Three young osteosarcoma patients with small adenocarcinoma or atypical adenomatous hyperplasia of the lung.
ABSTRACT Three young osteosarcoma patients with adenocarcinoma (AD) or atypical adenomatous hyperplasia (AAH) of the lung are reported. A 14-year-old male patient with femoral osteosarcoma had solitary AD (case 1); a 23-year-old female patient with femoral osteosarcoma had AAH and lung metastasis (case 2); and a 17-year-old male patient with humeral osteosarcoma had AD and lung metastasis of osteosarcoma (case 3). They have been the youngest patients with lung cancer or AAH in our hospital. The maximum diameter of each lung tumor on computed tomography (CT) was 0.5, 0.6, and 0.5 cm, respectively. On immunohistochemical analyses, the p53 was positive in both AD and osteosarcoma and negative in both AAH and osteosarcoma. On genomic analyses, p53 mutation was detected in only one osteosarcoma (case 3). Epidermal growth factor receptor (EGFR) mutations, short in-frame deletion in exon 19, and insertion in exon 20 were found in AD, but not in AAH or osteosarcoma. There was no apparent genomic relationship between AD/AAH and osteosarcoma in the young patients in this study. Advances in CT and its applications to osteosarcoma patients as a method of assessing lung metastasis might contribute in large part to the detection of AD/AAH in patients younger than 30.
Article: Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications.[show abstract] [hide abstract]
ABSTRACT: Recently it has been reported that mutations in the tyrosine kinase domain of the epidermal growth factor receptor(EGFR) gene occur in a subset of patients with lung cancer showing a dramatic response to EGFR tyrosine kinase inhibitors. To gain further insights in the role of EGFR in lung carcinogenesis, we sequenced exons 18-21 of the tyrosine kinase domain using total RNA extracted from unselected 277 patients with lung cancer who underwent surgical resection and correlated the results with clinical and pathologic features. EGFR mutations were present in 111 patients (40%). Fifty-two were in-frame deletions around codons 746-750 in exon 19, 54 were point mutations including 49 at codon 858 in exon 21 and 4 at codon 719 in exon 18, and 5 were duplications/insertions mainly in exon 20. They were significantly more frequent in female (P < 0.001), adenocarcinomas (P = 0.0013), and in never-smokers (P < 0.001). Multivariate analysis suggested EGFR mutations were independently associated with adenocarcinoma histology (P = 0.0012) and smoking status (P < 0.001), but not with female gender (P = 0.9917). In adenocarcinomas, EGFR mutations were more frequent in well to moderately differentiated tumors (P < 0.001) but were independent of patient age, disease stages, or patient survival. KRAS and TP53 mutations were present in 13 and 41%, respectively. EGFR mutations never occurred in tumors with KRAS mutations, whereas EGFR mutations were independent of TP53 mutations. EGFR mutations define a distinct subset of pulmonary adenocarcinoma without KRAS mutations, which is not caused by tobacco carcinogens.Cancer Research 01/2005; 64(24):8919-23. · 7.86 Impact Factor
Article: Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas.[show abstract] [hide abstract]
ABSTRACT: HER-2/neu gene amplification and cell surface overexpression are important factors in breast cancer for prognosis and prediction of sensitivity to anti-HER-2/neu monoclonal antibody therapy. In lung cancer, the clinical significance of HER-2/neu expression is currently under evaluation. We investigated 238 non-small lung carcinomas for HER-2/neu protein overexpression by immunohistochemistry using the HercepTest. We found 2+ or 3+ overexpression in 39 patients (16%), including 35% in adenocarcinomas and 20% in large cell carcinomas, but only 1% of squamous cell carcinomas. Marked (3+) overexpression was uncommon (4%). The