18F-FDG PET/CT is Valuable in Detecting Soft-tissue Metastasis of Lung Cancer CURRENT STATUS:

Background Soft-tissue metastasis (STM) is a relatively rare, but not exceptional, manifestation of lung cancer. Since the lesions of STM are usually asymptomatic, they are easy to miss during clinical evaluation. The aim of the study was to explore the incidence and characteristics of STM in lung cancer using fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT), and evaluate its effect on tumor staging and treatment. Methods We analyzed 4543 patients with lung cancer who underwent 18 F-FDG PET/CT in our hospital between January 2013 and September 2018. 85 were diagnosed with STM and included in the study group. Imaging characteristics, clinical symptoms, and survival time (from confirmed STM to death) were recorded for all study subjects. Results A total of 219 lesions were identified by 18 F-FDG PET/CT: 215 were detected by PET (maximum standardized uptake value = 6.12); 139 were detected by CT. Muscle STM were primarily found in the hip, upper limb muscle; whereas subcutaneous STM were mainly distributed in the chest and abdomen, back. In 68 patients (80%), STM were found incidentally during routine 18 F-FDG PET/CT staging. The lesions were symptomatic in 17 cases (20%); in 10 patients (11.8%) STM was the first manifestation. Other site metastases were detected in 79 patients (92.9%). Isolated STM were found in 6 patients (7.1%), whose tumor staging and treatment were affected by PET/CT findings. At the end of the follow-up period, 69 patients were dead (median survival time= 5.0 months) and 5 were lost to follow-up. Conclusions STM may be a sign of advanced stage and poor prognosis in lung cancer. 18 F-FDG PET/CT is highly valuable in the detection of STM, and can impact tumor staging and management of lung malignancies.

Soft-tissue metastasis (STM) refers to the growth of tumor cells in soft tissue that is not connected to the primary tumor or regional lymph nodes, and comprises metastases to skeletal muscle and subcutaneous tissue [6][7][8]. Although skeletal muscle and subcutaneous soft tissue account for more than 50% of the human body weight, STM is relatively rare [6][7][8]. Lung cancer is the most common primary tumor of STM, with adenocarcinoma being the most common histological variant [9][10][11][12][13][14][15][16]. A recent study by Kanaji et al [17] showed that STM is associated with poor prognosis and worse response to treatment in lung cancer. Therefore, timely detection of STM can affect tumor staging and outcome.
Magnetic resonance imaging (MRI) is the gold standard for evaluation of soft tissue diseases owing to its good soft tissue contrast [4]. However, it necessitates long acquisition times and is affected by movement artifacts [18]. Moreover, studies [19] have shown that MRI is less sensitive than fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) in identifying STM. The latter technique uses a radioactive glucose analog, 18 F-FDG, to image glucose uptake in tumors and adjacent healthy tissue, enabling improved localization and characterization of tumors. Thus, 18 F-FDG PET/CT is an important tool for evaluation of patients with cancer, including identification of primary and metastatic lesions, guidance of biopsy, and assessing efficacy of anticancer therapies.
The widespread use of 18 F-FDG PET/CT has led to increased detection of STM in various malignancies.
However, reports on its use to identify STM of lung cancer are scarce, and most of them represent individual cases. The purpose of this study was to explore the incidence and characteristics of STM in a large cohort of patients with lung cancer using 18  presence of concomitant distant metastases; and survival time (from confirmed STM to death) were recorded for all study subjects. The patients were followed-up to assess health outcomes by telephone or electronic case inquiry until September 2019. All procedures were carried out in accordance with the principles of the Helsinki Declaration. This study was approved by the ethics committee of the Affiliated Hospital of Southwest Medical University. Because the study was retrospective, and included data from deceased patients, informed consent was waived.

Inclusion And Exclusion Criteria
The study inclusion criteria were as follows: 1) underwent 18 F-FDG PET/CT examination and had not been diagnosed with STM before; 2) primary lesion confirmed by puncture biopsy, fiberoptic bronchoscopy, or postoperative pathology; 3) STM confirmed by histopathology or clinical follow-up.
The exclusion criteria were as follows: 1) lymphoma, malignant melanoma, neurofibroma, or other soft tissue tumor; 2) STM caused by direct infiltration from primary lesion or bone metastasis; 3) presence of lymph nodes, infection, inflammation, and post-biopsy reactions.
Pet/ct Scanning 18 F-FDG was prepared using the Siemens Eclipse HD cyclotron and 18 F-FDG automated chemical synthesis system, and had radiochemical purity of > 95%. The patients were asked to avoid strenuous physical activity the day before the scan, and fast for at least 6 h prior to intravenous administration of 18 F-FDG (5.5 MBq/kg body weight) to ensure a blood glucose level of < 11.1 mmol/L. Following the injection, the patients rested for 40 min-1 h in the dark, drank 300-500 mL of lukewarm water, then underwent PET/CT scanning on a Philips Gemini TF 16 scanner after emptying the bladder. First, a 16slice spiral CT scan was performed, ranging from the base of the skull to the middle upper thighs, with the arms raised above the head (120 kV, 100 mA, layer thickness 0.5 mm, matrix 512 × 512 pixels, window width 300-500 HU, window level 40-60 HU). If a patient was known to have abnormal lesions in the limbs, they were scanned from the top of the head to the feet, with the arms at the sides of the body. After CT was complete, three-dimensional PET was performed for 70-90 s per bed position, for a total of 7 bed positions. The resulting images were corrected by attenuation and reconstructed by iterative method to obtain transverse, coronal, and sagittal views of the PET/CT scans. Delayed imaging was performed 2 h after 18 F-FDG injection, if necessary.

