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The classification of neuroendocrine tumors of the lung is evolving and complex. For a long time, most pathologists recognized two variant, a carcinoid tumor and small cell carcinoma. As diagnostic procedures become more precise, many new variants appeared. The presentation of these tumors range from an incidental finding on chest x-ray to an aggressive tumor, complete with a paraneoplastic syndromes. In many cases, the clinical behavior may be unpredictable and await further stratification by pathologists who are applying increasingly sophisticated diagnostic tests to these tumors.


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Carcinoid tumorlet
Peripheral adenomas
Atypical hyperplasia of bronchiolar epithelium
Minute peripheral pulmonary tumors
Microscopic oat cell carcinomas
Pulmonary tumorlets
Carcinoid tumor
Carcinoid tumor
Atypical carcinoid tumor
Atypical carcinoid tumor
Small cell carcinoma
Oat cell carcinoma
Carcinoid tumorlet
May be found in up to 2% of autposy and surgical resection specimens
Carcinoid and atypical carcinoid tumor
1-2% of all lung tumors
May occur in childhood and are most common lung tumor of childhood
Small cell carcinoma
20-25% of all lung cancers
34,000 new cases/year in USA
Carcinoid tumorlet
Carcinoid and atypical carcinoid tumor
Mean 55 years
Small cell carcinoma
Mean 60 years
Range (32-79 years)
Large cell neuroendocrine carcinoma (LCNEC)
Median 64 years
Range (35-75 years)
Carcinoid tumorlet
Carcinoid and atypical carcinoid tumor
Small cell carcinoma
2:1 (Greatly increasing in women)
Large cell neuroendocrine carcinoma (LCNEC)


Carcinoid tumorlet Bronchiectasis, interstitial fibrosis, chronic abscesses
Small cell carcinoma Strong association with smoking
MEN type I  


Small cell lung carcinoma and carcinoid tumor cell lines regulate dendritic cell maturation and function

Mod Pathol 2001;14:40-45

Dendritic cell markers CD1a and CD83 were analyzed on tumor cell lines indicating the tumors produce factors that inhibit dendritic cell generation or maturation and may also induce apoptotic cell death of dendritic cell precursors in vitro

Malignancy-associated X chromosome allelic losses in foregut endocrine neoplasms: further evidence from lung tumors.

D'Adda T, Bottarelli L, Azzoni C, Pizzi S, Bongiovanni M, Papotti M, Pelosi G, Maisonneuve P, Antonetti T, Rindi G, Bordi C.

1Department of Pathology and Laboratory Medicine, Section of Pathological Anatomy, University of Parma, Parma, Italy.

Mod Pathol. 2005 Jun;18(6):795-805. Abstract quote  

Association of X chromosome allelic losses with tumor malignancy has been identified in foregut but not in midgut endocrine neoplasms.

The aim of this study was to investigate the association of deletions on X chromosome with malignancy in lung neuroendocrine tumors, another family of foregut neoplasms comprising four categories with increased malignancy: typical and atypical carcinoids, large cell neuroendocrine and small cell lung carcinomas.

To evaluate loss of heterozygosity, DNA extracted from nine typical carcinoids, 17 atypical carcinoids, six large cell neuroendocrine carcinomas and five small cell lung carcinomas was PCR-amplified for 18 microsatellite markers spanning the whole X chromosome. All tissue samples were formalin-fixed and paraffin-embedded. X chromosome losses were absent in typical carcinoids, whereas they were found in nine out of 17 atypical carcinoids and in five out of six large cell neuroendocrine carcinomas (involving 28 and 70% of informative loci, respectively). On the contrary, deletions on X chromosome were an extremely rare event in small cell lung carcinomas. In atypical carcinoids, the presence of losses was associated with larger tumor size, higher pT status and advanced stage. No death occurred in atypical carcinoid patients without deletions on X chromosome, whereas all atypical carcinoid patients who had died from disease showed allelic losses.

In conclusion, X chromosome allelic losses, absent in benign 'typical' carcinoids, progressively increased in frequency from intermediate-grade 'atypical' carcinoids to high-grade large cell neuroendocrine carcinomas. These results extend the association of deletions on X chromosome with malignancy, already demonstrated in other foregut endocrine neoplasms, to lung neuroendocrine tumors. The absence of X chromosome allelic losses in small cell lung carcinomas underlines a striking difference from large cell neuroendocrine carcinomas, possibly linked to different pathogenetic mechanisms of these two highly aggressive neuroendocrine lung tumors.

Chromosomal aberrations in a series of large-cell neuroendocrine carcinomas: Unexpected divergence from small-cell carcinoma of the lung

Reinhard Ullmann, PhD
Susanna Petzmann, MS
Anu Sharma, MD
Philip Theo Cagle, MD
Helmut Hans Popper, MD

Hum Pathol 2001;32:1059-1063. Abstract quote

Large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC) are high-grade neuroendocrine tumors of the lung. Despite different morphologic appearances, loss of heterozygosity and oncogene studies on LCNEC to date suggest genetic similarities.

We analyzed 13 LCNEC and 5 mixed SCLC/LCNEC tumors by comparative genomic hybridization and subsequently compared our results with previously published data on 32 SCLCs. Comparison with SCLC showed several shared chromosomal aberrations, specifically losses of 3p, 4q, 5q, and 13q and gains of 5p. However, these aberrations are no special feature of neuroendocrine lung tumors but can also be found in other high-grade lung carcinomas.

From this point of view, genetic similarities of LCNEC and SCLC are less important than the nonrandom changes that differ between these 2 tumor types. A gain of 3q observed in 66% of all SCLCs was detected only once in the LCNEC group. In contrast to the pure LCNEC, all mixed types with a SCLC component had a gain of 3q. Gains of 6p occurred more frequently in LCNEC. Deletions of 10q, 16q, and 17p were less frequent in LCNEC than in SCLC.



Expression of Cell Adhesion Molecules, CD44s and E-Cadherin, and Microvessel Density in Carcinoid Tumors

Xiaoping Sun, M.D., Ph.D., Yun Gong, M.D., Mark S. Talamonti, M.D. and M. Sambasiva Rao, M.D.

Department of Pathology (XS, YG, MSR) and Surgery (MST), Northwestern University Medical School, Chicago, Illinois


Modern Pathology 2002;15:1333-1338 Abstract quote

Although all carcinoids are potentially malignant, their biologic behavior is quite variable. Currently there are no reliable morphological criteria to predict metastatic potential. Cell adhesion molecules, such as CD44 and E-cadherin, are considered important in regulating invasion and metastasis of tumors. Also, angiogenesis has been shown to be associated with tumor growth and progression.

In this study, we examined 51 carcinoids, including 13 carcinoids with known lymph node and/or visceral metastasis, for expression of CD44s (the standard form of CD44) and E-cadherin by immunohistochemistry. We found that 55% and 37% of carcinoids were negative for CD44s and E-cadherin, respectively. Carcinoids with lymph node and/or visceral metastasis were significantly more frequently negative for CD44s than were those without demonstrated metastasis (P = .030). Ten of 11 tumors with lymph node metastasis lacked CD44s (P = .022), whereas E-cadherin was negative in only 3 (P = .975). Additionally, we analyzed microvessel density to evaluate the role of tumor angiogenesis in the tumor behavior.

Carcinoid tumors in general demonstrated high microvessel density (160 ± 82/five 200x fields), irrespective of location and with and without metastasis. These results suggest that loss of CD44s, but not E-cadherin, may be a useful predictor of metastatic potential of carcinoid tumors.

Forkhead box A2 transcription factor is expressed in all types of neuroendocrine lung tumors.

Khoor A, Stahlman MT, Johnson JM, Olson SJ, Whitsett JA.
Hum Pathol. 2004 May;35(5):560-4. Abstract quote  

Forkhead box A2 (Foxa2) is a winged helix nuclear transcription protein that regulates the expression of genes that are critical to lung morphogenesis, differentiation, and function, including thyroid transcription factor-1, surfactant proteins, and Clara cell secretory protein.

We examined the immunoreactivity of Foxa2 in paraffin sections of 75 lung tumors: 17 typical carcinoids, 2 atypical carcinoids, 4 large cell neuroendocrine (NE) carcinomas, 23 small cell carcinomas, 19 adenocarcinomas, 7 squamous cell carcinomas, and 3 (non-NE) large cell carcinomas, using a polyclonal rabbit Foxa2 antibody and a biotin-streptavidin detection system. In the adjacent lung, Foxa2 was detected in normal and hyperplastic type II cells. Foxa2 immunoreactivity was detected in 13 typical carcinoids (76%), 2 atypical carcinoids (100%), 2 large cell NE carcinomas (50%), 11 small cell carcinomas (48%), and 1 adenocarcinoma (5%). Squamous cell carcinomas and (non-NE) large cell carcinomas uniformly lacked Foxa2 staining.

Expression of Foxa2 in the entire spectrum of NE lung tumors is another indication of differentiation shared by typical carcinoid, atypical carcinoid, large cell NE carcinoma, and small cell carcinoma.

hASH1 expression is closely correlated with endocrine phenotype and differentiation extent in pulmonary neuroendocrine tumors.

Jiang SX, Kameya T, Asamura H, Umezawa A, Sato Y, Shinada J, Kawakubo Y, Igarashi T, Nagai K, Okayasu I.

Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
Mod Pathol. 2004 Feb;17(2):222-9 Abstract quote.  

The human homolog 1 of the Drosophila neurogenic achaete-scute genes, hASH1, is specifically expressed in fetal pulmonary neuroendocrine cells and in some neuroendocrine tumor cell lines.

However, no data have been gathered regarding its in vivo expression in tumors. hASH1 mRNA expression was investigated by in situ hybridization in 238 surgically resected lung carcinomas, and the correlations between hASH1 expression status and immunostaining results of neuroendocrine markers chromogranin A, neural cell adhesion molecule, gastrin-releasing peptide and calcitonin, and clinical outcome were analyzed. hASH1 expression was detected in 2/20 (10%) adenocarcinomas, 4/30 (13.3%) typical carcinoids, 11/13 (84.6%) atypical carcinoids, 38/67 (56.7%) large-cell neuroendocrine carcinomas and 56/78 (71.8%) small-cell carcinomas, respectively, but not in any squamous cell carcinoma (0/21) or large-cell carcinoma (0/9). The 2 hASH1+ adenocarcinomas also expressed multiple neuroendocrine markers.

Thus, hASH1 expression was restricted to lung cancers with neuroendocrine phenotypes. However, not all neuroendocrine tumors expressed hASH1. Within the entities of large-cell neuroendocrine carcinoma and small-cell carcinoma, hASH1 expression correlated very closely with chromogranin A, gastrin-releasing peptide and calcitonin expression (P<0.0001, r=0.852), but was not related to neural cell adhesion molecule expression (P=0.8892), suggesting that hASH1 expression, at least in lung cancer, is associated with endocrine phenotype expression other than 'neuroendocrine differentiation' in a broad sense.

The fact that hASH1 was virtually absent in almost fully differentiated typical carcinoids, but was expressed in most, if not all, less differentiated atypical carcinoids as well as large-cell neuroendocrine carcinomas and small-cell carcinomas, suggests that hASH1 expression in lung cancer imitates its early and transient expression in fetal development, and that hASH1 is instrumental in the establishment, but not in the maintenance, of a cellular endocrine phenotype. Finally, hASH1 expression correlated with a significantly shortened survival in small-cell carcinoma patients (P=0.041).