association between protein expression and gene copy number per cell, as determined by fluorescence in situ hybridisation assay, was investigated in 51 of these NSCLC tumours. Twenty-seven tumours (53%) were negative by both tests. Marked (3+) protein expression and gene amplification were present in only 4% of samples. In 11 tumours (21%), gene gain was accompanied by chromosomal aneusomy and did not result in high protein levels while in 7 (14%) the score 2+ was associated with maximum number of signals per cell <9. The prognostic implication of HER-2/neu protein expression was studied in 187 surgically resected tumours. No statistical difference in survival was observed comparing patients with positive (2+/3+) and negative tumours (0/1+), although 3+ patients showed a tendency to shorter survival. The therapeutic implications of protein expression and gene amplification in lung cancer need to be examined in prospective clinical trials.British Journal of Cancer 05/2002; 86(9):1449-56. · 5.04 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: It has been reported that the c-erbB-2 protooncogene is frequently amplified and overexpressed in many types of cancers, except sarcomas and hematological malignancies. Expression of ErbB-2 in the tumors of 26 patients with conventional osteosarcoma was evaluated by immunoblotting. DNA from osteosarcoma tissues that expressed ErbB-2 were analyzed by Southern blot hybridization to examine gross rearrangement of the gene. The DNA was also surveyed for the presence of genetic mutation in the transmembrane domain of ErbB-2 by polymerase chain reaction-single-stranded DNA conformation polymorphism analysis. In addition, possible correlation of ErbB-2 expression with gender, age, histopathologic subtype, and response to chemotherapy was analyzed. Survival analysis was performed by the Kaplan-Meier test using the approximate chi-square statistic for the log-rank test. The ErbB-2 protein was detected in 11 of 26 osteosarcoma tissues (42%) by immunoblot analysis. Expression of ErbB-2 was confirmed by immunohistochemical studies using specific anti-ErbB-2 monoclonal antibody. However, neither amplification of the c-erbB-2 gene nor evidence of significant genetic mutation was found in these osteosarcomas. Expression of ErbB-2 examined by immunoblotting was most strongly correlated with early pulmonary metastases (P < 0.05). Among the entire group of 26 patients in this study, Kaplan-Meier life table survival of the patients with apparent ErbB-2 expression was significantly worse than that of the patients with little ErbB-2 expression (P < 0.01). In 42% of the osteosarcomas, the tumor cells expressed ErbB-2. Expression of ErbB-2 was strongly correlated with early pulmonary metastasis and poor survival rate for the patient. These data suggest that ErbB-2 plays a significant role in aggressive tumor growth and in the promotion of metastatic potential in osteosarcomas. ErbB-2 in the osteosarcoma tissues would be a useful prognostic marker for patients.Cancer 02/1996; 77(1):71-8. · 4.77 Impact Factor
358Ann Thorac Cardiovasc Surg Vol. 16, No. 5 (2010)
Three Young Osteosarcoma Patients with Small
Adenocarcinoma or Atypical Adenomatous
Hyperplasia of the Lung
Kenji Shiraishi, MD, PhD,1 Takeshi Mori, MD, PhD,1 Yasuomi Ohba, MD,1
Kazunori Iwatani, MD,1 Kentaro Yoshimoto, MD,1 and Ken-ichi Iyama, MD, PhD2
From 1Department of Thoracic Surgery, Graduate School of
Medical Sciences; and 2Division of Surgical Pathology, Kumamoto
University Hospital, Kumamoto University, Kumamoto, Japan
Received June 10, 2009; accepted for publication July 31, 2009
Address reprint requests to Takeshi Mori, MD, PhD: Department
of Thoracic Surgery, Graduate School of Medical Sciences,
Kumamoto University, Honjo, 1–1–1, Kumamoto 860–8556, Japan.
©2010 The Editorial Committee of Annals of Thoracic and
Cardiovascular Surgery. All rights reserved.
