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Neuroendocrine Differentiation Is an Independent
Prognostic Factor in Chemotherapy-Treated Nonsmall
Cell Lung Carcinoma
Jeffrey T. Schleusener, M.D.*'
Henry D. Tazelaar, M.D.'
Sin-ho JUng, Ph.D.2
Stephen S. Cha, M.s.~
Peter J. Cera, M.D?
Jeffrey L. Myers, M.D.'
Edward T. Creagan, M.D?
Richard M. Goldberg, M.D?
Robert F. Marschke, Jr., M.D?
Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
Department of Cancer Center Statistics, Mayo
Clinic, Rochester, Minnesota.
Department of Pathology, Geisinger Clinic,
Geisinger Medical Center, Danville, Pennsylvania.
Department of Medical Oncology, Mayo Clinic,
Rochester, Minnesota.
Division of Hematology and Medical Oncology,
Mayo Clinic Scottsdale, Scottsdale, Arizona.
BACKGROUND. Neuroendocrine differentiation can be identified in 10-30% of patients with nonsmall cell lung carcinoma (NSCLC) by immunohistochemical or
electron microscopic techniques. However, its clinical significance is not well established.
METHODS. Tumors from 107 patients with Stage IIIA, IIIB, and IV NSCLC treated
with cisplatinletoposide with or without hydrazine in the North Central Cancer
Treatment Group and Mayo Clinic protocols were analyzed immunohistochemically with antibodies to chromogranin A (CGA), Leu 7 (CD 57), and synaptophysin
(SY). These results were compared with clinical outcomes.
RESULTS. Keratin AElIAE3, used as a control, was positive in 99.1% of cases; 34.6%
had positive staining for at least 1 neuroendocrine marker, and 11.3% had positive
staining for 2 or more markers. CGA was positive in 4.7%, Leu 7 in 18.7%, and SY
in 24.3% of cases. A significant increase in survival was seen in patients with tumors
expressing any one neuroendocrine marker or any combination of neuroendocrine
markers ( P 5 0.01). There was no correlation between the presence of neuroendocrine differentiation and either response to chemotherapy or time to disease progression (P> 0.3), nor was there any correlation between chemotherapy response,
time to progression, or survival with staining intensity or percent of cells positive
per case.
CONCLUSIONS. Neuroendocrine differentiation may be of prognostic significance
in patients with advanced stage NSCLC treated with chemotherapy. Cancer 1996;
77:1284-91. 0 1996 American Cancer Society.
KEYWORDS Nonsmall cell lung carcinoma, neuroendocrine, chromogranin, synaptophysin, Leu 7, small cell lung carcinoma.
This study was supported in part by the North
Central Cancer Treatment Group, NIH CA 25224.
Address for reprints: Henry D. Tazelaar, M.D.,
Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905.
Received June 21, 1995; revision received September 25,1995; accepted December 21,1995.
0 1996 American Cancer Society
ung cancer is the leading cause of cancer-related death in the United
States and is responsible for 33% of cancer-related deaths in men and
24% in women. An estimated 158,700 patients will have died of lung
carcinoma in 1996,' and it is estimated that 2 million patients will be
diagnosed worldwide in the year 2000. Despite recent therapeutic advances, the overall 5-year survival rate has improved little in the past 30
years and remains at a dismal 14%. Tumor stage is the most important
prognostic factor; 5-year survival rates for patients with Stage I disease
are about 50%, but are less than 5% for patients with Stage IIIB or N
Histologic subtyping shows only a weak correlation with outcome
when considered as an independent prognostic variable. The World
Health Organization classifies lung cancer into four main histologic types:
small cell lung carcinoma (SCLC), squamous cell carcinoma, adenocarcinoma, and large cell c a r ~ i n o m a .The
most important distinction
Neuroendocrine Expression in Lung Cancer/Schleusener et at.