Small-cell neuroendocrine carcinoma displays unique profiles of tumor-suppressor gene loss in relationship to the primary site of formation.

Dacic S, Finkelstein SD, Baksh FK, Swalsky PA, Barnes LE, Yousem SA.

Department of Pathology, Division of Anatomic Pathology, University of Pittsburgh Medical Center, Presbyterian University Hospital, Pittsburgh, PA.

Hum Pathol 2002 Sep;33(9):927-32 Abstract quote

Small-cell neuroendocrine carcinoma (SCNC) is a well characterized malignancy with distinctive cellular morphology and aggressive biologic behavior most frequently encountered in the lung but also noted for origin from other sites. The basis for this difference in incidence and the impact of primary site location on the molecular pathogenesis of the neoplasm is not well understood.

To address this issue and to identify reliable molecular markers of potential diagnostic value for primary site localization of this tumor, we have compared the genetic profile of cancer-related gene damage of SCNC arising from a variety of organ sites. The analysis involved microdissected paraffin-embedded formalin fixed specimens of SCNC. Tumors were organized into 3 groups: lung (n = 18), head and neck region (n = 5), and gastrointestinal tract (n = 5). Genotyping evaluated allelic imbalance (loss of heterozygosity) involving genomic regions containing p53 (17p13), L-myc (1p34), OGG1 (3p26), MCC/APC (5q21), p16 (9p21), PTEN (10q23), and point mutational change in K-ras-2 (12p12) using polymerase chain reaction-based microsatellite analysis and DNA sequencing. Distinct genotypic profiles of allelic imbalance using this panel was seen for each group of SCNC enabling primary site determination to be suggested based on genotypic profiling of microdissected tissue samples.

Despite similarity in histologic appearance, our study suggests that SCNC have a unique pattern of acquired allelic damage that is determined in part by primary site of tumor development. These attributes can be effectively used for primary localization of metastatic SCNC, thereby assisting in the diagnosis and classification of this neoplasm.

p16/Cyclin D1/Rb PATHWAY  

The P16/cyclin D1/Rb pathway in neuroendocrine tumors of the lung.

Beasley MB, Lantuejoul S, Abbondanzo S, Chu WS, Hasleton PS, Travis WD, Brambilla E.

Department of Pathology, Tulane University, New Orleans, LA, USA.


Hum Pathol 2003 Feb;34(2):136-42 Abstract quote

Rb protein in its hypophosphorylated form acts as a cell cycle regulator for G1 arrest. Both cyclin D1 overexpression and P16(INK4) loss of protein produce persistent hyperphosphorylation of Rb with resultant evasion of cell cycle arrest.

To better establish the mechanisms of loss of Rb function in neuroendocrine lung tumors, we performed an immunohistochemical analysis of the P16(INK4)/cyclin D1/Rb pathway in the spectrum of neuroendocrine tumors, including 34 typical carcinoids (TCs), 25 atypical carcinoids (ACs), 42 large cell neuroendocrine carcinomas (LCNECs), and 79 small cell lung carcinomas (SCLCs). Absence of Rb expression was not observed in TCs but was seen in 21% of ACs, 68% of LCNECs, and 87% of SCLCs. P16 was expressed in 91% of TCs, 77% of ACs, 78% of LCNECs, and 93% of SCLCs. Cyclin D1 was overexpressed in 6% of TCs, 20% of ACs, 9.5% of LCNECs, and 1.3% of SCLCs. There was an inverse relationship between Rb and P16 in high-grade tumors (P < 0.001) and a direct relationship between cyclin D1 and Rb (P < 0.001) in all tumors, demonstrating that P16 and cyclin D1 act exclusively on the Rb pathway for cell cycle regulation. Overall, the Rb pathway (Rb/P16(INK4)/cyclin D1) was altered more frequently in ACs than in TCs (P = 0.001) and more frequently in LCNECs than in ACs (P = 0.001). Although Rb-negative tumors had shorter survival in the overall group (P < 0.001) as a result of lack of Rb in most SCLCs, cyclin D1 overexpression and P16 loss did not influence survival in any individual category.

We conclude that Rb pathway of G1 arrest is consistently compromised in high-grade neuroendocrine lung tumors (92%), primarily through loss of Rb protein, and is intact in low-grade TCs. In ACs an intermediate level of alterations (59%) is seen, consistent with their less-aggressive behavior compared with high-grade tumors. The specific profile of the Rb pathway parameters might provide specific therapeutic targets in neuroendocrine lung tumors.


Paraneoplastic syndromes

May occur with carcinoid and other neuroendocrine tumors-has not been reported in LCNEC

Cushing syndrome
Carcinoid syndrome


The potential role of flow cytometry in the diagnosis of small cell carcinoma.

Cornfield D, Liu Z, Gorczyca W, Weisberger J.

Section of Hematopathology, Health Network Laboratories/Lehigh Valley Hospital, Allentown, Pa 18103, USA

Arch Pathol Lab Med 2003 Apr;127(4):461-4 Abstract quote

CONTEXT: Virtually no information exists in the medical literature on the immunophenotyping of small cell carcinoma by flow cytometry. CD56, or neural cell adhesion molecule, is widely expressed by small cell carcinoma and easily measured by flow cytometry.

OBJECTIVE: To determine the potential usefulness of flow cytometry in the diagnosis of small cell carcinoma.

DESIGN AND SETTING: Retrospective data and archival material on 27 patients were obtained from community hospitals. Specimens (needle aspirations and tissue biopsies) from all patients demonstrated cytomorphologic and flow cytometric features consistent with small cell carcinoma. All measurements were performed at a large reference laboratory. Routine 3- and 4-color flow cytometry using a lymphoma antibody panel, including anti-CD56, was performed. Anti-cytokeratin antibody was also used in the last 12 cases. Immunohistochemical staining with a panel of conventional markers for neuroendocrine neoplasms was performed on available tissue for purposes of confirmation of small cell carcinoma.

PATIENTS: Twenty-seven patients whose tissue specimens showed a clearly defined population of CD45-CD56+ cells by flow cytometry and cytomorphologic features consistent with small cell carcinoma.

INTERVENTIONS: Needle aspiration (n = 3) and tissue biopsy (n = 24) from a variety of sites.

RESULTS: CD56 positivity by flow cytometry was 100 to 1000 times that of the matched isotype control in 25 cases and 10 to 100 times that of the control in 2 cases. Cytokeratin positivity by flow cytometry was found in 12 of 12 cases. Immunohistochemical staining showed positivity for at least 1 cytokeratin and 1 or more neuroendocrine markers in 26 of 27 cases and confirmed the diagnosis of small cell carcinoma.

CONCLUSIONS: Routine flow cytometry can identify a neuroendocrine phenotype that shows a strong correlation with confirmatory immunohistochemical markers in cases exhibiting cytomorphologic features of small cell carcinoma. Flow cytometry appears to complement and may possibly be a satisfactory alternative to immunohistochemical staining when small cell carcinoma is suspected.


Carcinoid tumorlet Defined as <0.5 cm
Usually incidental fidning
May be 3-4mm gray nodules
Usually periphery of the lung
Carcinoid tumor

Usually indolent but may present with hemoptysis, obstructive pneumonitis, or dyspnea

Divided into central and peripheral types

60-84% of carcinoids
Mean diameter 3.1 cm
Large endobronchial component with fleshy smooth polypoid mass protruding into bronchial lumen
16-40% of carcinoids
Mean diameter of 2.4 cm
Subpleural parenchyma usually unassociated with a bronchus
Atypical carcinoid tumor Carcinoid appearance with necrosis or hemorrhage
Mean diameter of 3.6 cm
Small cell carcinoma

Rapidly growing tumor and widespread mets common
Symptomatic early with coughing, chest pain, hemoptysis

May present with superior vena cava syndrome, recurrent laryngeal nerve paralysis, paraneoplastic syndrome, and dysphagia

70% present as hilar mass with extensive necrosis
5% present as peripheral coin lesion

Large cell neuroendocrine carcinoma (LCNEC) All sites within the lung
Average 3 cm
Necrosis and hemorrhage may be extensive



Small Cell Lung Carcinoma (SCLC): A Clinicopathologic Study of 100 Cases With Surgical Specimens.

Nicholson SA, Beasley MB, Brambilla E, Hasleton PS, Colby TV, Sheppard MN, Falk R, Travis WD.

Am J Surg Pathol 2002 Sep;26(9):1184-97 Abstract quote

Separation of small cell lung carcinoma (SCLC) from nonsmall cell lung carcinoma (NSCLC) is a critical distinction to be made in the diagnosis of lung cancer. However, the diagnosis of SCLC is most commonly made on small biopsies and cytologic specimens, and practicing pathologists may not be familiar with all its morphologic guises and frequent combination with NSCLC elements, which may be seen in larger specimens.

Following the most recent WHO classification of lung tumors and with the hope of identifying prognostic markers, we examined in detail the histology of 100 surgical biopsies or resections with a diagnosis of SCLC from the AFIP and pathology panel of the International Association for the Study of Lung Cancer (IASLC). Multiple clinical and histologic features were studied by Kaplan-Meier analysis. Neuroendocrine architectural patterns, including nested and trabecular growth, with peripheral palisading and rosette formation were common in SCLC. Necrosis and apoptotic debris was prominent in all cases, but crush artifact was infrequent. Cell size in surgical biopsy specimens appears larger than in bronchoscopic biopsy specimens and occasional cells may show prominent nucleoli and vesicular nuclear chromatin, but this does not preclude the diagnosis of SCLC. A high percentage of cases (28%) showed combinations with NSCLC, with large cell carcinoma the most common, followed by adenocarcinoma and squamous cell carcinoma.

Because of the frequency of a few scattered large cells in SCLC, we arbitrarily recommend that at least 10% of the tumor show large cell carcinoma before subclassification as combined SC/LC. However, combined SCLC is easily recognized if the additional component consists of other NSCLC subtypes such as adenocarcinoma or squamous cell carcinoma, so no percentage requirement is needed. Stage remained the only predictor of prognosis.

Carcinoid tumorlet Neuroendocrine cells resembling carcinoid tumor, usually in fibrotic stroma
Carcinoid tumor-Typical

Growth patterns of organoid, trabecular, insular, palisading, ribbon, or rosette-like suggesting neuroendocrine differentiation

Cells have uniform cytologic features with moderate eosinophilic, finely granular cytoplasm, and nuclei with a finely granular chromatin pattern

Nucleoli may be present but usually rare

Mitoses <2/10 hpf and lacking necrosis
May show slight cytologic atypia, increased cellularity, and lymphatic invasion

Carcinoid tumor-Atypical

Carcinoid tumor with 2-10 mitoses/10 hpf and/or foci of necrosis

May have cytologic atypia, lymphatic invasion, nucleoli, increased cellularity, and disorganized architecture

Ki-67 Immunoreactivity in the Differential Diagnosis of Pulmonary Neuroendocrine Neoplasms in Specimens With Extensive Crush Artifact

Deniz L. Aslan, MD, H. Evin Gulbahce, MD, Stefan E. Pambuccian, MD, J. Carlos Manivel, MD, and Jose Jessurun, MD
Am J Clin Pathol 2005;123:874-878 Abstract quote

The aim of the present study was to evaluate the usefulness of immunohistochemical markers in the differential diagnosis of pulmonary neuroendocrine tumors with particular emphasis on the preservation of immunoreactivity in areas showing crush artifacts.

