Maman et al.

EJNMMI Reports (2024) 8:1 European Journal of

https://doi.org/10.1186/s41824-024-00187-8
Hybrid Imaging

ORIGINAL ARTICLE Open Access

Diagnostic value of FDG PET‑CT

in differentiating lung adenocarcinoma
from squamous cell carcinoma
Adem Maman1* , Sadık Çiğdem2, İdris Kaya3, Rabia Demirtaş4, Onur Ceylan4 and Sevilay Özmen4

*Correspondence:
adem.maman@atauni.edu.tr Abstract
1
Department of Nuclear Background: Lung cancer is the leading cause of cancer-related deaths worldwide.
Medicine, Faculty of Medicine, The combination of fluorine-18 fluorodeoxyglucose positron emission tomography
Atatürk University, Erzurum, (18F-FDG PET) and computed tomography (CT) has a major impact on the diagnosis,
Turkey
2
Vocational School of Health staging, treatment planning and follow-up of lung cancer patients. The maximum
Services, Istanbul Aydın standardized uptake value (SUVmax) is an easily performed and most widely used
University, Istanbul, Turkey semi-quantitative index for the analysis of FDG PET images and estimation of metabolic
3
Department of Radiology,
Private Buhara Hospital, Erzurum, activity. This study aimed to investigate the role of PET/CT in differentiating adenocar-
Turkey cinoma (ADC), the most common lung cancer, from squamous cell carcinoma (SCC)
4
Department of Medical by comparing FDG uptake measured as SUVmax.
Pathology, Faculty of Medicine,
Atatürk University, Erzurum, Results: Between 2019 and 2022, 76 patients diagnosed with non-small cell lung
Turkey cancer (NSCLC) at the Department of Pathology, Atatürk University Faculty of Medi-
cine, with histopathologic evidence of adenocarcinoma or squamous cell carcinoma,
underwent retrospective analysis using PET/CT scanning to measure PET parameters
of the lesions and compare them with histopathology. Among 76 NSCLC patients
included in the study, 43 (57%) were histopathologically diagnosed as ADC and 33
(43%) as SCC. SUVmax, SUVmean, metabolic tumor volume (MTV) and total lesion gly-
colysis (TLG) values of lesions in patients with SCC were statistically significantly higher
than those in patients with ADC (p values 0.007, 0.009, 0.003 and 0.04, respectively).
Conclusions: Lung SCC has higher metabolic uptake values than ADC, and PET/CT
can be used to differentiate them.
Keywords: Non-small cell lung cancer, Squamous cell carcinoma, Adenocarcinoma,
Fluorine-18 fluorodeoxyglucose positron emission tomography

Introduction
Lung cancer is the most common cancer worldwide and is responsible for most cancer-
related deaths. According to the World Health Organization (WHO), lung cancer is
the leading cause of cancer deaths globally (Mattiuzzi and Lippi 2019). Lung cancers are
divided into two main groups: small cell lung cancer (SCLC) and non-small cell lung cancer
(NSCLC). NSCLC is the most common type and accounts for approximately 80–85% of all
lung cancer cases. The main histologic types of NSCLC are adenocarcinoma (ADC) and

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Maman et al. EJNMMI Reports (2024) 8:1 Page 2 of 8

