Jpn J Clin Oncol1999;29(4 )219-225
A Case of Synchronous Double Primary Lung Cancer with
Neuroendocrine Features
Seiji Niho 1,2, Tomoyuki Yokose2, Kanji Nagai1, Yutaka Nishiwaki1, Tetsuro Kodama 3 and Kiyoshi Mukai2
1Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, 2Pathology Division, National
Cancer Center Research Institute East, Chiba and 3Department of Internal Medicine, National Cancer Center
Hospital, Tokyo, Japan
We report a case of unique double primary lung cancers with neuroendocrine features in a
63-year-old male smoker. The mass in the left lower lobe (LLL) was a small cell/large cell
carcinoma with spindle cell sarcomatous areasand organoid structure. The massin the leftupper
lobe (LUL) was a tubular adenocarcinoma with neuroendocrine features including organoid nests
showing occasional rosette formation, nuclear palisading in the periphery ofthe nests and positive
immunoreaction for CD56, chromogranin A and synaptophysin. The difference in histological
structures between the two masses led us to diagnose double primary lung cancer. The
combination of small cell lung carcinoma and spindle cell carcinoma is very uncommon. The
relationship between LLL and LUL tumors remains unclear. Multiple lung cancers with
neuroendocrine features have only rarely been reported in the literature. The patient in our case
diedof widespread cancer2 years and4 months afterthe surgery without adjuvant chemotherapy,
a longer postoperative survival time than in cases of ordinary extensive small cell lung cancer.
Multiple lungcancers with neuroendocrine features are extremely rareandsimilarcaseshavenot
been reported in the literature. Neuroendocrine differentiation hasattracted widespread attention
and, therefore, examining neuroendocrine features in lung cancers is important.
Key words: small cell carcinoma - spindle cell carcinoma - double primary lung cancers - adenocarcinoma
- neuroendocrine feature
INTRODUCTION
The classification of neuroendocrine tumors of the lung used to
be complex and confusing. Recent!y, Travis et al. (1) reported the
following spectrum of pulmonary neuroendocrine (NE) lesions:
(i) minute NE lesions, (ii) common neoplasms with an NE light
microscopic appearance, (a) typical carcinoid, (b) atypical
carcinoid, (c) large cell NE carcinoma and (d) small cell lung
carcinoma, (iii) non-small cell lung carcinoma with NE features
and (iv) uncommon primary NE neoplasms. The classification of
small cell lung carcinoma (SCLC) has changed over time. The
World Health Organization (WHO) defined the subtypes of
SCLC in 1981 as oat cell type, intermediate cell type and
Received September 11, 1998; accepted December 21, 1998
For reprints and all correspondence: Seiji Niho, Division of Thoracic
Oncology, National Cancer Center Hospital East, 5-1, Kashiwanoha
6-chome, Kashiwa, Chiba 277-8577, Japan. E-mail: [email protected]
Abbreviations: LLL, left lower lobe; LUL, left upper lobe; NE,
neuroendocrine; SCLC, small cell lung carcinoma; WHO, World Health
Organization; IASLC, International Association for the Study of Lung
Cancer; CEA, carcinoembryonic antigen; MRI, magnetic resonance
imaging; ABC, avidin-biotin complex; Sp-A, surfactant apoprotien A;
Sp-D, surfactant apoprotein D; GRP, gastrin-releasing peptide
combined type (2). The International Association for the Study of
Lung Cancer (IASLC) redefined the subtypes in 1988 as small
cell carcinoma, mixed small cell/large cell carcinoma and
combined small cell carcinoma (3). Almost all combined SCLCs
contain a component of squamous cell carcinoma or adenocarcinoma; however combinations can occur with spindle cell
carcinoma (4) and giant cell carcinoma (5)' We present a case of
double primary lung cancers with NE features, one tumor
consisting of small cell/large cell lung cancer combined with
spindle cell sarcomatous lesions and the other an adenocarcinoma
with NE features in a different lobe.