Specimens from 9 carcinoid tumors (CTs) and 13 small cell carcinomas (SCCs) with crush artifact were stained with antibodies to Ki-67, chromogranin A, synaptophysin, and cytokeratin. The immunoreactivity was well preserved in the crushed areas. Ki-67 was expressed in the crushed areas of all SCCs. Reactivity was diffuse or at least present in 25% of the crushed areas. In contrast, the immunoreactive areas in CTs never exceeded 10%. Immunoreactivity for Ki-67, synaptophysin, chromogranin A, and cytokeratin is well preserved in tissue with crush artifacts and can be interpreted reliably.

The diagnosis of SCC should be questioned if fewer than 25% of cells show reactivity for Ki-67.
Distinguishing carcinoid tumor from small cell carcinoma of the lung: correlating cytologic features and performance in the College of American Pathologists Non-Gynecologic Cytology Program.

Renshaw AA, Haja J, Lozano RL, Wilbur DC; Cytology Committee, College of American Pathologists.

Department of Pathology, Baptist Hospital of Miami, Miami, Fla, USA.

Arch Pathol Lab Med. 2005 May;129(5):614-8. Abstract quote  

CONTEXT: The cytologic features of carcinoid tumor of the lung are well described. Nevertheless, some carcinoids may be difficult to distinguish from small cell carcinomas.

OBJECTIVE: To correlate the cytologic features of individual cases of carcinoid tumor of the lung in fine-needle aspiration specimens in the College of American Pathologists Non-Gynecologic Cytology Program with the frequency of misclassification as small cell carcinoma.

DESIGN: We reviewed 1100 interpretations from 26 different cases of carcinoid tumor in lung fine-needle aspiration specimens in the College of American Pathologists Non-Gynecologic Cytology Program and correlated the cytologic features with the performance in the program.

RESULTS: Cases were divided into those that were frequently misclassified as small cell carcinoma (at least 20% of the responses, 19 cases) and those that were infrequently misclassified as small cell carcinoma (<10% of all responses, 7 cases). All cases had areas with classic features of carcinoid tumor. Cases were reviewed independently by 3 cytopathologists specifically looking for cytologic features that might be responsible for misclassification as small cell carcinoma. All 7 cases that were infrequently misclassified consisted of numerous monotonous well-preserved tumor cells that were either entirely round or were a mixture of round and spindle-shaped cells. Six of 7 cases showed a prominent streaming vascular pattern with tumor cells attached to the endothelial cell core. In contrast, cases that were frequently misclassified had 1 of 6 patterns that were not seen in cases that were rarely misclassified. These 6 patterns were: (1) poorly preserved and pale-staining cells with fine chromatin and a suggestion of molding (5 cases); (2) numerous large, well-preserved, spindle-shaped cells (2 cases); (3) numerous cells varying markedly in both size and shape (both round and spindle-shaped cells), with a common finding of degenerated, smudgy, small round and spindle-shaped cells (9 cases); (4) hypocellular specimens (8 cases); (5) obscuration of cells by blood (2 cases); and (6) tumor cells present predominantly in groups, with few isolated cells (8 cases). In none of these cases were mitoses or true necrosis identified.

CONCLUSIONS: Frequent misclassification of carcinoid tumor as small cell carcinoma in lung fine-needle aspiration specimens in this program correlates strongly with specific cytologic features, some of which are common in small cell carcinoma (fine chromatin, molding, smudgy chromatin) and others that are not (spindle-shaped cells). In addition, hypocellular specimens or specimens with cellular obscuration performed poorly, along with specimens exhibiting absence of the commonly described carcinoid feature of streaming vascularity. Awareness of these patterns may aid in avoiding misdiagnosis.
Distinguishing small cell carcinoma from non-small cell carcinoma of the lung: correlating cytologic features and performance in the College of American Pathologists Non-Gynecologic Cytology Program.

Renshaw AA, Voytek TM, Haja J, Wilbur DC; Cytology Committee, College of American Pathologists.

Department of Pathology, Baptist Hospital of Miami, Miami, Fla, USA.

Arch Pathol Lab Med. 2005 May;129(5):619-23. Abstract quote  

CONTEXT: The cytologic features of small cell carcinoma of the lung are well described. Nevertheless, some small cell carcinomas may be difficult to reproducibly distinguish from non-small cell carcinomas, and this distinction carries significant clinical importance.

OBJECTIVE: To correlate the cytologic features of individual cases of small cell carcinoma of the lung in fine-needle aspiration specimens from the College of American Pathologists Non-Gynecologic Peer Comparison Cytology Program with the frequency of misclassification as non- small cell carcinoma.

DESIGN: We reviewed 1185 interpretations of 23 different cases of small cell carcinoma in lung fine-needle aspiration specimens and correlated the cytologic features noted in these cases with performance in the program.

RESULTS: Cases were divided into those that were frequently misclassified as non-small cell carcinoma (at least 10% of the responses, 11 cases) and those that were infrequently misclassified as non-small cell carcinoma (<5% of all responses, 12 cases). All cases had areas on the slides with classic features of small cell carcinoma. However, 10 of 11 cases that were frequently misclassified as non-small cell carcinoma had cells with either increased cytoplasm (4 cases), cytoplasmic globules (so-called paranuclear blue bodies) (3 cases), or apparent intracytoplasmic lumina (3 cases). These features were not identified in cases that were infrequently misclassified (P = .005). In addition, cases more frequently misclassified as non-small cell carcinoma tended to show better overall cellular and group preservation.

CONCLUSIONS: Frequent misclassification of small cell carcinoma as non-small cell carcinoma in lung fine-needle aspiration specimens in this program correlates strongly with the presence of cytoplasmic features that may suggest non-small cell carcinoma or with the presence of paranuclear blue bodies. Misclassification in this program may reflect a variety of factors, including the variation in the cytologic features of individual cases, but also the lack of wide recognition that some features of non-small cell carcinoma may also be noted in well-preserved cases of small cell carcinoma.
Typical and Atypical Pulmonary Carcinoid Tumor Overdiagnosed as Small-Cell Carcinoma on Biopsy Specimens: A Major Pitfall in the Management of Lung Cancer Patients.

Pelosi G, Rodriguez J, Viale G, Rosai J.

From the *Division of Pathology and Laboratory Medicine, European Institute of Oncology and University of Milan School of Medicine; and daggerDepartment of Pathology, National Cancer Institute, Milan, Italy.

Am J Surg Pathol. 2005 Feb;29(2):179-187. Abstract quote  

Seven patients with typical or atypical pulmonary carcinoid tumors overdiagnosed as small-cell carcinoma on bronchoscopic biopsies are described. Bronchial biopsies from 9 consecutive small-cell lung carcinoma patients were used as control group for histologic and immunohistochemical studies (cytokeratins, chromogranin A, synaptophysin, Ki-67 [MIB-1], and TTF-1).

The carcinoid tumors presented as either central or peripheral lesions composed of tumor cells with granular, sometimes coarse chromatin pattern, high levels of chromogranin A/synaptophysin immunoreactivity, and low (<20%) Ki-67 (MIB-1) labeling index. The tumor stroma contained thin-walled blood vessels. Small-cell carcinomas always showed central tumor location, finely dispersed nuclear chromatin, lower levels of chromogranin A/synaptophysin, and high (>50%) Ki-67 (MIB-1) labeling index. The stroma contained thick-walled blood vessels with glomeruloid configuration. Judging from this study, overdiagnosis of carcinoid tumor as small-cell carcinoma in small crushed bronchial biopsies remains a significant potential problem in a worldwide sample of hospital settings.

Careful evaluation of hematoxylin and eosin sections remains the most important tool for the differential diagnosis, with evaluation of tumor cell proliferation by Ki-67 (MIB-1) labeling index emerging from our review as the most useful ancillary technique for the distinction.

Malignant epithelial tumor consisting of small cells with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin, and absent or inconspicuous nucleoli

Cells are usually <3x size of resting lymphocytes

Round, oval and spindle-shaped cells with prominent nuclear molding

High mitotic count


Bronchial Carcinoid Tumor With Crystalloid Cytoplasmic Inclusions

Karen L. Grogg, MD, Chandrashekar Padmalatha, MD, and Kevin O. Leslie, MD

From the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minn (Dr Grogg); the Department of Pathology, Memorial Hospital of Carbondale, Ill (Dr Padmalatha); and the Department of Pathology, Mayo Clinic Scottsdale, Scottsdale, Ariz (Dr Leslie).

Arch Pathol Lab Med 2002;Vol. 126, No. 1, pp. 93–96. Abstract quote

We report a bronchial carcinoid tumor with distinctive, cytoplasmic, rod-shaped crystalloid inclusions that were visible by light microscopy. These cytoplasmic structures were immunoreactive with antibodies against chromogranin A and synaptophysin in paraffin-embedded tissue.

Ultrastructural studies showed them to be paracrystalline in nature and located within lysosomes.

This case highlights an interesting, and potentially confusing, histologic manifestation in an otherwise typical bronchial carcinoid tumor.


Features of organoid nesting, trabecular, rosette-like and palisading patterns that suggest neuroendocrine differentiation-this is confirmed by immunohistochemistry or electron microscopy

Usually high mitotic counts >10/10 hpf

Immunohistochemical Differential Diagnosis Between Large Cell Neuroendocrine Carcinoma and Small Cell Carcinoma by Tissue Microarray Analysis With a Large Antibody Panel

Jun-ichi Nitadori, MD, etal.
Am J Clin Pathol 2006;125:682-692 Abstract quote

To elucidate additional phenotypic differences between large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), we performed tissue microarray (TMA) analysis of surgically resected LCNEC and SCLC specimens.

Immunostaining with 48 antibodies was scored based on staining intensity and the percentage of cells that stained positively. Four proteins were identified as significantly expressed in LCNEC as compared with SCLC: cytokeratin (CK)7, 113 vs 49 (P < .0301); CK18, 171 vs 60 (P < .0008); E-cadherin, 77 vs 9 (P < .0073); and b-catenin, 191 vs 120 (P < .0286). Immunostaining of cross-sections containing LCNEC and SCLC components revealed significant expression of CK7, CK18, and b-catenin in the LCNEC component compared with the SCLC component in 2 of 3 cases.

Our results indicate that significant expression of CK7, CK18, E-cadherin, and b-catenin is more characteristic of LCNEC than of SCLC, and these findings provide further support that these tumor types are separate entities morphologically and immunophenotypically, if not biologically.

Morphometry Confirms the Presence of Considerable Nuclear Size Overlap Between "Small Cells" and "Large Cells" in High-Grade Pulmonary Neuroendocrine Neoplasms

Alberto M. Marchevsky, MD
Anthony A. Gal, MD
Swati Shah, MD
Michael N. Koss, MD

Am J Clin Pathol 2001;116:466-472 Abstract quote

We morphometrically evaluated 5-µm H&E-stained sections from 28 surgically resected high-grade pulmonary neuroendocrine neoplasms, including 16 small cell lung carcinomas (SCLCs) and 12 large cell neuroendocrine carcinomas (LCNECs).