Three young osteosarcoma patients with adenocarcinoma (AD) or atypical adenomatous
hyperplasia (AAH) of the lung are reported. A 14-year-old male patient with femoral osteo-
sarcoma had solitary AD (case 1); a 23-year-old female patient with femoral osteosarcoma
had AAH and lung metastasis (case 2); and a 17-year-old male patient with humeral osteo-
sarcoma had AD and lung metastasis of osteosarcoma (case 3). They have been the youngest
patients with lung cancer or AAH in our hospital. The maximum diameter of each lung
tumor on computed tomography (CT) was 0.5, 0.6, and 0.5 cm, respectively. On immunohis-
tochemical analyses, the p53 was positive in both AD and osteosarcoma and negative in both
AAH and osteosarcoma. On genomic analyses, p53 mutation was detected in only one osteo-
sarcoma (case 3). Epidermal growth factor receptor (EGFR) mutations, short in-frame
deletion in exon 19, and insertion in exon 20 were found in AD, but not in AAH or osteosar-
coma. There was no apparent genomic relationship between AD/AAH and osteosarcoma in
the young patients in this study. Advances in CT and its applications to osteosarcoma patients
as a method of assessing lung metastasis might contribute in large part to the detection of AD/
AAH in patients younger than 30. (Ann Thorac Cardiovasc Surg 2010; 16: 358–361)
Key words: lung cancer, young patient, osteosarcoma, computed tomography
Lung cancer in a young patient is very rare. Among
13,121 cases of lung cancer treated surgically in Japan in
1999, only 23 patients (0.2%) were less than 30 years old.1)
In our hospital, 3 patients under 30, none of whom had
ever smoked, with lung cancer or atypical adenomatous
hyperplasia (AAH) had osteosarcoma. All of their tumors
were found before the initiation of chemotherapy for
osteosarcoma. These facts suggest the relationship between
lung cancer, especially adenocarcinoma (AD) and AAH,
and osteosarcoma. We report 3 cases of AD/AAH combined
with osteosarcoma. Immunohistochemical and genomic anal-
yses for AD/AAH and the osteosarcoma are also provided.
A 14-year-old male patient underwent amputation of the
left femur for osteosarcoma in July 1997. Preoperative
chest computed tomography (CT) revealed a 0.5-cm
diameter nodule in the superior segment of the lower
lobe of the left lung. No changes in size or features of the
nodule were observed on CT after perioperative chemo-
therapy for osteosarcoma. In November 1997, a thoracoscopic
wedge resection of the tumor was performed. The tumor
was diagnosed histopathologically to be AD. This case
Three Young Osteosarcoma Patients with Small Adenocarcinoma or Atypical Adenomatous Hyperplasia of the Lung
Ann Thorac Cardiovasc Surg Vol. 16, No. 5 (2010)359
had been reported previously.2) The patient died in October
2000 of respiratory failure because of multiple lung
metastases from osteosarcoma.
A 23-year-old female patient underwent artificial knee
joint replacement following wide resection of the right
femur for osteosarcoma in January 2006. Preoperative
CT revealed a 0.6-cm diameter ground-glass opacity
(GGO) in the anterobasal segment of the lower lobe of
the right lung (Fig. 1). No changes in size or features of
the nodule were observed on CT after perioperative che-
motherapy for osteosarcoma. In February 2006, a
thoracoscopic wedge resection of the tumor was per-
formed. The tumor was diagnosed histopathologically to
be AAH (Fig. 2). A follow-up CT in May 2007 revealed
a 1.2-cm diameter nodule with a cavity in the superior
segment of the lower lobe of the right lung. In June 2007,
a thoracoscopic wedge resection of the tumor was per-
formed, and it was histopathologically proved to be
metastasis of osteosarcoma. The patient has been alive
without disease for 23 months since the metastasectomy.
A 17-year-old male patient underwent artificial shoulder
joint replacement following wide resection of the left
humerus for osteosarcoma after preoperative chemotherapy
Fig. 1. Chest computed tomography showed small
ground-glass opacity in the anterobasal segment of
the lower lobe of the right lung (Case 2).
Fig. 2. Microscopic findings of the lung tumor. The monotonous
tumor cells were lining intermittently according to the thick-
ened alveolar septa (Case 2).
in June 2007. Postoperative chest CT revealed a 0.5-cm
diameter nodule in the laterobasal segment of the lower
lobe of the right lung, and a 0.5-cm diameter GGO in the
posterobasal segment of the lower lobe of the right lung
(Fig. 3). Retrospective review confirmed that the appearance
of the GGO in the posterolateral segment was unchanged
compared with that observed on the CT in March 2007.
