2008, Volume 24, Number 3, Page(s) 174-178
Three cases of combined small cell lung carcinoma with review of the literature
İrem Hicran ÖZBUDAK1, Güzide Ayşe GÖKHAN1, Gülay ÖZBİLİM1, Ömer ÖZBUDAK2, Esin ÖZEL3, Alpay SARPER4
1 Akdeniz Üniversitesi Tıp Fakültesi, Patoloji Anabilim Dalı, ANTALYA
2 Akdeniz Üniversitesi Tıp Fakültesi, Göğüs Hastalıkları Anabilim Dalı, ANTALYA
3 Antalya Patoloji Merkezi, ANTALYA
4 Akdeniz Üniversitesi Tıp Fakültesi, Göğüs Cerrahisi Anabilim Dalı, ANTALYA
Keywords: Combined small cell carcinoma, lung
Combined small cell lung carcinoma is an uncommon
entity and constitutes 1-3% of all cases with small cell
lung carcinoma (SCLC). We reported three cases of
combined small cell lung carcinoma. All the cases were
male (ages: 77, 60 and 55 years, respectively) with a history
of heavy smoking and presented with lung masses.
Additionally, first case had been a history of asbestos
exposure for 5-6 years. Histopathological examination
of biopsy specimens revealed a rare variant of small cell
lung carcinoma ie combined small cell lung carcinoma.
In addition to histological evidence of small cell lung
carcinoma, the first biopsy specimen also contained
areas of squamous cell carcinoma and the other two biopsy
specimens revealed adenocarcinomatous cells. Immunohistochemical
findings supported the diagnosis.
Combined small cell lung carcinoma is very rare, but is
nevertheless a well described diagnostic category among
lung cancers. In this case report, because of the rarity
of these tumors, we discussed combined small cell lung
carcinoma in view of the literature.
Under the headline of small cell lung carcinoma
(SCLC), two different categories have
been recognized according to the criteria of
World Health Organization/International Association
for the Study of Lung Cancer (WHO/
IASLC) since 1999. These are; SCLC and combined
. SCLC accounts for 10-20% of
all lung cancers and among them the incidence
of combined SCLC has been reported as 1-3%.
Affected patients are usually male and heavy
. Combined SCLC contains
any subtypes of non-small cell lung carcinoma
(NSCLC) such as adenocarcinoma (AC), squamous
cell carcinoma (SCC), large cell carcinoma
and less commonly spindle cell or giant cell
carcinoma in addition to small cell carcinoma
. In this report, we present three cases
of combined SCLC and review the literature.
A 77-year-old man was admitted
to the hospital because of dispnea and cough. He
had a history of asbestos exposure and heavy cigarette
smoking. Chest computerized tomographic
(CT) scans demonstrated a 9x10 cm lung
mass located in the left upper lobe. Pleural involvement
and contralateral hilar lymphadenopathy
were detected, and so the case was evaluated
clinically as Stage III B. Bronchoscopic and
pleural biopsies were performed for diagnosis.
Bronchoscopic and pleural biopsy specimens
revealed two different tumor cell types.
The SCLC component was characterized by
small round cells which had finely granular and
hyperchromatic nuclei, inconspicuous nucleoli
and scant cytoplasm. A very common artifact,
which is defined as “nuclear molding” was seen.
The other part of the tumor was composed of
medium-sized cells with pleomorphic nuclei
containing vesicular chromatin and abundant
keratinized eosinophilic cytoplasm. This component
was diagnosed as squamous cell carcinoma
He was treated with 4 cycles of chemotherapy
involving cisplatin and etoposide.
Case 2: A 62-year-old man with a strong
history of cigarette smoking (100 packet/year)
was hospitalized because of vena cava superior
syndrome. On chest CT scan, a 13x7x5 cm mass
was found in the right paratracheal area. On the
radiological examination distant metastases were
detected in surrenal glands bilaterally. A supraclavicular
lymphadenopathy was found on clinical
examination and it was excised for microscopic
evaluation. By this data, the case was clinically
evaluated as Stage IV. He was treated
with cisplatin, etoposide and thoracal radiotherapy
was performed for vena cava superior involvement.