Histologic Types of Lung Carcinoma Studied and Frequency of
Neuroendocrine Differentiation
Percentage of Cases of Nonsmd Cell Lung Carcinoma Reacting with
a Panel of Immunohistochemical Neuroendocrine Markers
Frequency of
Histologic type
Squamous ceU carcinoma
Large cell carcinomainonsmall ceU
carcinoma, not otherwise specified
Adenosquamous carcinoma
histologic type
No. of cases (%)
% showing
differentiation (%)
62 (58)
22 (21)
18 (17)
5 (5)
Leu 7
Leu 7 t SY
Leu 7 t CGA
Leu 7 t SY t CGA
SY: SvnaDtoDhVsin: CGA chromoeranin A
is between SCLC and the others, which can be considered
together as nonsmall cell lung carcinoma (NSCLC).SCLC
tends to be more chemo-and radiosensitive than NSCLC,
yet it shows a more dismal overall survival. SCLCs are, in
general, not amenable to surgical intervention, whereas
surgery is the primary mode of therapy for Stage I and I1
Neuroendocrine lung tumors comprise a spectrum
of epithelial neoplasms ranging from low grade carcinoid
tumors to SCLC. Most SCLCs show neuroendocrine differentiation when studied by immunohistochemistry4 or
electron micro~copy.~
A significant minority, approximately 10-30%, of NSCLCs also show neuroendocrine
differentiation when similarly e~amined.~,’
Recent studies
have shown varied and sometimes conflicting results regarding the therapeutic and prognostic significance of
neuroendocrine differentiation in NSCLC.8-’6 The purpose of this study was to determine the relationship between neuroendocrine differentiation in NSCLC and response to chemotherapy, disease progression, and survival in patients with inoperable NSCLC who were
entered into two cisplatinletoposide-based chemotherapy protocols.
All study patients were enrolled in North Central Cancer
Treatment Group (NCCTG)protocol 89-24-5117and Mayo
Clinic protocol 88-24-01. Protocol eligibility required histologically or cytologically proven, measurable, or evaluable Stage 111or IV NSCLC’ not amenable to surgical or
radiation therapy. Patients who had received previous
chemotherapy or significant radiation therapy were excluded. The NCCTG protocol randomized patients to receive cisplatinletoposide with or without hydrazine sulfate. The Mayo Clinic protocol utilized either continuous
infusion or bolus cisplatinletoposide in its study design.
Patients from both arms of the study had similar outcomes and were included in the present analysis.
Two hundred seventy-seven patients (184 men and
93 women) ranging in age from 33 to 80 years were enrolled in the 2 protocols from 1988 to 1992. Of these,
sufficient histologic or cytologic (cell block) material was
available for pathologic review in 107 cases. Patient characteristics including age, sex, weight, performance status,
disease stage, and the presence and location of metastases from the group with sufficient material for pathologic
review were similar to patient characteristics of the larger
group. Patient characteristics were also similar between
the two protocols.
Pathologic material was obtained via transbronchial
biopsy, open lung biopsy or resection, or fine-needle aspiration or biopsy of a metastasis. Tissues were fixed in
10% buffered formalin and 5-p hematoxylin and eosinstained sections were reviewed to assess histologic subtype. Tissue blocks available ranged from 1 to 12 blocks
per case (mean, 1.4 blocks). When more than one block
was available, the two or three blocks containing the best
preserved and most abundant tumor were selected for
Paraffin sections were stained for a panel of neuroendocrine and epithelial markers including chromogranin A
(CGA) (1:lOOO) (Boehringer-Mannheim, Indianapolis,
IN), Leu 7 (1:5) (Becton-Dickinson,San Jose, CAI, synaptophysin (SY) (1:40),(ICN,Costa Mesa, CAI, and cytokeratin AEl/AE3 (1:lOO) (Boehringer-Mannheim, Indianapolis, IN) using the avidin-biotin peroxidase method.18Positive controls, including normal pancreas for CGA and SY,
normal tonsil for Leu 7, and small intestine for cytokeratin
and negative controls (consisting of patient tissues omitting the primary antibody) were used for all cases. Staining reactions were semiquantitatively assessed to include
strength of reactivity (0: none; 1+: weak 2+: moderate;
3+: strong; and 4+: very strong) and percentage of tumor
cells reacting (0:none; 1+: 1-25%; 2+: 26-50%; 3+: 5175%; and 4+: >75%). Reviewing pathologists were
blinded to clinical outcomes in all cases.