For each case, 200 tumor nuclei and 20 to 100 normal lymphocytes were measured. The frequency distributions of tumor cell/lymphocyte (TC/L) size ratios were plotted in bins ranging from 1 to 6, classified into 6 histogram types with TC/L size ratio peaks ranging from 2 to 6 (A-E) and a histogram with a wide distribution (F). SCLCs fit histograms A through E; LCNECs, A through F. Morphometry demonstrated considerable nuclear size overlap in high-grade neoplasms. Approximately one third of SCLCs exhibited considerable numbers of neoplastic cells that were larger than 3 normal lymphocytes, while 4 of 12 LCNECs had a predominant number of small cells. Ten tumors exhibited a B histogram with a "borderline" peak TC/L of 3. The rule that a TC/L size ratio larger than 3 helps distinguish "large" from "small" neoplastic cells was confirmed in only 9 of 28 cases.

The use of more generic terminology such as "high-grade neuroendocrine carcinoma" or "grade III neuroendocrine carcinoma" for SCLC and LCNEC is discussed.

LARGE CELL CARCINOMA WITH NEUROENDOCRINE FEATURES (LCC-NE) These tumors have no neuroendocrine pattern by light microscopy but immunohistochemistry or electron microscopy demonstrates neuroendocrine features
Nonsmall Cell Lung Carcinoma With Neuroendocrine Differentiation-An Entity of No Clinical or Prognostic Significance.

*Pathology and Laboratory Medicine, Vancouver General Hospital double daggerMedical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada daggerPhenopath Laboratories, Seattle section signMedicine, University of Tasmania, Hobart, Tasmania, Australia.


Am J Surg Pathol. 2007 Jan;31(1):26-32. Abstract quote

The existence of non-small cell lung carcinoma with neuroendocrine differentiation as a distinct entity and its relevance for prognostic and treatment purposes is controversial.

This study assesses the frequency and biologic and prognostic significance of neuroendocrine (NE) expression of synaptophysin (SNP), chromogranin (Ch), and neural cell adhesion molecule (N-CAM) using tissue microarray (TMA) and immunohistochemistry. Six hundred nine nonsmall cell lung carcinomas (NSCLCs) were reviewed for subclassification. TMA blocks were made using duplicate 0.6-mm-diameter tissue cores and slides stained with SNP, Ch, and N-CAM. Immunoreactivity was considered if 1% or more of tumor cells were positive.

Hematoxylin and eosin-stained sections were subclassified as: 243 adenocarcinoma (ACA), 272 squamous cell carcinoma (SCC), 35 large cell carcinoma, 32 non-small cell carcinoma NOS, and 6 other (carcinosarcoma, giant cell carcinoma). Positivity for either marker was identified in 13.6% of NSCLC (76/558). NSCLC showed reactivity for Ch in 0.4% of cases (2/524), for SNP in 7.5% of cases (39/521) and for N-CAM in 8.6% of cases (44/511), whereas only 0.2% of cases (1/517) showed coexpression of SNP and Ch and none of all 3 markers.

The assessment of NE differentiation in NSCLC is unnecessary and expensive and is of no clinical or prognostic significance. SNP or N-CAM stains a small minority of NSCLC, whereas Ch immunoreactivity is less common. Positivity for any 2 NE markers is rare. SNP is more likely to be expressed in adenocarcinoma (P=0.01) and N-CAM in squamous-cell carcinoma (P=0.008). Otherwise there was no correlation between immunoreactivity and tumor morphology.

Disease specific and overall survival is not influenced by NE differentiation and therefore non-small cell lung carcinoma with neuroendocrine differentiation should not be a subclass distinct from the other NSCLC.

Combined large cell neuroendocrine carcinoma and spindle cell carcinoma of the lung

Mahmoud Khalifa, MD, FRCPC
George Hruby, MD, FRANZC
Lisa Ehrlich, MD, FRCPC
Cyril Danjoux, MD, FRCPC
Bayardo Perez-Ordoñez, MD, FRCPC

From the Departments of Anatomic Pathology and Nuclear Medicine, Sunnybrook and Women's College Health Science Centre, Toronto; and the Department of Radiation Oncology, Toronto-Sunnybrook Regional Cancer Centre and University of Toronto, Toronto, Ontario, Canada.

Ann Diagn Pathol 5: 240-245, 2001 Abstract quote

We report a unique case of a combined pulmonary large-cell neuroendocrine carcinoma and spindle-cell carcinoma.

The patient was a 54-year-old female smoker who presented with a 4-month history of increased left-sided chest pain and exertional dyspnea. The left upper lobectomy specimen revealed an 8.0-cm mass with central necrosis. Microscopically, the epithelial areas were composed of well-defined nests of large cells with peripheral palisading expressing low-molecular-weight keratin, synaptophysin, chromogranin, and neuron-specific enolase. The spindle-cell component consisted of pleomorphic cells arranged in fibrosarcoma and malignant fibrous histiocytoma-like patterns. These spindle cells were positive for low-molecular-weight keratin and vimentin with focal expression of CD68 and muscle-specific actin. Electron microscopy in the spindle-cell areas showed cell junctions and numerous tonofilaments, indicative of epithelial differentiation. The tumor behaved aggressively and the patient died with extensive metastases 4 months after surgery.

The combination of neuroendocrine malignancies and spindle-cell carcinomas appears to be uncommon in the lung. Previous reports have described this association in single case reports of anaplastic small-cell carcinoma and atypical carcinoid, but not in large-cell neuroendocrine carcinoma.


Special stains  
Neuroendocrine markers Synaptophysin
CD117 (c-KIT)  

Kit expression in small cell carcinomas of the lung: effects of chemotherapy.

Rossi G, Cavazza A, Marchioni A, Migaldi M, Bavieri M, Facciolongo N, Petruzzelli S, Longo L, Tamberi S, Crino L.

Department of Pathologic Anatomy and Forensic Medicine, Section of Pathology, University of Modena and Reggio Emilia, Bologna, Italy
Mod Pathol. 2003 Oct;16(10):1041-7. Abstract quote  

A significant number of small cell lung carcinomas shows overexpression of the proto-oncogene c-kit product, a tyrosine kinase known as Kit or CD117. This molecular pathway seems somewhat implicated in promoting the neoplastic growth of small cell lung carcinoma.

The current pharmacological availability of its selective inhibitor, together with the promising clinical results in the management of CD117-positive neoplasms such as advanced gastrointestinal stromal tumors, aroused great interest among oncologists in also adopting this therapeutic strategy in other CD117-positive tumors.

We evaluated a series of 27 small cell lung carcinomas, comparing the expression of CD117 of the primary naive tumor (before first-line chemotherapy) with the expression of the same neoplasm after postchemotherapy relapse. All the patients underwent similar chemotherapeutic regimens (cisplatin/carboplatin plus etoposide). At diagnosis, 21 of 27 cases (78%) showed strong immunoreactivity for CD117. Among these 21 originally positive tumors, CD117 remained overexpressed in 10 after relapse (48%), whereas the other 11 cases became negative. No originally CD117-negative small cell carcinomas displayed immunoreactivity after chemotherapy. CD117 expression was not statistically correlated with overall survival, occurrence of chemoresistance, or clinical response to chemotherapy. We also evaluated CD117 expression in a series of 46 surgically resected non-small cell lung carcinomas (8 squamous cell carcinomas, 10 adenocarcinomas, 5 pleomorphic carcinomas, 10 typical and 3 atypical carcinoids, and 10 large cell neuroendocrine carcinomas). Apart from small cell carcinomas, CD117 overexpression was observed in 6 of 10 large cell neuroendocrine carcinomas, whereas all the other histotypes resulted unstained.

We speculate that loss of CD117 expression after chemotherapy in a high proportion of SCLC indicates that in this tumor, Kit unlikely represents the product of a constitutive mutation, as instead shown in gastrointestinal stromal tumors. Keeping this finding in mind, oncologists could re-test CD117 expression in relapsing small cell lung carcinomas in order to establish the best candidates for enrollment in ongoing clinical trials with Kit inhibitors.

Practically speaking, CD117 may be helpful in discriminating between pulmonary high-grade neuroendocrine tumors and other histotypes, but pathologists should be aware that treated small cell lung carcinomas may remain unstained in a not insignificant number of cases.


Histidine decarboxylase expression as a new sensitive and specific marker for small cell lung carcinoma.

Matsuki Y, Tanimoto A, Hamada T, Sasaguri Y.

Department of Pathology and Cell Biology (YM, TH, YS), School of Medicine, University of Occupational and Environmental Health, Kitakyushu.


Mod Pathol 2003 Jan;16(1):72-8 Abstract quote

Histidine decarboxylase is one of the enzymes of the amine precursor uptake and decarboxylation system and is known to be distributed in mast cells and enterochromaffin-like cells. With the hypothesis that histidine decarboxylase expression is a marker for neuroendocrine differentiation, we studied the immunoreactivity of histidine decarboxylase in neuroendocrine cells and tumors of the thyroid gland, adrenal medulla, lung, and gastrointestinal tract.

Formalin-fixed paraffin sections were subjected to immunohistochemistry using anti-histidine decarboxylase antibody, and the sensitivity and specificity were compared with those of conventional neuroendocrine markers (CD56, chromogranin A, synaptophysin, and neuron-specific enolase). Enterochromaffin or enterochromaffin-like cells, adrenal chromaffin cells, and thyroid C-cells were positive for histidine decarboxylase, and related tumors (carcinoid tumor, pheochromocytoma, medullary carcinoma) showed a high percentage of positive staining. Furthermore, we used the antibody to distinguish small cell lung carcinoma from non-neuroendocrine lung carcinoma and also to detect neuroendocrine differentiation in large-cell neuroendocrine carcinoma and gastrointestinal small-cell carcinoma. The anti-histidine decarboxylase antibody stained most small cell lung carcinoma (18 of 23, sensitivity 0.78), and was rarely reactive with non-neuroendocrine lung tumors (2 of 44; specificity, 0.95). These values were close to those obtained from CD56 staining (sensitivity/specificity, 0.87/0.98). Histidine decarboxylase was also positive for 6 of 12 large cell neuroendocrine carcinomas and 4 of 7 gastrointestinal small cell carcinomas.

In conclusion, we demonstrated that histidine decarboxylase is useful to distinguish between small cell lung carcinoma and non-neuroendocrine carcinoma and to demonstrate neuroendocrine differentiation.


Microtubule-Associated Protein-2: A New Sensitive and Specific Marker for Pulmonary Carcinoid Tumor and Small Cell Carcinoma

Yulin Liu, M.D., Charles D. Sturgis, M.D., Dana M. Grzybicki, M.D., Ph.D., Katherine M. Jasnosz, M.D., Peter R. Olson, M.D., Ming Tong, David D. Dabbs, M.D., Stephen S. Raab, M.D. and Jan F. Silverman, M.D.

Department of Pathology and Laboratory MedicineAllegheny General Hospital, Pittsburgh, Pennsylvania


Mod Pathol 2001;14:880-885 Abstract quote

Microtubule-associated proteins (MAPs) are a major component of cytoskeleton family proteins associated with microtubule assembly. MAP-2 has been shown to be specifically expressed in neuronally differentiated cells. Pulmonary neuroendocrine carcinomas such as carcinoid tumors and small cell carcinomas are derived from neuroendocrine cells.