CASE REPORT
A 63-year-old man was admitted to the National Cancer Center
Hospital East in October 1994 because of cough, sputum and
hemoptysis. He had smoked 20 cigarettes daily over 40 years. The
patient's mother died of leukemia at the age of 38. Laboratory
data were within normal limits except for a low serum albumin
(2.9 g/dl) and elevated CEA (7.2 ng/ml). Chest radiography
revealed a round nodule in the left lower lobe (LLL). Bronchoscopic examination showed a white polypoid mass obstructing the
LLL bronchus. The biopsy specimen contained malignant cells;
however, the cell type could not be determined because of the
© 1999 Foundation for Promotion of Cancer Research
220
Lung cancer with neuroendocrine features
Figure 1. (a) Macroscopic findings for LLL tumors. A yellow- white well definedmass measuring 14 x 10.5 x 8 em in the LLL was compressing the surrounding
normal lung parenchyma with formation of a capsule-like structure. (bHe) Microscopic findings for LLL tumor. Small cell component consists of smallcells with
largeN/Cratio,scantycytoplasm andfinely granular nuclearchromatin withhighmitoticactivity (b). Cellsin smallcell/large cellcomponent have eosinophilic larger
cytoplasmand vesicular nucleuswithdistinctnucleolus (c). Organoid components form welldemarcated roundto ovoidclusters resembling atypical carcinoidin the
background of smallcell/large cells or spindlecells(d).Sarcomatous components havespindle-shaped cellsof VaI;OUS sizes(e).Hematoxylin andeosinstain;original
magnifications, x333 (b, c), x l67 (d), x130 (e).
small size of the specimen. Computed tomography of the chest
showed no enlargement of the mediastinal or hilar lymph nodes.
Magnetic resonance imaging (MRI) of the brain showed a 6 x 6
mm solitary mass in the right cerebellar hemisphere. The LLL
was resected in December 1994. Part of the left upper lobe (LUL)
of the lung was also resected because another nodule was found
in the LUL during the operation. Radiation therapy to the brain
was performed when the brain mass was found to have grown to
14 x 14 mm on MRI in January 1995, suggesting a brain
metastasis. After 50 Gy of radiation to the brain, the nodule could
Jpn J Clin OncoI1999;29(4)
221
Figure 2. (a) Macroscopicfindings for LLL and LUL tumors. A white round nodulemeasuring2.1 x 1.7 x 1.5 em was presentin the LUL(S1+2) with a clear margin.
(b), (c) Microscopicfindings for LUL tumor. The tumor consists of glandularstructure lined by tall columnar cells with hyperchromatic nucleiand coarse-granular
chromatin (b). There were organoid nests showing occasional rosette formation (c). Hematoxylin and eosin stain; original magnifications, x83 (b), x4 10 (c).
no longer be detected on MRI of the brain. No chemotherapy was
given. Left leg pain occurred in February 1997 due to bone
metastasis. Computed tomography of the chest showed multiple
pulmonary metastases. Dyspnea developed and the patient died
in February 1997, 2 years and 4 months after the operation. An
autopsy was not performed.
We performed an immunohistochemical analysis to the formalin-fixed, paraffin-embedded sections by the avidin-biotin
complex (ABC) method (6). Biotinylated secondary antibody
and ABC reagents were purchased from Dako Japan (Kyoto,
Japan). Primary antibodies used were against keratin (AE1/AE3,
Dako, Dakopatts, Glostrup, Denmark; CAM5.2, Becton Dickinson, San Jose, CA, USA), surfactant apoprotien A (Sp-A) (PE-lO,
Dako), surfactant apoprotein D (Sp-D) (6B2, Yamasa, Chiba,
Japan), CD56 (Lu243, Nippon Kayaku, Tokyo, Japan), chromogranin A (Dako) , synaptophysin (Dako), CDS7 (Leu7, Becton
Dickinson), gastrin-releasing peptide (GRP) (Dako) , serotonin
(SHT-H209, Dako), calcitonin (Dako) , CEA (011, Mochida,
Tokyo, Japan), vimentin (V9, Dako), myoglobin (Dako), desmin
(033, Dako) , alpha-smooth muscle actin (lA4, Dako), S-lOO
protein (Dako), Factor VIII (Dako), p53 (Nichirei, Tokyo, Japan)
and Rb (MK-15-1 , MBL, Nagoya, Japan).
