcinomas (LCNECs), and 71 small-cell lung carcinomas (SCLCs) using immunohistochemistry. We quantified apoptosis by terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) in 31 of these cases. There was a significant increase of p53 mutant immunophenotype (defined as immunoreactivity with at least two antibodies for at least 20% of tumor cells) between atypical/typical carcinoids group and the LCNEC/SCLC group (P = 0.0003). There was an inverse correlation (P < 0.0001) between the scores of Bax and Bcl2 expression in individual tumors and a significant inversion of the Bcl2. Bax ratio between low-grade (typical and atypical carcinoids) and high-grade (LCNECs and SCLCs) tumors with a predominant Bax expression in the first group and predominant Bcl2 expression in the second. Whereas carcinoids had variable apoptotic indexes, LCNECs had high indexes (1.3 to 6.8%), Bcl2 overexpression, Bax down-regulation, and Bcl2.Bax ratio > 1 correlated with lower apoptotic index in both LCNEC and the pool of LCNECs and SCLCs (P < 0.05) and a lower survival rate in the group of atypical and typical carcinoids and LCNECs (P < 0.002). The highest levels of Bcl2 expression and Bcl2.Bax ratios were associated with p53 mutant immunophenotype (P = 0.02). Our results suggest that aggressiveness in NE lung tumors could be linked, in addition to proliferation, to apoptosis-related factors.

Differential diagnostic patterns of lung neuroendocrine tumours. A clinico-pathological and immunohistochemical study of 122 cases.Virchows Arch A Pathol Anat Histopathol. 1992;420(3):201-11.

A series of 3 tumourlets (TLs), 81 typical carcinoids (TCs), 14 atypical carcinoids (ACs) (well-differentiated neuroendocrine carcinomas, WDNCs) and 24 small cell-intermediate cell carcinomas (SCC-ICCs) of the lung were studied. Histopathological features were correlated with amine and peptide hormone immunoreactivity and with clinical data. All types of tumours expressed general neuroendocrine (NE) markers: Grimelius positivity and chromogranins were detected more frequently in well-differentiated (TLs, TCs) than in less well differentiated tumours [ACs (WDNCs) and SCC-ICCs] whereas neuron specific enolase (NSE) was prominent in the latter tumours. TLs and peripheral TCs were benign, often showing a paraganglioid pattern and frequently expressing gastrin-releasing peptide (GRP), which is present in the peripheral airways of normal lung. Central TCs were associated with lymph node metastases in 8.5% of the cases, frequently had a trabecular architecture, often associated with human milk fat globule 2 (HMFG2)-positive acinar and rosette-like structures, and were mainly immunostained for the alpha-subunit of human chorionic gonadotrophin (alpha-hCG) and serotonin. ACs (WDNCs) were associated with intrathoracic and/or extrathoracic metastases in 57.1% of the cases with a mortality rate of 35.7%. Their histological and cytological features were intermediate between those of TCs and SCC-ICCs. ACs (WDNCs) expressed serotonin and alpha-hCG less frequently than TCs. All SCC-ICCs were surgically treated and displayed a mortality rate of 91.6% with a mean survival of 10.2 months after operation. These tumours were characterized by high expression of HMFG2 and NSE, while the expression of both orthotopic (serotonin, GRP) and ectopic (ACTH) specific NE substances was very low. Since all TCs (either central or peripheral) had a favourable outcome, while about 36% of ACs (WDNCs) were fatal, the latter seem more appropriately designated "well-differentiated NE carcinomas". The differential diagnosis between different NE tumours of the lung is important and is mainly based on morphology. Both panendocrine and specific immunohistochemical markers are helpful in distinguishing the less aggressive, mostly benign varieties from the more malignant varieties.

Bronchial carcinoid tumors: a retrospective analysis of 126 patients. Ann Thorac Surg 1992;54:50–55.

From 1970 until 1990, 8,958 cases of primary carcinoma of the lung were diagnosed at the Duke University Medical Center. During the same period, 126 patients (mean age, 53 +/- 13 years) were diagnosed with bronchial carcinoid. The overall survival was 78% for 5 years and 71% for 10 years. Surgical treatment in 106 patients included pneumonectomy (15), lobectomy (63 with 9 bronchoplastic procedures), stapled wedge resection (22), and bronchoscopic laser resection (6). The method of diagnosis was chest roentgenography (121), chest computed tomography (77), mediastinal tomography (31), bronchoscopy (81), bronchoscopic brushing and washing (50), bronchoscopic biopsy (40), transthoracic needle biopsy (27), thoracotomy (100), and autopsy (5). Univariate analysis of the medical history, presenting signs and symptoms, diagnostic test results, and pathologic data predicted improved survival (p less than 0.001) for: female sex (n = 58), asymptomatic presentation (n = 47), normal serum serotonin or urinary hydroxyindoleacetic acid levels (n = 76), peripheral location of the primary tumor (n = 50), pathologic stage I or II (n = 91), negative lymph nodes (n = 80), primary tumor 2 cm or less in diameter (n = 67), and typical histology (n = 80). No significance (p greater than 0.1) was observed for age, smoking history, race, family history of carcinoid, environmental exposure, or hemoptysis. The most important factors affecting survival defined by multivariate analysis were (p less than 0.01) pathologic stage, atypical histology, and asymptomatic presentation. Bronchial carcinoid tumors are unique, making up 1% to 2% of primary lung neoplasms and having an excellent prognosis after resection with a 95% 5-year and 93% 10-year survival for pathologic stage I disease.