Clinical Outcomes
Clinical outcomes measured included: (1) response to
chemotherapy (50% reduction in measurable disease or
CANCER April 1,1996 / Volume 77 / Number 7
FIGURE 1. lmmunohistochernical staining. Low grade squamous cell carcinoma with (a) 2(+) staining for synaptophysin and (b) 3(+) staining for
Leu 7. (c) High grade squamous carcinoma with focal 4(+) staining for chromogranin A. (d) Large cell undifferentiated carcinoma with 4(+) staining
for Leu 7.
definite decrease in tumor size in evaluable disease); (2)
time to disease progression (time from enrollment into
treatment protocol to time when 2 25% increase in tumor
size was detected); and (3) patient survival (time from
enrollment to time of death). The presence of neuroendocrine differentiation was compared with clinical outcomes using Fisher's exact test and log rank test statistical
methods. Multivariate analyses were also performed to fit
a Cox proportional hazards model. A backward regression
was used to find the most significant variables. The maximum likelihood estimate was obtained by adjusting the
rest of the nonsignificant covariables. All P values were
Sixty-six patients were men and 41 were women with a
median age of 63 years (range, 33-80 years). Two patients
had Stage IIIA disease, 14 had Stage IIIB disease, and 91
had Stage IV disease. Median survival for all patients was
257 days; median time to disease progression was 115
days. A response to chemotherapy was seen in 31.8% of
Sixty-two tumors (58%) were adenocarcinomas, 22
(21%) were squamous cell carcinomas, 18 (17%) were
large cell undifferentiated carcinomas or NSCLC not otherwise specified, and 5 (5%) were adenosquamous carcinomas (Table 1).There were no cases that were classified
as large cell neuroendocrine c a r ~ i n o m a 'present
in the
study group.
Examples of immunohistochemical staining results
are shown in Figure 1. Because there proved to be no
correlation between staining intensity or percent of positive tumor cells and the outcome variables, any degree
of positivity was considered significant. Immunoreactiv-
Neuroendocrine Expression in Lung Cancer/Schleusener et al.
800700 -
257 dmys
100 -
100 7
100 1
FIGURE 2. Clinical outcomes versus neuroendocrine differentiation. (a) Survival versus neuroendocrine differentiation. (b) Survival versus individual
neuoendocrine marker. (c) Response to chemotherapy versus neuroendocrine differentiation. (d) Response to chemotherapy versus individual neuroendocrine marker. ( f ) Time to disease progression versus individual neuroendocrine marker. (b and 1: open-ended bars indicate some patients are still alive
at close of the study. CGA: chromogranin A; SY: synaptophysin).
ity for at least 1 neuroendocrine marker was present in
37 (34.6%) cases; 12 cases (11.3%) were immunoreactive
for 2 or more neuroendocrine markers. Table 1 shows the
percentage of cases with neuroendocrine differentiation
by histologic subtype. Table 2 shows the number of cases
staining with each marker and each combination of
The presence of neuroendocrine differentiation sig-
nificantly correlated with survival: 249d: all neuroendocrine markers negative versus 3 1 Id: 1 or more neuroendocrine markers positive, G = 0.01; and 2493: all neuroendocrine markers negative versus 464d: 2 or more
neuroendocrine markers positive, P = 0.005 (Figs. 2A and
3). lmmunoreactivity for specific neuroendocrine markers, whether considered alone or together, was also significantly correlated with survival: 255d: CGA negative
CANCER April 1,1996 / Volume 77 / Number 7
Years from randomization
FIGURE 3. Kaplan-Meier curve for survival versus neuroendocrine differentiation in nonsmall cell lung cancer.
versus 569d: CGA positive, P = 0.04; 249d: Leu 7 negative
versus 422d: Leu 7 positive, P = 0.006; 251d: SY negative
versus 318d: SY positive, P = 0.02 (Fig. 2B). Time to disease progression was significantlyprolonged only in cases
expressing both CGA and SY (112d: CGA and SY negative
versus 386d: CGA and SY positive, P = 0.04). Otherwise
there was no correlation between the presence of neuroendocrine differentiation and either response to chemotherapy or time to disease progression (Figs. 2C-F), disease stage, or tumor grade. In addition, in those cases
with any neuroendocrine staining, combining the staining intensity score with the percentage of tumor cells
reacting score showed no correlation with survival, response to chemotherapy, or time to disease progression.
By multivariate analysis, immunoreactivity for any
given neuroendocrine marker was an independent predictor of survival when considered together with age, sex,
tumor grade, and stage. Performance status was also an
independent predictor of survival (Table 3).