squamous cell carcinoma (SCC) (Goldstraw et al. 2007). The location within the lung is one
of the differences between SCC and ADC. SCC tends to be central and may have internal
cavitation, while ADC tends to be peripheral and solid (Gharraf et al. 2020). Lung adeno-
carcinoma is the most common type of lung cancer, accounting for about 40% of all lung
cancers. It tends to arise in the periphery of the lungs as it originates from small airway epi-
thelial cells that secrete mucus and other substances (Zappa and Mousa 2016). SCC is the
second most common type of lung cancer after lung adenocarcinoma and originates from
the bronchial surface epithelium. Tumor cells are characterized by a squamous appearance
similar to that observed in epidermal cells. Lung SCC is more strongly linked to tobacco
smoking than other forms of NSCLC. It usually arises in the center of the larger bronchi
and often metastasizes to the locoregional lymph nodes early in its course, but spreads
outside the thorax later than other major types of lung cancer (Sabbula et al. 2023). Early
and accurate diagnosis of lung cancer is invaluable for successful treatment and good out-
comes. The 5-year survival rate of small, localized stage 1 NSCLCs with surgical resection
is approximately 70–90%. However, the majority of patients, 3 out of 4, are diagnosed at an
advanced stage and have a poor prognosis (Goldstraw et al. 2007; Walters et al. 2013).
Positron emission tomography/computed tomography (PET/CT) with fluorodeoxyglu-
cose (FDG) labeled with fluorine-18 (F-18), a glucose analog, is now routinely used in clini-
cal practice for both the evaluation of lung nodules and the staging of lung cancer. Due to
its high diagnostic accuracy in lung cancer, FDG PET/CT imaging is now included as a rou-
tine diagnostic modality in many clinical lung cancer guidelines (Ettinger et al. 2019; Kita-
jima et al. 2016). FDG PET/CT has become an important tool in the diagnosis and staging
of NSCLC. The maximum standard uptake value (SUVmax) in FDG PET/CT is the ratio of
activity in tissue per unit volume relative to the dose carried by body weight. SUVmax of
primary tumors has been found to correlate with stage, nodal status, histological type, dif-
ferentiation and tumor progression in patients with NSCLC. Furthermore, high SUVmax
value has been shown to have serious effects on prognostic factor in patients with NSCLC
(Shimizu et al. 2014). However, the application of treatments other than surgery in patients
with FDG PET/CT positive lesions requires histopathologic confirmation (Ettinger et al.
2019). There is a 20% risk of pneumothorax during transthoracic biopsy. With FDG PET/
CT imaging, it may be possible to overcome this risk in many patients with lung nodules. In
addition, in the case of a malignant lesion, a possible pneumothorax may delay other proce-
dures for diagnostic evaluation, which increases the importance of non-invasive FDG PET/
CT imaging (Madsen et al. 2016).
In this study, we aimed to investigate whether semi-quantitative parameters of FDG PET/
CT correlated with the main histological types of NSCLC, ADC and SCC, in retrospectively
screened NSCLC patients. In particular, we tried to analyze whether SUVmax, SUVmean,
metabolic tumor volume (MTV) and total lesion glycolysis (TLG) values of FDG PET/CT
differed in patients diagnosed with lung SCC and ADC.

Materials and methods

Study design
Seventy-six NSCLC cases diagnosed as adenocarcinoma and squamous cell carcinoma
with pneumonectomy, lobectomy, segmentectomy and wedge resection materials in the
pathology department of the university hospital, between 2019 and 2022, were included
Maman et al. EJNMMI Reports (2024) 8:1 Page 3 of 8

in this study. Information on age, gender, tumor histological type, tumor diameter, lymph
node involvement, visceral pleural invasion status and pathological stage were obtained
from the hospital automation system and the Ministry of Health e-Nabız system. H&E
stained preparations of the resection materials were re-examined by two observers, and
histopathologic typing was performed according to WHO 2021 criteria.

PET/CT
Patients enrolled in the study were fasted for at least 6 h. Blood glucose levels were con-
firmed to be less than or equal to 140 mg/dl before 18F FDG infusion. 5.5 MBq/kg 18F
FDG was administered intravenously 1 h before imaging. One hour after the injection,
imaging was performed from the upper thigh to the head with the patient in the supine
position for 3 min per bed by Biograph 6 PET/CT (Siemens Medical Systems, Germany).
Whole-body PET/CT images were evaluated by an experienced nuclear medicine spe-
cialist. Clinical staging of the patients was performed according to the TNM system of
the 8th version of the American Joint Committee on Cancer/Union for International
Cancer Control (AJCC/UICC). Pathologic lesion areas were drawn by the nuclear medi-
cine specialist, and Suvmax, Suvmean, MTV and TLG values were automatically meas-
ured and recorded by Siemens VIA program for FDG uptake.

Statistical analysis
Number, percentage, mean and standard deviation were used in the evaluation of the
data. Independent samples t test was used in the evaluation of normally distributed
data. Mann–Whitney U and Kruskall–Wallis tests were used for data that did not show
homogeneous distribution. p values of 0.05 and below were accepted as significant.

Results
A total of 76 patients, 15 (19.7%) females and 61 (80.3%) males, were included in our
study. The mean age of the patients was 59 ± 9.91 years (min 26, max 78). The clinical
characteristics of the patients are listed in Table 1. Excluding the incidence of ADC and
SCC in women, which may be explained by their regional non-smoking habits (Corn-
field et al. 2009), the parameters in Table 1 show an almost homogeneous distribution
between ADC and SCC. The slides of all cases were re-evaluated by two pathologists and
43 were confirmed as ADC and 33 as SCC. In addition, tumor size, pleural invasion and
tumor spread within the air spaces (STAS), which affect lung cancer stage and prognosis,
were evaluated. Pleural invasion was present in 22% of our cases (17 cases), while 78%
(59 cases) were negative. 41 patients had STAS, while 35 patients did not. Tumor size
is an important factor in the staging of lung cancers (Rami-Porta et al. 2015). Tumor
size should be given in the most accurate way because it can change the stage of the
tumor. In 41 cases, the tumor size was 1–3 cm and was considered as stage 1. Twenty-
seven cases were stage 2, i.e., tumor size was 3–4 cm or 1–3 cm with pleural invasion.
Six cases were stage 3, and two cases were stage 4. In 14 cases, lymph node metastasis
was observed, but not in 37 cases. In 25 cases there were no clear data about lymph node
metastasis. Lymphovascular invasion was detected in 43 cases.
The values of PET parameters (SUVmax, SUVmean, MTV and TLG) are compared
between ADC and SCC in Table 2. Statistical analysis was performed to assess whether
Maman et al. EJNMMI Reports (2024) 8:1 Page 4 of 8