The histological findings of supraclavicular
lymph node were very similar to Case 1 regarding
the SCLC component. However in this
tumor, the SCLC component was admixed with
irregular solid nests and glandular structures of
adenocarcinoma which had medium-sized cells
with hyperchromatic nuclei and abundant cytoplasm
Case 3: A 55-year-old man was admitted
to the hospital with complaints of cough and
chest pain. Radiological studies suggested a
mass in 1 cm diameter which originated from
the superior segment of the right lower lobe and
infiltrated through the upper lobe. Bilateral mediastinal
lymphadenopathy was also detected
and wedge resection with mediastinal lymph node
excision was performed.
Biopsy materials both from lung and
lymph node revealed tumoral involvement. Histopathologically,
SCLC component was similar
to the other cases whereas other part of the tumor
was consisted of moderately differentiated
adenocarcinoma that composed of adenoid
structures localized within desmoplastic stroma
Stage of tumor was evaluated as III B according
to T1 N3 M0. Both chemotherapy and
radiotherapy are being planned for this patient.
Histochemistry and Immunohistochemistry
Histochemically, mucin stain was applied
to all cases. Immunohistochemistry was performed
using the following antibodies; Synaptophysin
(Neomarker, 1/100, RM-9111), Chromogranin
A (Neomarker, 1/100, MS-382), Neuron
Specific Enolase (NSE) (Neomarker, 1/100,
MS-335), Thyroid Transcription Factor-1 (TTF-1) (Novocastra, 1/100, NCL-L-TTF-1), High
Molecular Weight Cytokeratin (HMWC) (Neomarker,
1/50, MS-346) and Carcino Embriogenic
Antigen (CEA) (Neomarker, 1/50, MS-613).
SCLC component of all tumors was negative
for mucin stain and immunoreactive with
Synaptophysin, Chromogranin A, NSE and
TTF-1 (Figure 4a and 4b). Intracytoplasmic mucin
was shown in AC areas. SCC and AC components
of tumors showed positive immunoreactivity
with HMWC and CEA respectively,
with the characteristic dot-like accentuation in
their cytoplasm (Figure 5 and 6) (Table 1). AC
cells were positive with TTF-1, whereas SCC
cells were negative.
Click Here to Zoom
|Figure 4a: Immunostaining of Synaptophysin adjacent to adenocarcinoma areas in Case 3 (x100).
Click Here to Zoom
|Figure 4b: Immunostaining of Chromogranin A in small cell carcinoma cells of Case 1 (x100).
Click Here to Zoom
|Figure 5: HMWC positivity in squamous cell carcinoma areas of Case 1 (x200).
Many histopathologic classifications of
SCLC have been proposed during the last 30 years.
However, combined type SCLC as a separate
category was proposed for the first time by
WHO in 1981. SCLC was then subdivided into
oat cell, intermediate, and combined type categories.
After a while, WHO criteria were modified
by IASLC; the distinction between oat cell
and intermediate types was discarded and both
categories were referred to as small cell carcinoma.
In addition, a new category -the mixed
small cell/large cell carcinoma-was introduced
as a subtype of SCLC 2,4
. In 1999, WHO
adopted the IASLC pathology panel to comprise
the core membership of WHO committee and
to develop a new revised classification of lung
and pleural tumors. This classification is called
the WHO/IASLC Histological Classification of
Lung and Pleural Tumors. In this classification
mixed small cell/large cell carcinoma subtype
was discarded and finally a consensus was reached
to classify SCLC subtypes as pure SCLC
and combined SCLC 1,6
Combined SCLC is defined as a tumor
with predominant features of small cell carcinoma
with a minor (5% or less) component of any
histological types of NSCLC. Among these
components squamous cell carcinoma, adenocarcinoma
and large cell carcinoma are commonly
seen but spindle cell and giant cell carcinoma
variants have been also noted (1,7-9).