We hypothesize that neuroendocrine cells may also express MAP-2, and therefore, MAP-2 may be used as a marker for pulmonary carcinomas of neuroendocrine differentiation.

To investigate the utility of using MAP-2 expression to separate pulmonary neuroendocrine from non-neuroendocrine tumors, we examined the expression of MAP-2 immunohistochemically in 100 cases of pulmonary carcinomas. The immunoperoxidase method with antigen retrieval was used to characterize the expression of MAP-2, chromogranin, synaptophysin, and neuron-specific enolase in 25 small cell carcinomas, 25 carcinoid tumors, 25 adenocarcinomas, and 25 squamous cell carcinomas. All tumors were lung primaries.

All 25 cases of carcinoid tumors (100%) as well as 23 of 25 cases (92%) of small cell carcinomas were positive for MAP-2. Four of 25 cases (16%) of adenocarcinomas were positive for MAP-2 and synaptophysin. Among the 25 squamous carcinomas, 4 cases (16%) were positive for MAP-2, 2 cases (8%) were positive for synaptophysin, 11 cases (44%) were positive for neuron-specific enolase, and none was positive for chromogranin.

In conclusion, MAP-2 is a new sensitive and specific marker for the pulmonary tumors of neuroendocrine differentiation. We recommend that MAP-2 be added to immunohistochemical panels to separate non-neuroendocrine from neuroendocrine lung tumors.

p63 and TTF-1 Immunostaining
A Useful Marker Panel for Distinguishing Small Cell Carcinoma of Lung From Poorly Differentiated Squamous Cell Carcinoma of Lung

Maoxin WuMD, PhD
Beverly WangMD
Joan GilMD
Edmond SaboMD
Lorraine MillerPhD
Li GanMD
David E. BursteinMD

Am J Clin Pathol 2003;119:696-702 Abstract quote

We studied the usefulness of p63 and thyroid transcription factor–1 (TTF-1) immunostains for differen-tiating poorly differentiated squamous cell carcinoma (PDSCC) from small cell lung carcinoma (SCLC).

We used monoclonal antibodies reactive to p63 or TTF-1 to stain 4-µm-thick sections from 30 formalin-fixed, paraffin-embedded lung biopsy and resection specimens and 7 alcohol-fixed, formalin-postfixed, paraffin-embedded cell blocks from lung fine-needle aspirations (FNAs). For p63, we used a streptavidin-biotin kit, diaminobenzidine as the chromogen, and a hematoxylin counterstain. We used automated immunostaining for TTF-1.

The 37 cases included 23 SCLCs, 13 PDSCCs, and 1 carcinoma initially diagnosed as PDSCC.
All 23 SCLCs were negative or, rarely, equivocal for p63; 20 (87%) of 23 were TTF-1+; nuclear staining ranged from strong and/or frequent to weak and/or uncommon. All 13 PDSCCs were TTF-1–/p63+ with intense staining of 50% to 100% of tumor cells. One case originally diagnosed as PDSCC was TTF-1+/p63–, suggestive of SCLC; after morphologic reexamination and immunostaining for neuroendocrine markers, it was reclassified as intermediate-type SCLC. TTF-1 immunostaining showed equal or increased sensitivity in alcohol-fixed cytologic cell block samples compared with formalin-fixed biopsy material; in 1 SCLC case, the biopsy specimen was TTF-1–; however, the FNA cell block stained positively.

p63 and TTF-1 appear to be useful for differentiating SCLC from lung PDSCC in formalin-fixed and alcohol-fixed, formalin-postfixed material.


Value of Thyroid Transcription Factor-1 Immunostaining in Distinguishing Small Cell Lung Carcinomas From Other Small Cell Carcinomas

Nelson G. Ordóñez, M.D. Wick MR, ed.

From the University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A.

Am J Surg Pathol 2000;24:1217-1223 Abstract quote

The distinction between small cell lung carcinoma (SCLC) and small cell carcinomas of other sites is difficult by routine histology. Thyroid transcription factor-1 (TTF-1) is a homeodomain-containing transcription factor that is selectively expressed in thyroid and pulmonary epithelial cells. TTF-1 expression has also been demonstrated in adenocarcinomas of the thyroid and lung, and SCLC. However, the value of TTF-1 immunostaining in discriminating between SCLC and nonpulmonary small cell carcinomas has not been investigated.

In the present study using an immunoperoxidase staining procedure on paraffin sections, we investigated the expression of TTF-1 and cytokeratin 20 (CK20), a marker that has previously been demonstrated in small cell carcinomas of the skin (Merkel cell carcinomas), in 82 small cell carcinomas from a wide variety of sites (28 lung, 18 skin, 12 gastrointestinal tract, 8 sinonasal, 5 bladder, 3 prostate, 3 uterine cervix, 2 thyroid, 2 salivary gland, and 1 pancreas).

Twenty-seven (96%) of the 28 SCLCs were positive for TTF-1. Among the nonpulmonary small cell carcinomas, two tumors of the gastrointestinal tract, one of the bladder, and one of the uterine cervix exhibited TTF-1 positivity. Sixteen (89%) of the 18 Merkel cell carcinomas and one SCLC were CK20-positive. All other small cell carcinomas were negative for this marker.

These results indicate that although TTF-1 is not a specific marker for SCLC, it may assist in distinguishing SCLC from some nonpulmonary small cell carcinomas, particularly Merkel cell carcinoma, especially when it is used in conjunction with CK20.

Thyroid Transcription Factor-1 Distinguishes Metastatic Pulmonary From Well-Differentiated Neuroendocrine Tumors of Other Sites

Andre M. Oliveira, M.D.; Henry D. Tazelaar, M.D.; Jeffrey L. Myers, M.D.; Lori A. Erickson, M.D.; Ricardo V. Lloyd, M.D., Ph.D.

From the Department of Laboratory Medicine and Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, U.S.A.

Am J Surg Pathol 2001;25:815-819 Abstract quote

Metastatic neuroendocrine neoplasms can have similar histologic appearances, and without an obvious primary, it may be difficult to determine the site of origin of the metastasis. Thyroid transcription factor-1 (TTF-1) is a nuclear protein expressed during the development of thyroid, lung, and forebrain. The clinical utility of TTF-1 to distinguishing between metastatic pulmonary and nonpulmonary well-differentiated neuroendocrine tumors (WDNET) has not been previously studied.

One hundred fifty-eight primary and metastatic WDNET were evaluated for TTF-1 expression. The tumors included 20 pulmonary WDNET, including 17 typical and 3 atypical carcinoid tumors, 10 metastatic pulmonary WDNET, 26 intestinal WDNET, 24 metastatic intestinal WDNET, 3 thymic mediastinal WDNET, 30 thyroid tumors (10 medullary carcinomas, 5 follicular carcinomas, 5 follicular adenomas, 5 papillary carcinomas, and 5 anaplastic carcinomas), 10 parathyroid adenomas, 20 pituitary adenomas, 10 pancreatic WDNET, and 5 pheochromocytomas. TTF-1 expression was found in 19 of 20 (95%) pulmonary WDNET, 8 of 10 (80%) metastatic pulmonary WDNET, and in 0 of 50 (0%) intestinal WDNET. All thyroid tumors were diffusely positive for TTF-1, except for three anaplastic carcinomas. All parathyroid and pituitary adenomas, pancreatic and thymic WDNET, and pheochromocytomas were uniformly negative for TTF-1.

These results indicate that TTF-1 is clinically useful in distinguishing metastatic pulmonary from metastatic WDNET of extrapulmonary origin.

Thyroid transcription factor 1 and cytokeratins 1, 5, 10, 14 (34E12) expression in basaloid and large-cell neuroendocrine carcinomas of the lung

Nathalie Sturm, MD
Sylvie Lantuéjoul, MD
Marie-Hélène Laverrière, MD
Mauro Papotti, MD
Pierre-Yves Brichon, MD
Christian Brambilla, MD
Elisabeth Brambilla, MD

Hum Pathol 2001;32:918-925. Abstract quote

Basaloid carcinoma (BC) and large-cell neuroendocrine carcinoma (LCNEC) are 2 recently recognized variants of large-cell lung carcinomas that may overlap in their morphology, and are discriminated by expression of neuroendocrine markers in LCNEC.

Because thyroid transcription factor 1 (TTF-1) is expressed in lung adenocarcinomas but not in squamous cell carcinomas (SCC), and 34E12 recognizes a set of high-molecular-weight cytokeratins characteristic of basal stem cells, we hypothesized that these 2 markers could help in distinguishing BC from LCNEC.

Immunostaining for TTF-1 was detected in 40.9% of pure LCNEC but in no BC or basaloid variant of SCC. In contrast, immunoreactivity for 34E12 was shown in all BC and basaloid variant of SCC but in only 1 LCNEC. Bouin fixation was less efficient than formalin in the immunodetection of both markers for its well-known deleterious effect on antigen preservation. Specificity of TTF-1 for LCNEC (100%) and that of 34E12 for BC (98.3%) exceeded that of NE markers for distinction of these 2 entities.

These data show that TTF-1 and 34E12, in association with specific neuroendocrine markers, represent a useful panel of antibodies in differentiating carcinomas presenting with a solid pattern, palisading, or pseudorosettes, the expression of TTF-1 excluding the diagnosis of BC, and staining with 34E12 excluding pure LCNEC.

Expression of thyroid transcription factor-1 in the spectrum of neuroendocrine cell lung proliferations with special interest in carcinoids.

Sturm N, Rossi G, Lantuejoul S, Papotti M, Frachon S, Claraz C, Brichon PY, Brambilla C, Brambilla E.

Laboratoire de Pathologie Cellulaire, Service de Chirurgie Thoracique and the Lung Cancer Research Group, INSERM 9924, Centre Hospitalo-Universitaire Albert Michallon, Grenoble, France; the Department of Morphological Sciences, Section of Pathology, University of Modena and Reggio Emilia, Modena, Italy; and the Department of Pathology, University of Turin, Torino, Italy.


Hum Pathol 2002 Feb;33(2):175-182 Abstract quote

The World Health Organization's classification of lung tumors separately categorizes neuroendocrine (NE) lung tumors, small cell lung carcinoma (SCLC), and large cell neuroendocrine carcinoma (LCNEC) as high-grade NE malignancies and carcinoids (typical, [TC] and atypical [AC]) as low- and intermediate-grade malignancies. Although these NE tumors are considered with NE hyperplasia (NEH) and tumorlets as part of a spectrum of NE proliferations, their derivation from a common progenitor cell has not received full agreement.

With the aim of refining their differential diagnosis and extending our understanding of their histogenesis, we studied the expression of thyroid transcription factor-1 (TTF-1), a transcription factor that regulates lung morphogenesis and differentiation, along the spectrum of NE lung tumors. Two hundred and twenty- seven NE proliferations and tumors were immunostained with TTF-1 antibody. Positive immunostaining for TTF-1 was detected in 47 of 55 (85.5%) pure SCLCs, in 31 of 64 (49%) pure LCNECs, but in none of 15 NEHs, 23 tumorlets, or 50 carcinoid tumors (27 TCs and 23 ACs). In 19 of 20 (95%) combined SCLCs and LCNECs, TTF-1 expression was identical in both NE and non-NE components.

