ONCOLOGY LETTERS 2: 827-830, 2011

Small-cell lung carcinoma with long-term survival: A case report

KAZUMI NISHINO1, FUMIO IMAMURA1, TORU KUMAGAI1, JUNJI UCHIDA1,
YUKI AKAZAWA1, TAKAKO OKUYAMA1 and YASUHIKO TOMITA2

1
Department of Thoracic Oncology; 2Institute of Pathology, Osaka Medical Center for
Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan

Received March 28, 2011; Accepted June 20, 2011

DOI: 10.3892/ol.2011.355

Abstract. Small-cell lung carcinoma is the most aggres- disease (2,3). In this study, we present a case of SCLC in a
sive among lung cancer subtypes, has a poor prognosis and never smoker who has survived for 14 years without achieving
is highly associated with smoking. We present a case of a complete remission following the initial relapse.
small‑cell lung carcinoma in a patient who had never smoked
and has survived for 14 years without achieving a complete Case report
remission since the first relapse. His long-term survival may be
ascribed to the slow growth of the cancer cells, limited metas- In November 1996, a 44-year-old male, with no history of
tasis and favorable responses to the treatments he has received. smoking, presented at the Osaka Medical Center for Cancer
During these 14 years, only two lymph node metastases and a and Cardiovascular Diseases with an abnormal hilar shadow
single metastasis to the brain developed. His small-cell lung in the left lung, complaining of cough and dyspnea. A comput-
carcinoma has been well controlled each time by the various erized tomography (CT) scan revealed a 4.5x3.0 cm hilar mass
treatments he has received, including chemotherapy, radio- in the left lung (Fig. 1A). The patient was cytologically diag-
therapy and surgery. Pathologically, the tumor was a typical nosed with SCLC by bronchoscopic examination (Fig.  1B).
small-cell lung carcinoma with extensive necrosis. Results Metastatic workup demonstrated that he had limited disease,
showed the mitotic rate and the cell proliferation markers cT2aN2M0 stage IIIA (the 7th edition of the TNM system for
to be greater than those in the intermediate-grade atypical lung cancer). The values of serum neuron-specific enolase and
carcinoid, but relatively low. Thus, we conclude that this case carcinoembryonic antigen were within normal limits and the
belongs to an overlap between intermediate- and high-grade pro-gastrin-releasing-peptide (ProGRP) was not measured at
neuroendocrine tumors. the time. The patient received four cycles of chemotherapy
consisting of cisplatin (CDDP) and etoposide, with concurrent
Introduction thoracic radiation of 44 Gy at 2.2 Gy/fraction daily. The treat-
ment resulted in a complete response. Prophylactic cranial
The 2004 World Health Organization (WHO) classification irradiation was not performed since there was no evidence to
proposed four subtypes of pulmonary neuroendocrine (NE) recommend it at the time (4).
tumors: low-grade typical carcinoid (TC), intermediate-grade The patient remained asymptomatic and no sign of disease
atypical carcinoid (AC) and two high-grade tumors, large cell recurrence was detected until December 1998, when right
neuroendocrine carcinoma (LCNEC) and small-cell lung mandibular lymphadenopathy was evidenced. By that time,
carcinoma (SCLC) (1). SCLC is a highly aggressive cancer the level of ProGRP had gradually been elevating from 25 pg/
and results in mortality in 2-4 months without treatment. Most ml in October 1997 to 76 pg/ml in August 1998 and 133 pg/
patients respond to primary therapy, but survival remains poor ml in December 1998 (normal range 0-45 pg/ml). Aspiration
and median survival times are reported to be approximately needle cytology of the lymph node revealed metastasis of
24 months in limited disease and 12 months in extensive SCLC, leading to the diagnosis of recurrence of SCLC as the
cancer cells obtained from the lymph node revealed almost
the same morphological features as the primary lung tumor
cells. Since imaging studies showed no recurrence with the
exception of the lesion, and the WBC count was ~3,000/µl, the
Correspondence to: Dr Kazumi Nishino, Department of Thoracic patient was administered palliative radiotherapy with a total
Oncology, Osaka Medical Center for Cancer and Cardiovascular
dose of 70 Gy without chemotherapy. The lymphadenopathy
Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan
E-mail: [email protected] disappeared and the level of ProGRP decreased to 14.1 pg/ml.
Two years later, in April 2000, the right axillary lymph node
Key words: small-cell lung carcinoma, pulmonary neuroendocrine was found to be enlarged and cytology revealed metastasis of
tumors, atypical carcinoid, The 2004 WHO Classification, long-term SCLC. Palliative radiotherapy with a total dose of 60 Gy was
survival administered to the lesion. The lymph node swelling did not
disappear completely, but the level of ProGRP decreased from
154 to  44  pg/ml. Although the level of ProGRP was slowly
828 NISHINO et al: A CASE OF SCLC WITH LONG-TERM SURVIVAL