In February 2008, a thoracoscopic wedge resection of the
tumors was performed. The tumor in the laterobasal seg-
ment was histopathologically proved to be metastasis of
osteosarcoma. The other tumor, located at the poster-
obasal segment, was diagnosed to be bronchioloalveolar
carcinoma (BAC) (Fig. 4). The patient has been alive
without disease for 15 months since the lung resection.
The study protocol for immunohistochemical and
genomic analyses of osteosarcoma and lung tumor speci-
mens was approved by the Ethical Committee of
Kumamoto University Hospital in June 2008. After written
informed consents from the patients and/or their families
had been obtained, immunohistochemistry of p53 and
genomic analyses of p53, epidermal growth factor receptor
(EGFR) mutations, K-ras, and human epidermal growth
factor receptor 2 (HER-2) were performed. The immuno-
histochemical and genomic analyses were both performed
by SRL Laboratory Inc., Tokyo, Japan.
For immunohistochemical analysis of p53 protein in
the tumor tissue, deparaffinized 4-μm-thick sections
were examined. A specific mouse anti-p53 protein antibody
(Novocastra Laboratories, Newcastle upon Tyne, UK)
Shiraishi et al.
Ann Thorac Cardiovasc Surg Vol. 16, No. 5 (2010)
was used for this study.
For genomic analyses of the tumor tissue, DNA was
extracted from formalin-fixed, paraffin-embedded speci-
mens. (1) For a detection of EGFR mutation, direct
sequencing from EGFR exon 18–21 was performed. (2)
For a detection of p53 mutation, a nonradioactive poly-
merase chain reaction-single strand conformation
polymorphism (PCR-SSCP) analysis was used to analyze
exons 5–8 of the p53 gene for sequence alterations. (3) For
K-ras mutation, the nested PCR amplification for exon 2
was performed. (4) For HER-2 mutation, a fluorescence
in situ hybridization (FISH) analysis was performed
using the PathVysion HER-2 DNA Probe Kit (Vysis,
Stuttgart, Germany). Hybridization was performed using
hybridization solution containing direct-labeled DNA
probes complementary to HER-2 and chromosome 17
centromere. HER-2 and chromosome 17 centromere sig-
nals were counted for 60 nuclei per tumor specimen.
Overlapping nuclei were excluded from analysis. HER-2
gene amplification was defined as HER-2: chromosome
17 centromere ratio of 2.0 using the Vysis probe. The
characteristics of immunohistochemical and genomic
analyses for these cases are shown in Table 1.
On immunohistochemical analysis, p53 was positive in
both AD and osteosarcoma in Cases 1 and 3, but negative
in both AAH and osteocarcoma in Case 2. EGFR muta-
tions, short in-frame deletion in exon 19 (Case 1), and
insertion in exon 20 (Case 3) were found in AD, but not
in AAH. EGFR mutation was not found in osteosarcoma.
Mutation of p53 in exon 7 was detected in osteosarcoma
(Case 3). No other genomic mutations were detected.
Lung cancer in young patients is very rare. Of 13,121 lung
cancer patients who underwent surgery in Japan in 1999,
only 23 (0.2%) were less than 30 years old.1) Of 627
patients with lung cancer or AAH of the lung treated
operatively in our hospital from 1999 to 2008, only three
under the age of 30 had osteosarcoma. These facts sug-
gested a relationship between lung cancer and osteosarcoma
in young patients.
Germline mutation of p53, such as Li-Fraumeni syn-
drome, which is characterized by multiple early-onset
primary malignancy, was a candidate to cause both AD/
AAH and osteosacrcoma in the same person.3,4) This
hypothesis was partly supported by an immunohistochemical
study of p53, but not by genomic analysis. EGFR muta-
tion has an important role for carcinogenesis in some
subsets of lung AD.5) In osteosarcoma, EGFR mutation
was also reported.6) In this study, it was detected only in
AD (Cases 1 and 3), but not in osteosarcoma.