These results show that TTF-1 is not expressed in normal and hyperplastic NE cells or in carcinoids, but is expressed in high-grade NE proliferations and in lung adenocarcinomas. This challenges the concept of a spectrum of NE proliferations and tumors and lends credence to the alternative hypothesis of a common derivation for SCLC and non-SCLC including LCNEC, with carcinoids deriving from a different stem cell.



Basaloid carcinoma, a rare primary lung neoplasm: report of a case and review of the literature.

Foroulis CN, Iliadis KH, Mauroudis PM, Kosmidis PA.

Department of Thoracic Surgery, Diagnostic and Therapeutic Center of Athens Hygeia, Kifisias Avenue and 4, Er. Stavrou Street, 15123 Maroussi, Athens, Greece

Lung Cancer 2002 Mar;35(3):335-8 Abstract quote

Basaloid carcinoma of the lung is a rare primary neoplasm, first described in 1992. Basaloid carcinoma is an aggressive subtype of Non small cell lung cancer, with poor 5-year survival, even in stage I and II resected tumors. Differential diagnosis from small cell, Neuroendocrine large cell and poorly differentiated squamous cell carcinoma is difficult to be made.

We report a patient with lung basaloid carcinoma, initially diagnosed and treated as small cell carcinoma. Thoracotomy and resection of the tumor following chemotherapy, established the correct diagnosis.

Immunohistochemical distinction between merkel cell carcinoma and small cell carcinoma of the lung.

Bobos M, Hytiroglou P, Kostopoulos I, Karkavelas G, Papadimitriou CS.

Department of Pathology, Aristotle University Medical School, Thessaloniki, Greece.

Am J Dermatopathol. 2006 Apr;28(2):99-104. Abstract quote  

We assessed the usefulness of several immunohistochemical stains in distinguishing these two neoplasms, including cytokeratin 7, cytokeratin 20 (CK20), neuron-specific enolase, chromogranin, synaptophysin, neurofilaments (NF), thyroid-transcription factor-1 (TTF-1), CD56 antigen, S-100 protein, vimentin, c-erbB-2 oncoprotein, and CD117 antigen. All 13 cases of Merkel cell carcinoma evaluated were positive for CK20, and negative for TTF-1. Twelve of 13

Merkel cell carcinoma cases were positive for NF. Eleven of 13 cases of small cell lung carcinoma were positive for TTF-1. All small cell lung carcinoma cases were negative for NF, and all but one were negative for CK20. In terms of the remaining antigens, there were no differences of significance between the two neoplasms.

These findings suggest that a set of three immunohistochemical stains, including CK20, NF, and TTF-1, is useful in affording a distinction between Merkel cell carcinoma and small cell lung carcinoma.


Carcinoid tumor

Poor factors include:

Atypical histologyAdvanced stage
Size>3 cm
Lymph node mets
Vascular invasion
Elevated S-phase fraction
Increased nuclear DNA content

5 Year Survival  
Carcinoid tumorlet
100% Rare deaths
Carcinoid tumor
100% Rare deaths
Atypical carcinoid tumor
Small cell carcinoma
6-13% survive 2 years and up to 5% survive 10 years
Large cell neuroendocrine carcinoma (LCNEC)
33% similar to squamous cell and large cell carcinoma
Carcinoid tumorlet
Rare lymph node mets reported
Carcinoid tumor
5-20% may have lymph node mets
Atypical carcinoid tumor
May have lymph node mets
Small cell carcinoma
Lymph node mets common
Large cell neuroendocrine carcinoma (LCNEC)
Lymph node mets common
Distinguishing small cell carcinoma from non-small cell carcinoma of the lung: correlating cytologic features and performance in the College of American Pathologists Non-Gynecologic Cytology Program.

Renshaw AA, Voytek TM, Haja J, Wilbur DC; Cytology Committee, College of American Pathologists.

Department of Pathology, Baptist Hospital of Miami, Miami, Fla, USA.

Arch Pathol Lab Med. 2005 May;129(5):619-23. Abstract quote  

CONTEXT: The cytologic features of small cell carcinoma of the lung are well described. Nevertheless, some small cell carcinomas may be difficult to reproducibly distinguish from non-small cell carcinomas, and this distinction carries significant clinical importance.

OBJECTIVE: To correlate the cytologic features of individual cases of small cell carcinoma of the lung in fine-needle aspiration specimens from the College of American Pathologists Non-Gynecologic Peer Comparison Cytology Program with the frequency of misclassification as non- small cell carcinoma.

DESIGN: We reviewed 1185 interpretations of 23 different cases of small cell carcinoma in lung fine-needle aspiration specimens and correlated the cytologic features noted in these cases with performance in the program.

RESULTS: Cases were divided into those that were frequently misclassified as non-small cell carcinoma (at least 10% of the responses, 11 cases) and those that were infrequently misclassified as non-small cell carcinoma (<5% of all responses, 12 cases). All cases had areas on the slides with classic features of small cell carcinoma. However, 10 of 11 cases that were frequently misclassified as non-small cell carcinoma had cells with either increased cytoplasm (4 cases), cytoplasmic globules (so-called paranuclear blue bodies) (3 cases), or apparent intracytoplasmic lumina (3 cases). These features were not identified in cases that were infrequently misclassified (P = .005). In addition, cases more frequently misclassified as non-small cell carcinoma tended to show better overall cellular and group preservation.

CONCLUSIONS: Frequent misclassification of small cell carcinoma as non-small cell carcinoma in lung fine-needle aspiration specimens in this program correlates strongly with the presence of cytoplasmic features that may suggest non-small cell carcinoma or with the presence of paranuclear blue bodies. Misclassification in this program may reflect a variety of factors, including the variation in the cytologic features of individual cases, but also the lack of wide recognition that some features of non-small cell carcinoma may also be noted in well-preserved cases of small cell carcinoma.

Neuroendocrine Lung Tumors: Grade Correlates with Proliferation but not Angiogenesis

Zoya K. Arbiser, M.D., Jack L. Arbiser, M.D., Ph.D., Cynthia Cohen, M.D. and Anthony A. Gal, M.D.

Department of Pathology, Southern Regional Medical Center (ZKA), Riverdale; Department of Dermatology, Emory University Hospital (JLA), Atlanta; and Department of Pathology and Laboratory Medicine, Emory University Hospital (CC, AAG), Atlanta, Georgia

Mod Pathol 2001;14:1195-1199 Abstract quote

Angiogenesis has been implicated in the progression of human neoplasia from benign precursor to invasive and metastatic phenotypes. The acquisition of dominant oncogenes in preneoplastic cells in vitro and in vivo has been associated with the increased ability of tumor cells to secrete angiogenic mediators and recruit blood vessels. However, in a subset of benign lesions, high levels of angiogenesis have been found before the conversion to invasive and metastatic phenotypes. In many of these benign lesions, dominant oncogenic pathways are activated first; then as malignant potential is acquired, there is a loss of nuclear tumor suppressor genes, such as p53 and p16.

We studied neuroendocrine lung tumors (NLT) ranging from typical and atypical carcinoid tumors to large cell neuroendocrine and small cell carcinomas in order to determine whether angiogenesis (as assessed by mean vessel density) and proliferation rates (as assessed by MIB-1 nuclear immunohistochemical staining) correlate with tumor type.

We found that increased rates of proliferation, but not angiogenesis, correlate with tumor type. The association of increased proliferation and tumor type may prove to be clinically useful and shed light on the role of sequential oncogenic alterations in NLT.

Pulmonary neuroendocrine carcinomas. A review of 234 cases and a statistical analysis of 50 cases treated at one institution using a simple clinicopathologic classification.

Huang Q, Muzitansky A, Mark EJ.

Department of Pathology, Massachusetts General Hospital, Boston, Mass., USA.


Arch Pathol Lab Med 2002 May;126(5):545-53 Abstract quote

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.


Analysis of c-kit protein expression in small-cell lung carcinoma and its implication for prognosis.

Naeem M, Dahiya M, Clark JI, Creech SD, Alkan S.

Loyola University Medical Center, Maywood, IL.

Hum Pathol 2002 Dec;33(12):1182-7 Abstract quote

Recently, therapies targeting signaling pathways involved in the pathogenesis of different tumors have been developed. Studies have shown that the tyrosine kinase inhibitor STI-571 (Gleevec) is used successfully against tumors expressing the c-kit oncogene, such as gastrointestinal stromal tumors (GISTs). A recent in vitro study also demonstrated an antiproliferative effect of STI-571 on small-cell lung cancer (SCLC) cell lines.

To determine the expression of c-kit in SCLC, we retrospectively analyzed presence of c-kit by immunohistochemistry in biopsy samples from patients with SCLCs. Formalin-fixed, paraffin-embedded archival tissue samples from 30 SCLCs were stained with an antibody directed against c-kit (CD117) by immunohistochemistry. Thirty cases of SCLCs, including 17 males (age 44 to 89) and 13 females (age 21 to 85), were examined. Sixteen of 30 (53.3%) SCLCs showed c-kit expression. Kaplan-Meier survival analysis with a log-rank test revealed that patients with c-kit expression had a tendency toward lower survival than c-kit-negative patients (median survival, 6 months versus 31 months, P =.062).

Based on previously established anti-c-kit effects of STI-571 on SCLC cell lines and our findings, clinical trials may be considered for selected SCLC patients with c-kit expression. Furthermore, determination of c-kit in SCLC may have a prognostic value in SCLC patients.

Prognostic Value of Lymphatic and Blood Vessel Invasion in Neuroendocrine Tumors of the Lung.

Schmid K, Birner P, Gravenhorst V, End A, Geleff S.

From the Departments of *Clinical Pathology and daggerCardio-Thoracic Surgery, Medical University of Vienna, Vienna, Austria.
Am J Surg Pathol. 2005 Mar;29(3):324-328. Abstract quote  

Few data on the influence of vessel invasion on the progression of neuroendocrine lung tumors are available. Because of the lack of specific markers, previous studies could not reliably discriminate lymphatic and blood vessels. By immunostaining for podoplanin, specific for lymphatic endothelium, and CD34 antigen, we assessed lymphatic and blood vessel invasion in 120 tissue specimens of patients with neuroendocrine lung tumors.

Lymphovascular invasion was correlated with clinicopathologic parameters, and its prognostic relevance was evaluated. Lymphatic vessels were identified exclusively at the tumor invasion front, whereas blood capillaries were also seen within tumors. Lymphatic vessel as well as lymphatic and blood vessel invasion was prevalent in patients with high-grade neuroendocrine tumors and advanced tumor stages, closely associated with lymph node metastases (P < 0.0001). In univariate analysis, these two invasion types correlated with decreased disease-free survival (both P < 0.0001), whereas blood vessel invasion alone did not. In multivariate analysis, only tumor grade and lymph node status remained statistically significant factors for prognosis (P = 0.016 and P < 0.0001).