Table 1 Demographic characteristics of the cases

Parameters Total number ADC SCC Significance
(percentage) (p value)

Number of patients (n) 76 43 (57%) 33 (43%) NA

Age (Year, Mean ± SD) 59 ± 9.9 59 ± 10.4 60 ± 9.3 0.633
Gender (F/M)
Female 15 (20%) 15 0 NA
Male 61 (80%) 28 33 NA
Pathologic staging (n)
Stage 1 41 (54%) 25 16 NA
Stage 2 27 (36%) 14 13 NA
Stage 3 6 (7%) 2 4 NA
Stage 4 2 (3%) 2 0 NA
TNM Staging
Stage 1 26 (34%) 18 8 NA
Stage 2 36 (48%) 18 18 NA
Stage 3 10 (13%) 5 5 NA
Stage 4 4 (5%) 2 2 NA
Lymphovascular invasion (n)
Positive 43 (57%) 27 16 NA
Negative 33 (43%) 16 17 NA
STAS status
Positive 41 (54%) 31 10 NA
Negative 35 (46%) 12 23 NA
Lymph node metastasis
Positive 14 (18%) 5 9 NA
Negative 37 (49%) 17 20 NA
NoS 25 (33%) 21 4 NA
Pleural invasion
Positive 17 (22%) 11 6 NA
Negative 59 (78%) 32 27 NA
ADC, adenocarcinoma; SCC, squamous cell carcinoma; NA, Not Applicable

Table 2 Comparison of PET parameters between ADC and SCC

ADC SCC Test value p value

SUVmax 8.19 ± 6.57 13.18 ± 9.04 t = − 2.78 p = 0.007

SUVmean 4.88 ± 3.74 7.60 ± 5.06 t = − 2.69 p = 0.009
MTV 10.79 ± 21.11 12.25 ± 14.64 MW-U = 430.00 p = 0.003
TLG 77.81 ± 211.01 150.47 ± 299.12 MW-U = 522.00 p = 0.04

there were significant differences in these variables. For the SUVmax, the mean value
in ADC was 8.19 ± 6.57, whereas it was 13.18 ± 9.04 in SCC. The t test revealed a sta-
tistically significant difference between the two groups (t = − 2.78, p = 0.007), indicating
that SUVmax values were significantly higher in SCC compared to ADC. Similarly, for
the SUVmean, the mean value in ADC was 4.88 ± 3.74, and in SCC, it was 7.60 ± 5.06.
The t test demonstrated a statistically significant difference (t = − 2.69, p = 0.009),
Maman et al. EJNMMI Reports (2024) 8:1 Page 5 of 8

suggesting that SUVmean values were significantly higher in SCC compared to ADC.
For MTV, the mean value in ADC was 10.79 ± 21.11, and in SCC, it was 12.25 ± 14.64.
The nonparametric Mann–Whitney U test indicated a statistically significant difference
(MW-U = 430.00, p = 0.003), implying that MTV values were significantly higher in SCC
compared to ADC. Lastly, for the TLG, the mean value in ADC was 77.81 ± 211.01,
while in SCC, it was 150.47 ± 299.12. The Mann–Whitney U test revealed a statistically
significant difference (MW-U = 522.00, p = 0.04), indicating that TLG values were sig-
nificantly higher in SCC compared to ADC. In conclusion, the statistical analysis dem-
onstrates significant differences in the parameters SUVmax, SUVmean, MTV, and TLG
between the two groups. Representative pictures of ADC and SCC in Fig. 1 also show
FDG uptake in SCC is higher than that in ADC. The results apparently suggest that there
are statistically significant differences between the two groups being compared for each
parameter, as indicated by the small p values (p < 0.05). SCC exhibits higher values for
PET parameters compared to ADC.