Neuroendocrine neoplasms of the lung. A clinicopathologic update.J Thorac Cardiovasc Surg. 1989 Sep;98(3):321-32.

One hundred forty-six cases of pulmonary neuroendocrine tumors are assessed according to the classification of Gould and associates and are evaluated for their clinical presentation and subsequent clinical course. Bronchial carcinoids are characteristically found to be central tumors often occurring in comparatively young patients; surgical resection with minimal but clear margins is usually curative. The long-term prognosis is excellent in the majority of patients, although rarely regional nodal and distant metastases develop. Well-differentiated neuroendocrine carcinomas are most frequently peripheral tumors. In stage I and II disease, surgical resection alone is curative and patients with locally advanced tumors may have a prolonged disease-free interval. The overall prognosis is less favorable than that of bronchial carcinoids but considerably better than that of small cell neuroendocrine carcinomas, with which they are still at times confused. Intermediate-sized cell neuroendocrine carcinomas are often wrongly categorized as large cell undifferentiated carcinoma. They have a distinctly aggressive clinical course comparable with that of small cell neuroendocrine carcinoma and should be treated similarly. Small cell neuroendocrine carcinomas are aggressive, rapidly disseminating neoplasms. Even in clinical stage I tumors, patients must be considered to have disseminated metastases. The role of surgical therapy in these two latter tumor types is adjuvant to aggressive systemic chemotherapy.

Neuroendocrine neoplasms of the bronchopulmonary tract. A classification of the spectrum of carcinoid to small cell carcinoma and intervening variants.J Thorac Cardiovasc Surg. 1985 Jun;89(6):819-25.

Eighty-one primary pulmonary neuroendocrine neoplasms were assessed by the classification of Gould and associates. The neuroendocrine features of these tumors were studied by a combination of conventional light microscopy, electron microscopy, and immunohistochemical staining for hormonal substances and neuron-specific enolase. In each case, clinical follow-up was obtained to test the prognostic value of this new pathological classification. This study indicated that bronchial carcinoids are very low-grade neuroendocrine neoplasms that are locally invasive and only occasionally metastasize late in their course. Well-differentiated neuroendocrine carcinomas are relatively low-grade carcinomas that either present with or subsequently develop nodal or distant metastases in 73% of patients. Intermediate cell neuroendocrine carcinomas are highly aggressive tumors often mistakenly called "large cell undifferentiated carcinoma." Their clinical course is comparable to that of small cell neuroendocrine carcinomas, which has a mean survival of 9 months. The different clinical courses of these tumors demonstrate the predictive value of the proposed classification. It appears particularly valuable to identify well-differentiated neuroendocrine carcinoma as a low-grade carcinoma, distinct from true bronchial carcinoids. This classification may resolve some discrepancies regarding the therapy for and prognosis of "carcinoids" and their presumed variants.

Carcinomas of the lung with neuroendocrine differentiation.Semin Diagn Pathol. 1985 Nov;2(4):235-54.