Our results suggest that evaluation of lymphatic vessel invasion is important in neuroendocrine lung tumors serving as a prognostic parameter for disease-free survival.
Immunohistochemical Staining of Cytologic Smears With MIB-1 Helps Distinguish Low-Grade From High-Grade Neuroendocrine Neoplasms

Oscar Lin, MD, PhD,1 Semra Olgac, MD,1 Ileana Green, MD,2 Maureen F. Zakowski, MD,1 and David S. Klimstra, MD

Am J Clin Pathol 2003;120:209-216 Abstract quote

Neuroendocrine neoplasms (NENs) of the lung and gastrointestinal tract constitute a pathologic and biologic spectrum of tumors. Accurate cytologic diagnosis of a neuroendocrine neoplasm is important since definitive treatment frequently is based on low- and high-grade categories without histologic sampling. In many instances, however, low- and high-grade NENs share cytologic features, hindering a precise classification.

Since the histologic diagnostic criteria for separation of low- from high-grade categories can be based on the proliferation rate, we proposed to evaluate the usefulness of the immunocytochemical stain for the proliferation marker MIB-1 in the grading of NENs. Cytologic preparations of 63 NENs were retrieved from the files of Memorial Sloan-Kettering Cancer Center, New York, NY. One representative alcohol-fixed slide from each case was destained and restained immunocytochemically for MIB-1.

When MIB-1 immunoreactivity was considered, all low-grade NENs showed immunoreactivity in fewer than 25% of the neoplastic cells, and all high-grade NENs demonstrated immunoreactivity in more than 50% of neoplastic cells. Our study demonstrates that MIB-1 dramatically stratifies NENs as low-grade or high-grade. Therefore, the proliferation index also correlates with grade of NEN in cytology specimens.
Carcinoid tumorlet
Surgery-usually incidental finding
Carcinoid tumor
Surgery-usually lobectomy
Atypical carcinoid tumor
Surgery-usually lobectomy
Small cell carcinoma

Combination chemotherapy with radiotherapy has improved survival to 10-16 months with limited disease and 6-11 months with extensive stage disease

May induce complete remission

Large cell neuroendocrine carcinoma (LCNEC)
Surgery with chemotherapy and/or radiation

Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: perceptible progress.

Chute JP, Chen T, Feigal E, Simon R, Johnson BE.

Naval Medical Research Institute and Division of Hematology/Oncology, National Naval Medical Center, Bethesda, MD 20889-5105, USA.

J Clin Oncol 1999 Jun;17(6):1794-801 Abstract quote

PURPOSE: All cooperative group studies performed in North America for patients with extensive-stage small-cell lung cancer (SCLC) were evaluated to determine the pattern of the clinical trials and the outcome of patients over the past 20 years.

PATIENTS AND METHODS: Phase III trials for patients with extensive-stage SCLC were identified through a search of the National Cancer Institute Cancer Therapy Evaluation Program database from 1972 to 1993. Patients with extensive-stage SCLC treated during a similar time interval listed in the Surveillance, Epidemiology, and End Results (SEER) database were also examined. Trends were tested in the number of trials over time, the number and sex of patients entered onto the trials, and the survival time of patients treated over time.

RESULTS: Twenty-one phase III trials for patients with extensive-stage SCLC were initiated between 1972 and 1990. The median of the median survival times of patients treated on the control arms of the phase III trials initiated between 1972 and 1981 was 7.0 months; for those patients enrolled onto control arms between 1982 and 1990, the median survival time was 8.9 months (P =.001). Analysis of the SEER database of patients with extensive-stage SCLC over the same time period shows a similar 2-month prolongation in median survival time.

CONCLUSION: Analysis of 21 phase III trials initiated in North America and the SEER database from 1972 to 1994 demonstrates that there has been a modest improvement in the survival time of patients with extensive-stage SCLC.


Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593--a phase III trial of the Eastern Cooperative Oncology Group.

Schiller JH, Adak S, Cella D, DeVore RF 3rd, Johnson DH.

University of Wisconsin Hospital and Clinics, Madison, WI 53792, USA.

J Clin Oncol 2001 Apr 15;19(8):2114-22 Abstract quote

PURPOSE: To determine the efficacy of topotecan in combination with standard chemotherapy in previously untreated patients with extensive-stage small-cell lung cancer (SCLC), the Eastern Cooperative Oncology Group (ECOG) conducted a phase III trial.

PATIENTS AND METHODS: Eligible patients had measurable or assessable disease and an ECOG performance status of 0 to 2; stable brain metastases were allowed. All patients received four cycles of cisplatin and etoposide every 3 weeks (step 1; PE). Patients with stable or responding disease were then randomized to observation or four cycles of topotecan (1.5 mg/m(2)/d for 5 days, every 3 weeks; step 2). A total of 402 eligible patients were registered to step 1, and 223 eligible patients were registered to step 2 (observation, n = 111; topotecan, n = 112).

RESULTS: Complete and partial response rates to induction PE were 3% and 32%, respectively. A 7% response rate was observed with topotecan (complete response, 2%; partial response, 5%). The median survival time for all 402 eligible patients was 9.6 months. Progression-free survival (PFS) from date of randomization on step 2 was significantly better with topotecan compared with observation (3.6 months v 2.3 months; P <.001). However, overall survival from date of randomization on step 2 was not significantly different between the observation and topotecan arms (8.9 months v 9.3 months; P =.43). Grade 4 neutropenia and thrombocytopenia occurred in 50% and 3%, respectively, of PE patients in step 1 and 60% and 13% of topotecan patients in step 2. Grade 4/5 infection was observed in 4.6% of PE patients and 1.8% of topotecan patients. Grade 3/4 anemia developed in 22% of patients who received topotecan. No difference in quality of life between topotecan and observation was observed at any assessment time or for any of the subscale scores.

CONCLUSION: Four cycles of PE induction therapy followed by four cycles of topotecan improved PFS but failed to improve overall survival or quality of life in extensive-stage SCLC. Four cycles of standard PE remains an appropriate first-line treatment for extensive-stage SCLC patients with good performance status.

A multicenter randomized clinical trial comparing paclitaxel-cisplatin-etoposide versus cisplatin-etoposide as first-line treatment in patients with small-cell lung cancer.

Mavroudis D, Papadakis E, Veslemes M, Tsiafaki X, Stavrakakis J, Kouroussis C, Kakolyris S, Bania E, Jordanoglou J, Agelidou M, Vlachonicolis J, Georgoulias V;

Greek Lung Cancer Cooperative Group. Department of Medical Oncology, School of Medicine, University of Crete, Greece.

Ann Oncol 2001 Apr;12(4):463-70 Abstract quote

BACKGROUND: Previous phase I-II studies have shown that the combination of paclitaxel-cisplatin-etoposide (TEP) is very active and well tolerated in patients with small-cell lung cancer (SCLC). In order to compare the TEP combination to cisplatin etoposide (EP) regimen as front-line treatment in patients with SCLC, we conducted a randomised multicenter study.

PATIENTS AND METHODS: One hundred thirty-three chemotherapy-naive patients with histologically proven limited or extensive stage SCLC were randomised to receive either paclitaxel 175 mg/m2 i.v. three-hour infusion on day 1 and cisplatin 80 mg/m2 i.v. on day 2 and etoposide 80 mg/m2 i.v. on days 2-4 with G-CSF support (5 mcg/kg s.c. days 5-15) or cisplatin 80 mg/m2 i.v. on day 1 and etoposide 120 mg/m2 i.v. on days 1-3 in cycles every twenty-eight days.

RESULTS: Due to excessive toxicity and mortality observed in the TEP arm, an early interim analysis was performed and the study was closed. Sixty-two patients received two hundred sixty-one cycles of TEP and seventy-one patients three hundred twenty-three cycles of EP The two patient groups were well balanced for age, sex, performance status, stage of disease and the presence of abnormal LDH at diagnosis. In an intention-to-treat overall analysis both regimens were equally active with a complete and partial response rate of 50% (95% confidence interval (CI): 37.5%-62.4%) for TEP and 48% (95%) CI: 36.2%-59.5%) for EP (P = 0.8). The median time to disease progression was 11 months for TEP and 9 months for EP (P = 0.02). The duration of response, one-year survival and overall survival were similar in the two arms. Similarly, in an intention-to-treat subgroup analysis of patients with limited or extensive stage disease, there was no difference in the activity between the two regimens except of a longer median time to disease progression in the extensive stage in favour of the TEP regimen, eight versus six months (P = 0.04). However, there were eight toxic deaths in the TEP arm versus none in the EP arm (P = 0.001). Moreover, the TEP regimen was associated with more severe toxicity than the EP regimen in terms of grade 4 neutropenia (P = 0.04), grade 3-4 thrombocytopenia (P = 0.02), febrile neutropenia (P = 0.08), grade 3-4 diarrhea (P = 0.01), grade 3-4 asthenia (P = 0.05) and grade 3 neurotoxicity (P = 0.06).

CONCLUSIONS: In this early terminated study, the TEP regimen was significantly more toxic than the EP regimen. The TEP regimen is associated with significant toxicity and mortality, and should not be used outside of a protocol setting. For future investigations, dose and schedule modifications are necessary to reduce toxicity.

Superiority of high-dose platinum (cisplatin and carboplatin) compared to carboplatin alone in combination chemotherapy for small-cell lung carcinoma: a prospective randomised trial of 280 consecutive patients.

Hirsch FR, Osterlind K, Jeppesen N, Dombernowsky P, Ingeberg S, Sorensen PG, Kristensen C, Hansen HH.

Rigshospitalet, Finsen Center, Department of Oncology, Denmark.

Ann Oncol 2001 May;12(5):647-53 Abstract quote

PURPOSE: A prospective randomized trial in small-cell lung cancer (SCLC) was performed to determine if intensification of the platinum dose by giving cisplatin and carboplatin in combination to patients with SCLC yields higher response rates and survival, than carboplatin alone in a combination chemotherapy regimen.

PATIENTS AND METHODS: Between September 1992 and October 1997, 280 patients were included in a two armed prospective randomized trial, stratified by stage of disease, LDH and performance status. The treatment was in arm A: three courses induction chemotherapy with carboplatin (AUC = 4, day 1), cisplatin (35 mg/m2, days 2 and 3), teniposide (50 mg/m2, day 1-5), vincristine (1.3 mg/m2, day 1) every four weeks, followed by cyclophosphamide (3 g/m2, day 84), 4-epirubicin (4-epidoxorubicin) (150 mg/m2, day 112), and finally one course cisplatin, carboplatin, teniposide and vincristine, (days 140-144). Arm B also comprised a total of six courses, identical to those in arm A except for omission of cisplatin.

RESULTS: There were no significant differences in the overall treatment outcome for A vs. B, in terms of response rates (72% in both arms), complete response rates (40% and 34%, respectively), or median survival (314 days and 294 days, respectively). However, for patients with limited disease both the CR rate (54% vs. 37%, P < 0.05), overall survival (log-rank test, P < 0.05), and the two-year survival rate (11% vs. 6%, P < 0.05) were higher in the high-dose platinum arm compared to the carboplatin alone arm.

CONCLUSIONS: The intensification of platinum dose (cisplatin plus carboplatin) in combination chemotherapy significantly increased the complete response rate, overall survival and number of two-year survivors among SCLC patients with limited disease compared to combination therapy with carboplatin alone, suggesting that a more aggressive treatment to this category of patients is worthwhile, while no difference in treatment outcome was observed for patients with extensive disease.