A A

Figure 1. (A) A CT image in November 1996 revealed a 4.5x3.0-cm hilar

mass in the left lung. (B) Cytology of the material obtained bronchoscopi-
cally from the primary lung tumor revealed SCLC.

elevated to 150 pg/ml in November 2002, the patient observed

no further symptoms and subsequently stopped consultation
with the hospital. Figure 2. (A) Brain MRI in September 2006 showed a huge mass in the right
temporal lobe. (B) Hematoxylin and eosin (H&E) and immunohistological
The patient presented at the Osaka Medical Center for staining of the specimen from the resected brain tumor. The tumor cells
Cancer and Cardiovascular Diseases again in September were positive for CD56, chromogranin and synaptophysin, indicating the
2006. Neurological examinations at admission indicated neuroendocrine origin of the tumor. a, H&E stain; b, CD56 stain; c, chromo-
cerebral abnormality: left upper 1/4 homonymous hemianopsia granin stain; d, synaptophysin stain. Original magnification, x200.
and dysrhythmia on the electroencephalogram. The level of
ProGRP was markedly elevated (2,860 pg/ml). Magnetic reso-
nance imaging (MRI) of the brain revealed a huge mass in the
right temporal lobe (Fig. 2A). The brain tumor was completely detected on the MRI in November 2008 and the patient
excised and histopathological examination determined it to be underwent intensity-modulated radiotherapy (IMRT) for the
a metastasis of SCLC. The tumor was cytologically identical brain tumor. Following IMRT, the patient was administered
to the primary lung cancer, showing extensive necrosis, a high chemotherapy with CDDP and CPT11. However, compliance
nuclear-to-cytoplasmic ratio and fine nuclear chromatin. The to the chemotherapy was poor due to hematological toxicity.
mitotic rate was 14 mitoses per 10 high-power fields (HPF) in In September 2009, the patient was admitted for obstructive
this resected specimen. The Ki-67 labeling index was 25%. pneumonia in the left lower lobe with high fever, and treated
Immunohistochemical stains were positive for NE markers, successfully with antibiotics. The level of ProGRP elevated to
including chromogranin A, synaptophysin and CD56 (Fig. 2B). 724 pg/ml and distinct progression of the primary hilar tumor
The primary hilar tumor in the left lung and the right axillary in the left lung was again detected by CT. The patient refused
lymph node revealed an increased uptake of fludeoxyglucose to complete systemic chemotherapy and was followed up
in positron emission tomography (PET) scanning. The patient for 1 year. In November 2010, CT and PET detected distinct
received whole brain radiation therapy (WBRT) (30  Gy in progression of the primary lung tumor resulting in atelectasis
10 fractions), followed by systemic chemotherapy with CDDP of the left lower lobe and right axillary lymphadenopathy. The
and irinotecan hydrochloride (CPT11). Although the doses level of ProGRP was elevated to 1,640 pg/ml. Chemotherapy
of CDDP and CPT11 were reduced to 50 and 50 mg/m2, with amrubicin was administered in December 2010.
respectively, ProGRP levels decreased notably to 90.7 pg/ml, At present, the clinical course of the patient has continued
following chemotherapy. for 14 years following the initial diagnosis of SCLC and
From September 2007, the level of ProGRP was again 4 years following the diagnosis of brain metastasis. The
gradually elevated. Recurrence of brain metastasis was brain remains relapse-free at present. The patient is currently
 ONCOLOGY LETTERS 2: 827-830, 2011 829