Immunohistochemical evidence of neuroendocrine differentiation was present in more than one-third of our
cases of “ordinary” NSCLC and was associated with improved patient survival. Improved survival was seen when
any single marker (CGA, Leu 7, or SY) or combination of
markers was present. In addition, the majority of long
term survivors had tumors with neuroendocrine differentiation. Interestingly, the effect of neuroendocrine differentiation on survival was not attributable to either a
greater likelihood of response to chemotherapy, prolonged disease free interval, disease stage, or tumor
grade. Carles et al.’ showed similar findings with respect
to survival rates and chemotherapy response rates and
suggested that response to chemotherapy may not be as
important in predicting survival as was previously
thought. They also suggested that stable, nonprogressive
disease may be as important as chemotherapeutic response in predicting outcome.
Other recent studies comparing clinical outcomes
with neuroendocrine differentiation in chemotherapytreated NSCLC have shown conflicting results (Table 4).
Carles et al.’ showed that the presence of neuron specific
enolase (NSE) immunoreactivity correlated with an improved median survival of 3.5 months, but failed to show
that neuroendocrine differentiation correlated with response to chemotherapy. Graziano et al.’ showed that,
among patients who responded to chemotherapy, a 52week improvement in median survival was present in
patients with tumors that had 2 or more neuroendocrine
markers. This study also showed an increased response
rate to chemotherapy in patients with tumors with NSE
immunoreactivity (54%responders vs. 27% nonresponders, P = 0.04) and 2 or more positive neuroendocrine
markers (38% responders vs. 0% nonresponders, P <
0.01). Ruckdeschel et al.15and Skov et a1.l’ both showed
a significant trend toward response to chemotherapy in
tumors with NSE expression, but no correlation with survival.
Although there is some disagreement in the literature, most studies analyzing patients treated with surgery
Results of Multivariate Analysis Adjusted for Age, Sex, Stage, Grade, and Performance Status
NE differentiation (21NE
markers vs. 0 NE markers)
Age, (yr) (2 60 vs. < 60)
Sex (male vs. female)
Grade (3, 4 vs. I, 2)
Stage (lVvs. 111)
Performance status (2 vs. 0, 1)
N E neuroendocrine
P values
[chi square)
95% confidence
Risk ratio
Neuroendocrine Expression in Lung CancerEchleusener et al.
Summary of Previous Studies Examining Significance of Neuroendocrine Differentiation in Nonsmall Cell Lung Carcinoma
Effect of NE differentiation on clinical
Stage (No. of cases)
NE markers used %I positive
Skov et al?
(3 different
IIIA. 25%
IIIH, 27%
IV. 48%
NSE-lfi%: (>lo%?)
52%: (I-lO%-)
CGA- 19%: (>I O % t )
45%: (1-10%+)
So correlation with survival
Increased response to chemotherapy
Improved survival
No correlation uith response to chemotherapy
I14 cases nf
Carles et a,'
97 cases 01 SSCLC.
(8 different
Craziano et
52 cases 01 NSCLC
(4 cisplatin-based
1.ocoregional disease (39)
Ilistant mets (43)
Both (30)
Sundaresan et a1.I359 cases of KSC1.C
Surgical resection
I1 (75)
111 (63)
Graziano ct al."
260 cases of NSC1.C
Surgical resection
I (193)
I1 (67)
Linnoila e: al.'
23i cases of SSC1.C
Surgical resection
Sot stated
Eibbelaar et al."
226 cases oi NSCK
Berendsen et al. ' 111
cases of SSCLC
Surgical resection
Sot stated
IRU 7.2%
2 or more-12%
leu 7.31%
2 or more-19%
2 or more-30%
Leu 7-7.796
SY-I 1.2%
2 or more-23.5%
L ~ 7.8%
Gastrin-releasing peptide-1%
2 or more-12%
MAh 123C3 (NCM)-19.1%
So resection-43
I II (70)
I11 (71)
MOC 1, 21, 32, 51, 91 % (> 50% cells)
Improved survival
Increased response to chemotherapy
No correlation with survival
Increased likelihood of higher disease stage and
nodal metastases
No correlation k\ith survival
No correlation with survival
So correlation with disease recurrence
Decreased survival
Ilccreased sunival
YE: neurorridocrine; MI: neuron specific enolase GCA:chromogranin A; SY: synapmphysin; NSC1.C: nonsniall lung carcinoma; CK BE: creatinine lrinase B B NCAM neural ceii adhesion mokuie.