In SCLC, tumor cells are small, usually 7-10 μm in size and fusiform shaped. They have a
higher nuclear-cytoplasmic ratio with lack of
nucleoli and they frequently demonstrate nuclear
molding, smearing or crush artifact which are
termed as Azzopardi effect 7. Other types of
lung carcinomas, e.g. SCC or AC can be differentiated
from small cell carcinoma by their
abundant cytoplasm, different nuclear features,
histologic pattern and immunohistochemical
There is no difference in treatment modality
and prognosis between combined and pure
SCLC according to the literature 4,10. Adverse
clinical prognostic factors for both types of
SCLC include advanced stage of the disease,
poor performance status, elevated serum LDH
or alkaline phosphatase, low plasma albumin
and low plasma sodium levels 1. At molecular
level, c-kit positivity in tumor cells reported as
an independent prognostic factor 11. As to the
treatment, chemotherapy and radiotherapy are
performed for these patients.
In this report, three cases of combined
SCLC of an uncommon type were presented.
The first one showed a combination of small
cell carcinoma with squamous cell component.
Both second and third cases were composed of
small cell carcinoma and adenocarcinoma. All
of the cases were at an advanced stage so chemotherapy
and radiotherapy were performed for
the first and the second cases, and same protocols
are planning for the last patient.
Combined SCLC is an uncommon type of
the lung carcinomas and during clinical and histopathological
examination, the diagnosis of
combined SCLC especially from bronchoscopic
biopsy specimens may be difficult. Differentiation
between and combined SCLC is important
because of their different therapy modalities
than those performed for NSCLC.
1) Travis WD, Brambilla E, Müler-Hermelink K, Harris CC. Tumors of the lung. In: World Health Organization Classification of Tumours, Pathology & Genetics, Tumors of the lung, pleura, thymus and heart. Lyon: IARC, 2004; p.9-124,
2) Hasleton PS. Common Lung Cancers. In: Spencer's Pathology of the Lung. 5th ed. New York: McGraw-Hill,1996; p.1009-1065.
3) Hirsch FR, Matthews MJ, Aisner S, Campobasso O, Elema JD, Gazdar AF, et al. Histopathologic classification of the small cell lung cancer. Changing concepts and terminology. Cancer 1988;62:973-977.
4) Hage R, Elbers JRJ, Brutel de la Riviere A, van den Bosch JM. Surgery for combined type small cell lung carcinoma. Thorax 1998;53:450-453.
5) Rosai J. Lung and pleura. In: Rosai and Ackerman's Surgical Pathology. 9th ed. St Louis: Mosby, 2004; p.359-458.
6) Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y. The new World Health Organisation Classification of lung tumours. Eur Respir J 2001;18:1059-1068.
7) Chetty R. Combined large cell neuroendocrine, small cell and squamous carcinomas of the lung with rhabdoid cells. Pathology 2000;32:209-212.
8) Shikata H, Ueda Y, Tsuchishima S, Nonaka T, Watanabe Y, Matsubara J. Single primary lung cancer consisting of three cancer cell types (small cell carcinoma, adenocarcinoma and squamous cell carcinoma) in which each had metastasized to different lymph nodes. Jpn J Thorac Cardiovasc Surg 2002;50:216-219.
9) Yekeler H, Dağlı AF, Deveci F, Karaoğlu A, Çobanoğlu B. Bronkoskopik fırça ve lavaj sitolojisi ile tanı konulan kombine tip primer akciğer karsinomu: Olgu sunumu. FÜ Sağlık Bil. Dergisi 2004;18:243-246.
10) Mangum MD, Greco FA, Hainsworth JD, Hande KR, Johnson DH. Combined small cell and non small cell lung cancer. J Clin Oncol 1989;7:607-612.
11) Rohr UP, Rehfeld N, Pflugfelder L, Geddert H, Müller W, Steidl U, et al. Expression of the tyrosine kinase ckit is an independent prognostic factor in patients with small cell lung cancer. Int J Cancer 2004;111:259-263.