continuing treatment with amrubicin for SCLC and his prognosis, with an over 14-year survival, support the diag-
performance remains positive. nosis of AC, while the morphological, immunohistochemical
and structural features of the tumors are typical of SCLC.
Discussion We believe that this case fits the diagnostic criteria of SCLC
according to the WHO classification, but it is a borderline case
NE tumors represent approximately 20% of all primary lung between AC and SCLC. Asamura et al reported that 5-year
neoplasms (5). NE tumors of the lung are separated into four survival rates for TC, AC, LCNEC and SCLC in Japanese
subgroups: low-grade TC, intermediate-grade AC and two surgical cases of NE tumors were 96.2, 77.8, 40.3 and 35.7%,
high-grade malignancies, LCNEC and SCLC, according respectively (8). An analysis of Japanese lung cancer patients
to WHO in 2004 (1). SCLC is the most common NE tumor registered in 2002 revealed that SCLC accounted for 9.2% of
(20% of total lung cancers), followed by LCNEC (3%), TC new lung cancer cases in Japan, and 5-year survival rates were
(2%) and AC (0.2%) (6). The tumors differ morphologically, 17.2% for stage IIIA, 12.4% for stage IIIB, 3.8% for stage IV
immunohistochemically and structurally. The WHO clas- and 14.7% overall (11).
sification defines SCLC as a NE tumor with greater than The prognosis is particularly dismal in SCLC patients with
10 mitoses/10  HPF and small-cell cytologic features. TC is brain metastasis. In the practice guidelines recently published
considered a NE tumor with carcinoid morphology, fewer in the Journal of Neurooncology, the authors recommend
than 2 mitoses/10 HPF and lacking in necrosis, while AC is surgical resection followed by WBRT for newly-diagnosed
defined as a NE tumor with carcinoid morphology showing single brain metastases, which improves outcomes when
2-10 mitoses/10 HPF or necrosis (1). The grade of malignancy compared to WBRT alone. However, these authors indi-
of each NE subtype is correlated with clinicopathological cate that the recommendation does not apply to relatively
behavior and prognosis of the disease. TC and AC are rela- radiosensitive tumors such as SCLC (12). By contrast, Jesien-
tively slow-growing tumors and generally exhibit a favorable Lewandowicz et al assert that patients with solitary brain
outcome, while LCNEC and SCLC are very aggressive with a metastasis from SCLC should be treated radically, in particular
dismal prognosis (5,6). those at younger ages with a small primary tumor in the lung,
The accurate differential diagnosis of carcinoids from good performance status and lack of systemic dissemination
SCLC is critical in the selection of the appropriate treatment. (13). Four case reports describe excellent long-term survival
Usually, SCLC is rarely mistaken for carcinoids, with the following resection of a solitary metastatic brain tumor of
exception of small biopsy materials. There are also certain SCLC and adjuvant WBRT (13-16). In the present case,
differences in the clinical background and profiles according to surgical resection followed by WBRT and chemotherapy was
the subgroup of NE tumors. Unlike carcinoids, SCLC is mark- successful. Imai et al suggest that a subtype of slow-growing
edly associated with a history of smoking (7,8). Carcinoids SCLC, which shows different biological properties, should be
tend to occur in younger patients (mean age 45-50 years), distinguished from the common type SCLC (16). Although
whereas the high-grade NE tumors affect older patients (mean unusual, patients with this subtype of NE tumor may poten-
age 65 years). The former are capable of distant metastases in tially achieve longer survival than those with typical SCLC,
less than 20% of cases (most commonly to liver and bones), and should be treated with local and multimodality treatment
and SCLC tends to metastasize to the brain, liver, adrenal on a case-by-case basis.
glands and bone with higher frequency (5,6). Due to the low In conclusion, we present a case report of a SCLC patient
response rates for chemo- and radiotherapy, surgical resection who has survived for 14 years following initial diagnosis
is primarily used in the treatment of carcinoids, whereas the with persistent disease, in spite of repetitive multimodality
standard treatment for limited-stage SCLC includes combined therapies. This case suggests the existence of borderline cases
chemoradiotherapy due to high sensitivity. between intermediate- and high-grade NE tumors, and that
This case was initially diagnosed as SCLC in 1996 by long-term survival may be expected with suitable treatments.
cytological sampling obtained using bronchoscopy. The initial A method should be established to select SCLC patients with
chemoradiotherapy resulted in a complete response. Ten a favorable prognosis, such as this case, and to find optimal
years later, a metastatic brain tumor was excised. Although therapeutic approaches for such patients.
the clinical course was not typical for SCLC, the histo-
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