A yellow-white, well defined mass measuring 14 x 10.5 x 8 cm
in S10 of the LLL was compressing the surrounding normal lung
parenchyma with formation of a capsule-like structure; the center
of the mass revealed extensive hemorrhage and necrosis . (Fig.
1a). The LLL showed poor aeration and moderate anthracosis and
fibrosis , especially beneath the pleura, but no emphysema.
A round, white nodule measuring 2.1 x 1.7 x 1.5 em and having
well defined margins was found in Sl+2 of the LUL . The tumor
was solid and there was no evidence of hemorrhage or necrosis.
A sharp pleural indentation was detected (Fig. 2a).
The LLL tumor was largely necrotic, but there were viable
tumor cells in the periphery. It consisted of four components:
small cell, large cell, organoid and sarcomatous . The small cell
component was composed of oval to spindle-shaped cells slightly
larger than lymphocytes and having a large N/C ratio, scanty
cytoplasm and oval nuclei with fmely granular chromatin but no
nucleoli (Fig. 1b). The large cell component consisted of
polygonal to round cells that were larger than the cells in the small
222
Lung cancer with neuroendocrine features
columnar cells. The tumor cells contained relatively abundant
eosinophilic cytoplasm and hyperchromatic nuclei with coarsegranular chromatin and distinct eosinophilic nucleoli (Fig. 2b).
Mitotic activity was high (25/10 HPF). The stroma was scant. The
tumor had a focal solid growth area with organoid nests showing
occasional rosette formation (Fig. 2c). Nuclear palisading was also
seen in the periphery of the nests. No lymphatic permeation or
vascular invasion was observed. Hilar lymph nodes contained no
metastatic tumors. Mediastinal lymph nodes were not explored.
The results of the immunohistochemical analysis are shown in
Table 1. The small cell/large cell component. of the LLL was
diffusely positive for CD56 (Fig. 3a) and chromogranin A and
partially positive for keratin.. The organoid component was
positive for CD56, chromogranin A, synaptophysin (Fig. 3b),
GRP and CEA. The sarcomatous component was positive for
vimentin (Fig. 3c) and some spindle-shaped also cells showed an
immunoreaction for keratin (Fig. 3d). The LUL tumor was
positive for CD56, chromogranin A (Fig. 4), GRP, calcitonin,
CEA and keratin. The positive rates for p53 were 79% of the cells
in the small cell/large cell component, 13% in the organoid
component, 80% in sarcomatous component and 8% in the LUL
tumor. Rb was positive only in the LUL tumor (30%) and
negative in all components of the LLL tumor.
cell component and they contained abundant eosinophilic cytoplasm and a vesicular nucleus with one or two prominent nucleoli
(Fig. 1c). Small cells and large cells were frequently intermingled.
Both types of cells had high mitotic activity [22/10 high power
field (HPF)] and clusters of pure small cell carcinoma cells were
also observed focally. In the organoid component, the neoplastic
cells formed well demarcated round to ovoid clusters resembling
atypical carcinoid in the background with small cell/large cells or
spindle cells (Fig. 1d). The cells forming the organoid structure
were polygonal to spindle shaped and had a fmely granular nucleus
with one or two prominent nucleoli. Mitotic activity was high
(24/10 HPF). The sarcomatous cells were spindle shaped and their
nuclei were variable in size and contained coarse chromatin with
one or two prominent nucleoli (Fig. Ie). The small cell/large cell
carcinoma, spindle cell sarcomatous carcinoma and organoid
components were highly intermingled with areas of transition
between them; the proportions of these components were about 65,
30 and 5%, respectively. No lymphatic permeation or vascular
invasion was observed. The remaining non-neoplastic pulmonary
parenchyma showed no evidence of carcinoid tumorlets or
neuroendocrine cell hyperplasia.