While there are examples of each of the histologic types of bronchogenic carcinoma in which ectopic hormone production has been demonstrated, three groups of lung cancers manifest this type of differentiation with great regularity. These are the carcinoid, atypical carcinoid, and the small cell carcinoma, which have been called neuroendocrine carcinomas of the lung. The carcinoids are neoplasms with a heterogeneous array of histologic appearances that share relatively uniform nuclear features, the absence of both tumor necrosis and mitotic figures, and a good prognosis. Neuroendocrine differentiation is demonstrable with such regularity in carcinoids that the diagnosis is not considered tenable in the absence of at least one of the following features: argyrophilia, the demonstration of neuron-specific-enolase or neuropeptides by immunohistochemistry or other techniques, or the demonstration of numerous dense-core membrane-bound granules, usually 150 to 250 nm in diameter, by electron microscopy. The atypical carcinoids (well or moderately differentiated neuroendocrine carcinomas) share the neuroendocrine differentiation of the carcinoids and many of their histologic features, but are distinguished by the presence of tumor necrosis, more anaplastic large cell nuclei with numerous mitotic figures, and a distinctly worse prognosis. They are a heterogeneous lot with some similarities to carcinoids, small cell carcinomas, and large cell or adenocarcinomas. The demonstration of at least one of the neuroendocrine features listed above is considered necessary for this diagnosis. Small cell carcinoma is also a heterogeneous group of neoplasma primarily distinguished by their finely granular chromatin pattern which correlates with a much worse prognosis but a higher likelihood of response to chemotherapy and radiotherapy. Many small cell carcinomas share the neuroendocrine differentiation of the carcinoids or atypical carcinoids, but some do not and the demonstration of these features is not a requisite for inclusion in the small group. The morphologic demonstration of neuroendocrine differentiation may be more difficult in small cell carcinomas, but they more frequently produce clinically important amounts of ectopic neuropeptides. While the term neuroendocrine carcinoma of the lung includes several quite different entities and does not by itself convey histogenetic or prognostic implications, the demonstration of neuroendocrine differentiation in pulmonary neoplasms is an important procedure when combined with the recognition of other cytologic and histologic features.

Immunohistochemical and ultrastructural analysis of bronchopulmonary neuroendocrine neoplasms. II. Well-differentiated neuroendocrine carcinomas.Ultrastruct Pathol. 1984;7(2-3):185-99.

We have attempted to characterize a group of bronchopulmonary neoplasms that share certain structural features with true carcinoids but appear distinctly more pleomorphic and behave far more aggressively. In reviewing our files from 1973 to 1982, 11 such neoplasms were identified; the original diagnoses were "atypical bronchial carcinoid" (3 cases), "malignant carcinoid" (1 case), "bronchial carcinoid" (3 cases), "peripheral carcinoid" (2 cases), and "peripheral oat cell carcinoma" (2 cases). Of the 11 neoplasms, 5 were central and 6 were peripherally located. At presentation, 7 patients had lymph node metastases and 1 had a distant metastasis. No patient had a conventionally defined hormonal syndrome; however, 2 patients had a history of episodic flushing, one of which was associated with diarrhea. All cases were studied by light microscopy and light microscopic immunohistochemistry for NSE (neuron-specific enolase), serotonin, and broad-spectrum neuropeptides. Five cases were studied by electron microscopy. By light microscopy, the tumors were composed of solid clusters of polygonal to fusiform cells in an evident organoid arrangement. Foci of glandular and/or squamous differentiation were seen in 7 cases. Pleomorphism was moderate and mitoses were readily found. Focal necrosis was seen. By immunohistochemistry, 10 cases expressed NSE immunoreactivity. All cases demonstrated hormonal immunoreactivity; in 9 cases, immunoreactivity for more than one hormone was observed. The hormones most frequently expressed were serotonin, bombesin, gastrin, leu-enkephalin, and ACTH. By electron microscopy, all cases studied contained heterogeneous populations of neurosecretory granules; the latter, however, were not abundant and tended to aggregate either in the basal pole of the cells or, more frequently, interlacing "dendritelike" cytoplasmic processes. Aggregates of intermediate filaments were frequently seen. Basal lamina deposition was seen but gaps and larger areas of discontinuity were frequent. We believe that these neoplasms constitute a distinct pathologic entity for which the term "well-differentiated neuroendocrine carcinoma" has been proposed. Clinically, these tumors merit special attention since they are demonstrably more aggressive than true carcinoids but are distinctly less malignant than the intermediate or small cell variants of neuroendocrine carcinoma.

Amine and peptide hormone production by lung carcinoid: a clinicopathological and immunocytochemical study.J Clin Pathol. 1984 Aug;37(8):931-6.

A consecutive series of 38 lung carcinoid tumours (36 surgical and two necropsy specimens) was studied. Histopathological features and amine and peptide hormone immunoreactivity were correlated with gross characteristics (size, location) and clinical data. Peripheral carcinoids were detected a decade later than central carcinoids and tended to be bigger. In general, the histological characteristics of peripheral and central carcinoids were similar; atypical features, however, were more common in peripheral carcinoids. Most carcinoids contained many argyrophilic cells (58%). Although argentaffinic cells were not found, serotonin immunoreactive cells were present in 32% of the tumours. Peptide hormone immunoreactivity (adrenocorticotrophic hormone (ACTH), calcitonin, somatostatin, gastrin) was rare. In one case massive ACTH production had caused clinically manifest Cushing's syndrome. In two other cases few ACTH immunoreactive cells were found and in one case calcitonin immunoreactive cells were present. The relative rarity of hormone production in lung carcinoids and the predominantly benign course of the tumour preclude the use of peptide hormone production as a prognostic indicator.