Expression of HER-2 was reported in both lung cancer7)
and osteosarcoma.8,9) K-ras and EGFR mutations were
reported to exhibit a mutually exclusive pattern in lung
AD.5) Both HER-2 and K-ras were negative in the AD/
AAH, but they were examined only in AD/AAH, not in
Fig. 3. Chest computed tomography showed small
ground-glass opacity in the posterobasal segment
of the lower lobe of the right lung (Case 3).
Fig. 4. Microscopic findings of the lung tumor. The monotonous
and crowding tumor cells were lining according to the thick-
ened alveolar septa (Case 3).
Three Young Osteosarcoma Patients with Small Adenocarcinoma or Atypical Adenomatous Hyperplasia of the Lung
Ann Thorac Cardiovasc Surg Vol. 16, No. 5 (2010) 361
Table 1. Characteristics of immunohistochemical and genomic mutation analyses for osteosarcoma and lung tumor
AD/AAH Immunohistochemistry Genomic mutations
Osteosarcoma Lung tumor Osteosarcoma Lung tumor
exon 19 delL747-T751
exon 20 insQ773-V774
AD: adenocarcinoma; AAH: atypical adenomatous hyperplasia; AD/AAH: AD or AAH; EGFR: epidermal growth factor receptor;
HER-2: human epidermal growth factor receptor 2; del: deletion; ins: insertion; L:Lysine; T: Threonine; Q: Glutamine; V: Valine
osteosarcoma. Although our immunohistochemical and
genomic exploration for a common oncogenic pathway of
AD/AAH and osteosarcoma was limited, none may be
Chemotherapy was thought to have no role for these
cases of AD/AAH because they were detected before
chemotherapy for osteosarcoma was initiated.
Although we could not deny the existence of a com-
mon oncogenic pathway between lung cancer and
osteosarcoma, the use of CT to screen for lung metastasis
from osteosarcoma was thought to contribute in large
part to the detection of AD/AAH in young patients under
the age of 30 in this study. Thus the number of young
patients with lung cancer might be higher than previously
1. Japanese Joint Committee of lung cancer. Lung cancer
in Japan. Analysis of lung cancer registry for resected
cases in 1999. (in Japanese) Jpn J Lung Cancer 2007;
2. Kobayashi H, Mori T, Yoshioka M, Tanaka M, Okuma
T, et al. A-14-year-old boy with small primary lung
cancer. (in Japanese) Jpn J Chest Surg 1999; 13: 144–7.
3. Kimura K, Shinmura K, Hasegawa T, Beppu Y,
Yokoyama R, et al. Germline mutation in a patients
with multiple primary cancers. Jpn J Clin Oncol 2001;
4. Izawa N, Matsumoto S, Manabe J, Tanizawa T, Hoshi
M, et al. A Japanese patient with Li-Fraumeni syn-
drome who had nine primary malignancies associated
with a germline mutation of the p53 tumor-suppressor
gene. Int J Clin Oncol 2008; 13: 78–82.
5. Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T,
et al. Mutations of the epidermal growth factor recep-
tor gene in lung cancer: biological and clinical
implications. Cancer Res 2004; 64: 8919–23.
6. Wen YH, Koeppen H, Garcia R, Chiriboga L, Tarlow
BD, et al. Epidermal growth factor receptor in osteo-
sarcoma: expression and mutational analysis. Hum
Pathol 2007; 38: 1184–91.
7. Hirsch FR, Varella-Garcia M, Franklin WA, Veve R,
Chen L, et al. Evaluation of HER-2/neu gene amplifi-
cation and protein expression in non-small cell lung
carcinomas. Br J Cancer 2002; 86: 1449–56.
8. Onda M, Matsuda S, Higaki S, Iijima T, Fukushima J,
et al. ErbB-2 expression is correlated with poor progno-
sis for patients with osteosarcoma. Cancer 1996; 77: 71–8.
9. Gorlick R, Huvos AG, Heller G, Aledo A, Beardsley
GP, et al. Expression of HER-2/erbB-2 correlates with
survival in osteosarcoma. J Clin Oncol 1999; 17: 2781– 8.