The LUL tumor had a clear margin and showed expansive
growth. It consisted of irregular-shaped glands lined by tall
Table 1. Immunohistochemical profiles of left lower lobe and left upper lobe tumors
LLL tumor
Antigens
S/L
Keratin (AEI/AE3)
Organoid
+ (partly)
Keratin (CAM5.2)
±
Sp-A
+ (partly)
+
LUL tumor
Sarcomatous
±
+
+
+++
Sp-D
+
+
Chromogranin A
+
+
Synaptophysin
+
+++
+
+ (partly)
CD56
+
CD57
GRP
Serotonin
+
Calcitonin
+
CEA
+
+
Vimentin
Myoglobin
Desmin
Alpha-smooth muscle actin
S-IOO protein
Factor VIII
p53*
Rb*
79%
13%
80%
8%
30%
LLL, left lower lobe; LUL, left upper lobe; S/L, small cell/large cell carcinoma; Sp-A, surfactant apoprotein A; Sp-D, surfactant apoprotein D; GRP, gastrin-releasing
peptide. *The percentage of immunoreactive cells counted in 500 cells.
Jpn J Clin OncoI1999;29(4)
223
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Figure 3. Immunohistochemical findings for LLL tumor. Small cell/large cell component was diffusely positive for CD56 (a), Organoid component was positive for
synaptophysin (b). Sarcomatous component was positive for vimentin (c) but some spindle-shaped cells showed immunoreaction for keratin (d). Original
magnification, x4 1O.
DISCUSSION
Our differential diagnosis of the LLL tumor was (i) small cell
carcinoma with spindle cell component, (ii) large cell NE
carcinoma and (iii) atypical carcinoid. The high mitotic activity
(22/10 HPF) ruled out atypical carcinoid, although some parts of
the LLL tumor showed features resembling atypical carcinoid,
such as an organoid growth pattern, tumor cells containing
moderately eosinophilic, finely granular cytoplasm and nuclei
possessing finely granular chromatin. Small cell carcinoma was
preferred over large cell NE cancer because the LLL tumor
consisted mainly of two kinds of cells, small-sized tumor cells
with a high N/C ratio and large-sized polygonal to round tumor
cells with one or two prominent nucleoli . In addition, the small
cells and large cells were highly intermingled and clusters of pure
small cell carcinoma cells were also observed focally, We
therefore concluded that the LLL tumor was a mixed small
cell/large cell carcinoma, one of the subtypes of small cell lung
carcinoma in the IASLC classification (3),
Spindle cell carcinoma has been found most often in association with giant cell carcinoma and adenocarcinoma, less
frequently with large cell carcinoma or squamous cell carcinoma
Figure 4. Immunohistochemical findings for LUL tumor. It was positive for
chromogranin A. Original magnification, x41O.
and infrequently with small cell carcinoma (7). Tsubota et al. (4)
reported a case of combined small cell (pure type) and spindle cell
carcinoma of the lung. The spindle cell carcinoma was predomi-
224
Lung cancer with. neuroendocrine features
nant and immunoreactive for smooth-muscle actin, but not for NE
markers, in their case, whereas the small cell/large cell component in our case occupied more of the tumor than the spindle cells.
Moreover, the spindle cell sarcomatous area in our case did not
show clear NE features or differentiation to mesenchyme but
exhibited epithelial differentiation, indicating poorly differentiated carcinoma or sarcomatoid change of carcinoma. The
spindle cell sarcomatous component was immunohistochemically positive for p53 and the frequency of positive cells was
almost same as in the small cell/large cell component, suggesting
that although their phenotypes were different, a similar genetic
abnormality may have occurred in both.
We considered three possible diagnoses for the LUL mass:
(i) moderately differentiated adenocarcinoma, tubular type, with NE
features, (ii) combined adenocarcinomaand large cell NE carcinoma
and (iii) metastatic carcinoma from the LLL tumor. The LUL tumor
exhibited glandular structures lined by tall columnar cells and
organoid nests of large pleomorphic cells with rosette formation and
nuclear palisading. The latter pattern may be seen in large cell NE
carcinoma (1); however, the clear glandular differentiation favored
adenocarcinoma rather than large cell NE carcinoma.