Discussion
In this study, we analyzed the variances in semi-quantitative SUVmax, SUVmean, MTV
and TLG values of FDG PET/CT between lung carcinomas diagnosed with ADC and
SCC. We found significant differences between ADC and SCC. According to our study,
SUVmax, SUVmean, MTV and TLG values were significantly higher in SCC patients
compared to ADC patients (p values 0.007, 0.009, 0.003 and 0.04, respectively).
Early and accurate diagnosis of lung cancer subtypes is of vital importance. Although
PET/CT technology, which can perform non-invasive tumor assessment for classifica-
tion, staging, efficacy and prognostic evaluation, has been shown to be useful in deter-
mining the subtype of cancers in recent studies, the parameters for its use in this field
have not yet matured (Sun et al. 2023). In this study, similar to recent studies (Salem
et al. 2021), we found that quantitative PET/CT values were higher in SCC (Table 2).
The advantage of FDG PET/CT is that it combines the functional-metabolic informa-
tion of PET with the detailed anatomical-morphologic information of CT in a single
hybrid study. PET/CT has also been used to assess metabolic activity in lung cancers.
Semi-quantitative PET parameters such as MTV and TLG values have previously shown
promising results in providing prognostic insight for disease progression of respiratory
system tumors (Jin et al. 2018).

Fig. 1 Representative pictures of ADC (left) and SCC (right). SUVmax values for ADC and SCC are 13.03 and
21.22, respectively
Maman et al. EJNMMI Reports (2024) 8:1 Page 6 of 8

The mRNA and protein expression of metabolic markers has been shown to be higher
in squamous cell carcinomas than in adenocarcinomas, whereas adenocarcinomas are
better vascularized (Goodwin et al. 2017). Adenocarcinomas have a worse disease-free
survival (DFS) compared to squamous cell carcinomas based on the potential for metas-
tasis. Adenocarcinomas have been shown to exhibit glycolysis under normoxic condi-
tions, whereas squamous cell carcinomas are subjected to diffusion-limited hypoxia
(Schuurbiers et al. 2014). Although squamous cell carcinomas have a higher FDG uptake,
which is generally considered a poor prognostic factor, adenocarcinomas have a higher
metastatic potential and a worse DFS (Schuurbiers et al. 2014). These findings suggest
that FDG PET should be interpreted in relation to histology. FDG PET may improve the
prognostic potential of the disease and its use in histology-related treatment strategies
could be expanded.
Studies on this subject are limited. Similar to the results of previous studies, Schur-
biers et al. and Hyun et al. showed that SCC had a higher SUV value compared to ADC
as a general trend although there was no statistically significant difference in the SUV
value of static PET between ADC and SCC in their study (Schuurbiers et al. 2014; Hyun
et al. 2019). This may provide a theoretical basis and technical support for early, accurate
and personalized treatment. The cellular reason for this may be that SCC has a higher
rate of glycolysis and less vascularization compared to the high perfusion and low rate
of glucose phosphorylation in ADC (Sun et al. 2023; Vriens et al. 2012). Patnaik et al.’s
meta-analysis showed that higher values of SUVmax, MTV and TLG predicted a higher
risk of recurrence or death in patients with surgical NSCLC. They recommended the use
of FDG PET/CT to select patients at high risk of disease recurrence or death who may
benefit from aggressive therapies (Patnaik et al. 2016).
The number of patients in the study is limited for a comprehensive conclusion; never-
theless, it provides important clues for a clear distinction between ADC and SCC. More-
over, our study was performed on operated patients, so the number of stage 4 patients
is small, and a more comprehensive study can be performed with a similar number of
patients at each stage.

Conclusions
In conclusion, 18F-FDG PET/CT imaging has a marked potential for the classification
of NSCLC and differential diagnosis of subtypes and thus may help clinicians to improve
the histopathologic diagnosis of lung cancer in a noninvasive manner.

Abbreviations
FDG PET Fluorine-18 fluorodeoxyglucose positron emission tomography
SUVmax Maximum standardized uptake value
SUVmean Mean standardized uptake value
ADC Adenocarcinoma
SCC Squamous cell carcinoma
NSCLC Non-small cell lung cancer
MTV Metabolic tumor volume
TLG Total lesion glycolysis

Acknowledgements
Not applicable.
Maman et al. EJNMMI Reports (2024) 8:1 Page 7 of 8

Author contributions
All authors were involved in the study conception and design. AM, İK, RD, OC and SÖ were involved in acquisition of
data. AM, SÇ and SÖ were involved in analysis and interpretation of the data and drafting of the manuscript and were
responsible for review, editing and supervision. All authors read and approved the final manuscript.

Funding
Atatürk University Hospital funded the salary for the authors affiliated in Faculty of Medicine.

Availability of data and materials

Data supporting our findings are available from the corresponding author upon reasonable request.

Declarations
Ethics approval and consent to participate
Our study was approved by the ethics committee of Atatürk University Faculty of Medicine for retrospective analysis and did
not require informed consent. The study was performed in accordance with the ethical standards as laid down in the 1964
Declaration of Helsinki and its later amendments or comparable ethical standards.

Consent for publication

Written informed consent was obtained from all the patients.

Competing interests
The authors declare no conflict of interest.

Received: 6 November 2023 Accepted: 19 December 2023

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