only have indicated that neuroendocrine differentiation
has no impact on survival (Table 4). Berendsen et al.'"
used multivariate analysis to show that neuroendocrine
differentiation in NSCLC had a negative impact on survival. Similarly, Sundaresan et al." showed that expression of neuroendocrine markers predicted for higher disease stage. IIowever. Linnoila et al.," Graziano et aI.,14
and Ruckdeschel et aI.,l5in larger series utilizing common
antibodies for neuroendocrine differentiation, showed no
correlation between neuroendocrine differentiation and
survival in their surgically treated patients. We are aware
of no series reporting a survival advantage for surgically
treated NSCLC with neuroendocrine differentiation.
Previous studies have identified neuroendocrine differentiation in approximately 10%-30% of NSCLCs." - 1 2 ~ 1 4 ~ 1 5
The frequency of neuroendocrine differentiation was simi-
lar for all histologic tumor types in our study ('fable 1).
Other seriesH~1".2"
have shown that adenocarcinoma is more
likely than squamous cell carcinoma to express neuroendocrine differentiation. The reasons for these discrepancies
are unknown.
Various terms have been applied to NSCI.Cs with
neuroendocrine differentiation, including atypical endocrine tumors2' and large cell (undifferentiated) carcinoma
with neuroendocrine differentiation." The term large cell
neuroendocrine carcinoma is reserved for tumors that
appear "neuroendocrine" by light microscopy (i.e., organoid, trabecular, andlor palisading growth pattern with
coarse chromatin) and show immunohistochemical or ultrastructural evidence of neuroendocrine differentiation.
Similar tumors have also been termed neuroendocrine
carcinomas of intermediate differentiati~n.'~
CANCER April 1,1996 I Volume 77 I Number 7
Three commercially available markers of neuroendocrine differentiation were used in this study: CGA, Leu 7 ,
and SY. CGA is a high molecular weight acidic glycoprotein originally isolated from adrenal medulla. It is released
along with neuroendocrine peptides through exocytosis
from dense-core neurosecretory granules and its detection is directly correlated with the presence of these neurosecretory granules.'" Anti-Leu 7 (HNK- 1) antibody was
initially established as a marker for natural killer cells but
was shown to cross-react with various neuroendocrine
tumors. It specifically recognizes myelin-associated glycoproteins and also cross-reacts with peripheral
nerve^.^^^^^ SY is a transmembrane 38 kilodalton glycoprotein that has been isolated from presynaptic vesicles of
neurons. In addition, SY is expressed in normal pancreatic islet cells and in a high percentage of neuroendocrine
We defined "neuroendocrine differentiation" as reactivity for any 1 marker because of the relatively specific
nature of neuroendocrine markers used in this study. Other
authors have defined "neuroendocrine differentiation" as
having two or more positive neuroendocrine markers, although all these studies included NSE, which we avoided
using because of its lack of specificity for neuroendocrine
NSE has been positive in between 40-68% of
cases of NSCLC from other ~ t ~ d i e ~ . "CGA
activity was present in less than 5% of our cases; Leu 7 and
SY expression was present in approximately 20% and 25%
of our cases, respectively, similar to previous ~ t ~ d i
Loy et al.3' found much higher rates of SY immunoreactivity
in NSCLCs, but used a polyclonal SY antibody that may be
less specific than the monoclonal antibody used in this
Our results, and results of previous studies, tend to
support the hypothesis that NSCLC expressing neuroendocrine markers may behave in a fashion intermediate
between SCLC and NSCLC: a poor prognosis in patients
treated with surgery alone (like SCLC) and survival (and
chemotherapy response) greater than that seen in typical
NSCLC in patients treated with multiagent chemotherapy. Additional, large, prospective studies are necessary
to determine whether neuroendocrine differentiation
predicts for improved survival in patients with resected
Stage I, 11, and 111tumors who are given adjuvant chemotherapy and whether chemotherapy similar to that given
for SCLC improves survival for patients with unresectable
NSCLC with neuroendocrine differentiation.
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