Immunohistochemical testing yielded different characteristics
in the LUL and LLL tumor. Calcitonin and Rb were positive only
in the LUL tumor. Furthermore, the LLL tumor exhibited no
evidence of glandular differentiation, indicating that the LUL
tumor was not a metastasis of the LLL tumor. Immunohistochemical study showed that both the organoid and the glandular
component of the LUL tumor had NE features, indicating that it
was an adenocarcinoma with NE features rather than a combination of adenocarcinoma and NE carcinoma.
The relationship between LLL and LUL tumors is a matter of
controversy. The LUL tumor was immunohistochemically positive for p53 the same as the organoid area in the LLL tumor, but
positive cells were less frequent than in the small cell/large cell
or spindle cell sarcomatous lesions. The NE marker study showed
that the LUL tumor and the organoid area in the LLL might
differentiate with NE feature better than small cell/large cell or
spindle lesions. LUL tumor. resembled the organoid component
in the LLL in the immunohistochemical pattern of the NE
markers (CD56, chromogranin A, synaptophysin, GRP). The
same genetic change may have occurred in the areas of these two
tumors exhibiting NE features, even though their morphology
was different. Genetic analysis might resolve this issue.
The only case of multiple lung cancer with NE features reported
previously was a case of bronchial carcinoid, small cell carcinoma
and adenocarcinoma of the right lung described by Jung-Legg et
al. (8) The series of synchronous double primary lung cancers
reported by Carey et al. (9) included cases of combined non-small
cell lung cancer and small cell lung cancer or carcinoid, but there
were no cases of double cancer with NE differentiation demonstrated by immunohistochemistry. Since these cases were not
immunohistochemically tested for NE markers, some of them may
have been double cancer, both of which had NE differentiation. In
any event, the occurrence of synchronous double cancers with NE
features in both appears to be a rare event.
The survival time in our case was 2 years and 4 months without
chemotherapy, longer than in ordinary small cell lung cancer (10).
The median survival for limited stage small cell lung cancer treated
by surgery alone has been reported to be about 6 months (11).
Tsubota et al. did not comment on the outcome of their case of a
combined small cell and spindle cell carcinoma of the lung. Small
cell lung cancer has a poor prognosis although it is sensitive to
chemotherapy and radiation. In contrast to small cell lung cancer,
spindle cell carcinoma is also generally considered to have a poor
prognosis and to be resistant to irradiation and chemotherapy
(12,13). The metastatic brain tumor in our case was as sensitive to
radiation therapy as small cell lung cancer; however, it recurred 2
years after surgery, a much longer latent period than in ordinary
small cell lung cancer. No lymph node metastasis was observed in
our case despite the large tumor, a finding also different from usual
small cell lung cancer. The reason for the comparatively good
outcome in our case remains unclear. Two-year disease-free
survivors represented 13% of patients presenting with limited
small cell lung cancer but only 2% of those with extensive disease
(10). More than 80% of 2-year survivors of small lung cell lung
cancer have been found to have received chest irradiation and
almost all extensive disease patients had metastases confmed to a
single organ system (11). In our case, however, the brain was the
only metastatic site at the time of presentation. Hardly any
long-term survivors of resected small cell lung cancer have had
lymph node metastases or distant metastases (14,15). The present
case was exceptional, because the patient survived for a long time
in spite of the brain metastasis and having been treated only by
resection of the lung tumors and radiotherapy to the brain. Slow
growth may have been one of the characteristics of the tumors in
our case, despite their high mitotic activity.
In conclusion, we have reported a unique case of synchronous
double primary lung cancers with a combination of small
cell/large cell carcinoma and a spindle sarcomatous component
in the LLL and adenocarcinoma with NE features in the LUL. At
presentation the tumor had metastasized to the brain, but not to
lymph nodes. Radiation to the brain after resection of the lung
tumors was very effective. The survival time in our patient, who
did not receive chemotherapy, was 2 years and 4 months. Multiple
lung cancers with NE features are extremely rare and similar
cases have not been reported in the literature.
Acknowledgments
This work was supported in part by a Grant from the Ministry of
Health and Welfare for the 2nd term Comprehensive Strategy for
Cancer Control and a Grant-in Aid for Cancer Research from the
Ministry of Health and Welfare, Japan.
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