Gemcitabine/carboplatin versus cisplatin/etoposide for patients with poor-prognosis small cell lung cancer: a phase III randomized trial with quality-of-life evaluation.

Steele JP.

Department of Medical Oncology, St Bartholomew's Hospital, London, EC1A 7BE, UK.

Semin Oncol 2001 Jun;28(3 Suppl 10):15-8 Abstract quote

Small cell lung cancer is a chemosensitive disease; however, patients with extensive-stage disease or adverse prognostic factors are rarely cured. Gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN), a new agent with good tolerability, interacts synergistically with platinum agents. Carboplatin is as effective as cisplatin, but is less toxic.

The London Lung Cancer Group is conducting a multicenter, open-label, randomized, phase III trial in patients with histologically or cytologically proven small cell lung cancer and extensive-stage, limited-stage but locally-advanced, or limited-stage disease with poor prognostic factors.

Chemotherapy consists of 21-day cycles of gemcitabine 1,200 mg/m(2) intravenous (IV) on days 1 and 8, plus carboplatin area under the curve of 5 IV on day 1, or cisplatin 60 mg/m(2) IV on day 1 plus etoposide 120 mg/m(2) IV on day 1 and 100 mg orally on days 2 and 3. Thirty-nine patients have been randomized to gemcitabine/carboplatin and 38 to cisplatin/etoposide (23 and 22 completed treatment, with 96 and 84 cycles, respectively).

Preliminary toxicity data indicate hematologic toxicity in 25% of cycles for gemcitabine/carboplatin and 16% for cisplatin/etoposide, although cisplatin/etoposide-treated patients experienced significant alopecia, nephrotoxicity, nausea and vomiting, and neutropenia.

This London Lung Cancer Group trial of gemcitabine/carboplatin may define an active, safe, and acceptable treatment for patients with extensive-stage and poor-prognosis small cell lung cancer.

Randomized phase II study of cyclophosphamide, doxorubicin, and vincristine compared with single-agent carboplatin in patients with poor prognosis small cell lung carcinoma.

White SC, Lorigan P, Middleton MR, Anderson H, Valle J, Summers Y, Burt PA, Arance A, Stout R, Thatcher N.

Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, United Kingdom.

Cancer 2001 Aug 1;92(3):601-8 Abstract quote

BACKGROUND: Information on the effect of chemotherapy in a group of patients with poor prognosis, poor performance status small cell lung carcinoma (SCLC) is scarce. A randomized study comparing single-agent carboplatin with combination chemotherapy in this largely unreported population of SCLC patients was undertaken.

METHODS: One hundred nineteen patients were allocated to four cycles of either cyclophosphamide, doxorubicin, and vincristine (CAV) or single-agent carboplatin. Patients had either a Karnofsky performance score < or = 50 and/or a prognostic score indicative of a 1-year survival rate } or = 15%.

RESULTS: Grade 3-4 neutropenia and intravenous antibiotic use were significantly more common with the CAV regimen (P < 0.005). Conversely, Grade 3-4 thrombocytopenia was more common (P < 0.0009) and platelet transfusion was more frequent (P < 0.05) with carboplatin therapy. Nonhematologic toxicity was similar in both treatment arms, except for alopecia with CAV therapy (P < 0.0007). Symptom relief occurred in 48% and 41% of patients in the CAV and carboplatin treatment arms, respectively. Dyspnea was improved in 66% and 41% of patients and cough was improved in 21% and 7% of patients in the CAV and carboplatin treatment arms, respectively. CAV therapy produced a higher response rate than carboplatin (38% vs. 25%), but this was not statistically significant (P = 0.15). The median overall survival for patients in the CAV and carboplatin treatment arms was 17 weeks and 15.9 weeks, respectively, with 1-year survival rates of 12% and 6%.

CONCLUSIONS: Single-agent carboplatin is a feasible treatment in patients with poor prognosis SCLC and produces response rates, relief of tumor-related symptoms, and survival similar to what is seen in patients who receive CAV chemotherapy. The lower risk of life-threatening sepsis and less need for hospitalization or intravenous antibiotic courses is advantageous in this susceptible patient population.

Cisplatin, etoposide, and paclitaxel with granulocyte colony-stimulating factor in untreated patients with extensive-stage small cell lung cancer: a phase II trial of the Southwest Oncology Group.

Kelly K, Lovato L, Bunn PA Jr, Livingston RB, Zangmeister J, Taylor SA, Roychowdhury D, Crowley JJ, Gandara DR

Southwest Oncology Group. University of Colorado, Denver, CO 80262, USA.

Clin Cancer Res 2001 Aug;7(8):2325-9 Abstract quote

PURPOSE: This study was designed to determine the efficacy and toxicity of cisplatin, etoposide, and paclitaxel (PET) in patients with extensive-stage small cell lung cancer (ES-SCLC).

EXPERIMENTAL DESIGN: Chemo-naive adult patients with a performance status (PS) of 0-2 and adequate organ function were eligible. Patients received cisplatin 80 mg/m(2) i.v., etoposide 80 mg/m-2 i.v., and paclitaxel 175 mg/m(2) i.v. over a 3-h period on day 1 followed by etoposide 160 mg/m(2) p.o. on days 2 and 3 every 21 days for six cycles. G-CSF 5 microg/kg was injected s.c. on days 4-14.

RESULTS: Eighty-eight patients were assessable. The median age was 60 years; 50% were male, 78% had PS of 0-1, 28% had PS of 2, 53% had multiple sites, and 13% had brain involvement. The overall response rate was 57% with 10 (12%) of 84 patients achieving a complete response. Median progression-free survival was 6 months [95% confidence interval (CI), 5-7 months] with a median survival of 11 months (95% CI, 8-13 months) and a 1-year survival rate of 43% (95% CI, 33-54%). Six patients (7%) died from toxicity. Grade 5 toxicity occurred in 3 (14%) of 22 patients (with a PS of 2) versus 3 (5%) of 61 patients (with a PS of 0-1; P, not significant). Grade 4 neutropenia developed in 40% of patients. Grade 3 nonhematological toxicities were primarily nausea (20%), vomiting (16%), and fatigue (14%).

CONCLUSION: The survival result achieved was superior to prior SWOG experiences; however, the toxic death rate was unacceptably high in PS-2 patients. These results provide the largest database for the ongoing randomized Intergroup trial comparing PET to cisplatin+etoposide in PS-0-1 patients with ES-SCLC.


Twice-daily prophylactic cranial irradiation for patients with limited disease small-cell lung cancer with complete response to chemotherapy and consolidative radiotherapy: report of a single institutional phase II trial.

Wolfson AH, Bains Y, Lu J, Etuk B, Sridhar K, Raub W, Markoe A.

Department of Radiation Oncology, University of Miami School of Medicine, Miami, Florida, USA.

Am J Clin Oncol 2001 Jun;24(3):290-5 Abstract quote

Prophylactic cranial irradiation (PCI) has been demonstrated to significantly reduce the incidence of brain relapse from limited disease small-cell lung cancer (LD SCLC), but concerns about neurologic toxicity remain.

The purpose of this report was to update a phase II institutional trial that explored the impact of twice-daily PCI on neurologic toxicity as well as outcome for this group of patients. All eligible subjects had documented complete response to induction chemotherapy and consolidative chest irradiation. The whole brain was treated with twice-daily fractions of 1.5 Gy with megavoltage irradiation to an approximate total dose of 30.0-36.0 Gy. Although not devised as a randomized study, approximately half of the eligible patients declined the protocol enrollment of their own volition and were retrospectively evaluated as a "historical" control group regarding the incidence of brain metastases. Fifteen patients accepted twice-daily PCI, with 12 deferring treatment. Median follow-up was 20 months. Disease-free survival at 2 years was 54% with twice-daily PCI versus 0% without any PCI (p = 0.013). Overall survival at 2 years was 62% with twice-daily PCI versus 23% without PCI (p = 0.032). No statistically significant neurologic deterioration was detected in the PCI group posttreatment.

Thus, twice-daily PCI should be considered for patients with LD SCLC who achieve a complete response to chemoirradiation. A multi-institutional randomized trial would be necessary before making definitive recommendations.


Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG).

Skarlos DV, Samantas E, Briassoulis E, Panoussaki E, Pavlidis N, Kalofonos HP, Kardamakis D, Tsiakopoulos E, Kosmidis P, Tsavdaridis D, Tzitzikas J, Tsekeris P, Kouvatseas G, Zamboglou N, Fountzilas G.

Athens Medical Center, Greece.

Ann Oncol 2001 Sep;12(9):1231-8 Abstract quote

BACKGROUND: Concurrent platinum etoposide chemotherapy given in combination with hyperfractionated thoracic radiation therapy (HTRT) in limited disease (LD) small cell lung cancer (SCLC) is associated with a high response rate and significant prolongation of survival. Given these results, the Hellenic Cooperative Oncology Group (HeCOG) performed a multicenter randomized phase II study in patients with LD SCLC to evaluate the timing of HTRT (early vs. late) when given concurrently with chemotherapy.

PATIENTS AND METHODS: To be eligible for the study, patients were required to have histologically or cytologically proven LD SCLC, confined to one hemithorax and/or ipsilateral mediastinal or supraclavicular lymphnodes and absence of pleural effusion or controlateral supraclavicular lymphnode involvement. Moreover, patients had to have a good performance status and adequate haematological, liver and renal function. Patients with LD SCLC were randomized to receive HTRT either concurrently with the first (Group A) or with the fourth (Group B) cycle of chemotherapy. Chemotherapy consisted of carboplatin administered at an AUC of six given as an i.v. 1-hour-infusion immediately followed by etoposide at a dose of 100 mg/m2 i.v. as a two-hour infusion for three consecutive days every three weeks up to a total of six cycles. Prophylactic cranial irradiation was also given to patients achieving a complete response.

RESULTS: 42 and 39 patients, were eligible for efficacy evaluation in group A and B respectively. The overall response rate was 76% in group A and 92.5% in group B (P = 0.07) with a complete response rate of 40.5% and 56.5%, respectively. After a median follow-up of 35 months, time to progression was 9.5 months in group A and 10.5 in group B (NS) while overall median survival was 17.5 and 17 months respectively (NS). The 2-year survival was 36% in group A and 29% in group B (NS) and the 3-year survival 22% and 13%, respectively (NS). The distant relapse rate was 38% in group A and 61% in group B (P = 0.046). Severe grade 3 4 anemia was recorded in 19% of group A and 12.5% of group B (NS), while severe leucopenia was recorded in 35.5% and 20.5% (P = 0.09) and neutropenic fever in 5% and 2.5% (NS), respectively. Severe thrombocytopenia did not differ significantly between the two treatment groups being 21.5% and 23%, respectively. Severe grade 2-3 esophageal toxicity was 19% in group A and 23% in group B (NS), while grade 3 lung toxicity was 5% and 7.5% (NS), respectively. No toxicity-related deaths were recorded.

CONCLUSION: Concurrent administration of HTRT with carboplatin etoposide is associated with a high response and survival rate. Although a trend for higher response rate was recorded in the group of patients who received late HTRT, the overall median, 2-year and 3-year survival rates did not differ significantly between the two treatment groups. The toxicity of this promising therapeutic approach was acceptable. Comparative phase III studies with an adequate number of patients are recommended in order to answer this question.

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