Image Analysis
The images were analyzed for the presence of STM by 3 experienced PET/CT physicians and a radiologist, using a combination of semi-quantitative analysis and visual assessment. Any disagreements were settled through negotiation. For the semi-quantitative analysis, a region of interest was drawn and the SUVmax was measured in the most intense area of focal 18 F-FDG accumulation. The lesions were considered PET-positive if their 18 F-FDG uptake was greater than that of surrounding healthy muscle and subcutaneous soft tissue. CT-positive lesions were defined as obvious nodules, masses, or abnormal tissue structure. The density, maximum diameter, shape, edge, and SUVmax of each lesion were measured. The final diagnostic criteria were pathological results or clinical follow-up.

Pathological type of lung cancer
The most common histological variant of primary lung cancer was adenocarcinoma (51 cases), followed by small cell lung cancer (12 cases), squamous cell carcinoma (11 cases), non-small cell carcinoma of unclear origin (6 cases), adenosquamous carcinoma (3 cases), and large cell carcinoma (2 cases). In 15 patients only, the presence of STM was confirmed by histopathology; in the remaining cases the diagnosis relied on clinical evaluation and imaging data.

Number And Imaging Characteristics Of Stm
Muscle STM occurred in 41 cases and subcutaneous STM in 34 cases. In 10 of the patients, both types of STM were present. A total of 219 metastases were located by 18 F-FDG PET/CT. Among them, 215 lesions were detected by PET (detection rate = 98.2%; median SUVmax = 6.12 (range 0.8-20.9)). CT identified 139 lesions (detection rate = 63.5%), out of which 109 were isodense and 30 were of low or slightly low density; 96 lesions were nodules or tissue masses, while 43 were accompanied by swelling and had unclear boundaries. Median lesion size was 2.12 cm (range 0.4-13.8).

Location Of Stm
Muscle lesions were primarily distributed in the hip muscle, upper limb muscle, and dorsal muscle (Table 1), with the highest frequency in erector spinae, gluteus major muscle, and psoas muscle.
Subcutaneous soft tissue lesions were most commonly located in the chest and abdomen, followed by back, head and neck, hip, and, occasionally, in the extremities ( Table 2).

Clinical Presentation
Most patients (80%) were asymptomatic and their STM were discovered incidentally during routine 18 F-FDG PET/CT. In the remaining cases, the lesions were symptomatic; STM to muscle were accompanied by local pain or swelling, while those to subcutaneous tissue were often painless, with some patients displaying redness, swelling, and pain. In 10 patients, STM was the first manifestation of primary malignancy (Fig. 1).
The vast majority of the patients (92.9%) had other distant metastases when STM was detected

Discussion
STM are defined as metastases to skeletal muscle and subcutaneous tissue [6][7][8]. Although soft tissue accounts for over 50% of the human body, and has abundant blood supply, it is a relatively rare site of metastasis. Factors such as changes to local blood flow; presence of various proteases and inhibitors; high partial pressure of oxygen; pH, pressure, and temperature changes; and local production of lactic acid are not conducive to the growth of tumor cells, making soft tissue relatively resistant to malignant penetration [3,7,17,[20][21][22][23][24]. Although infrequent, STM are still encountered in clinical practice and warrant greater attention of radiologists and clinicians [13].
Lung cancer is the most common primary malignant tumor leading to STM [9][10][11][12][13]. More than half of lung cancer cases are diagnosed at an advanced stage [1,2]. The most common sites of distant metastasis include the bone, brain, adrenal glands, and liver, with STM being much less common [3][4][5]. Usually, when lung cancer progresses to a certain extent, some of the tumor cells break away from the primary tumor and disseminate to remote sites through the bloodstream or lymphatic system [25][26][27]. If local tissue conditions are suitable, the cancer cells begin to divide and proliferate and gradually become metastatic foci [7]. 18 F-FDG PET/CT can show metabolic changes before morphological abnormalities occur, and is used to screen for extra-pulmonary metastases in patients with lung cancer [10]. It is a whole-body imaging technique, with high tumor-to-background FDG uptake ratio, which allows detection of hidden STM [13,28]. Despite these advantages, the use of 18F-FDG PET/CT for the detection of STM of lung cancer has not been widely researched. In previous studies, the prevalence of STM varied from 0.86-13% [13,28]. In our review, we found that approximately 1.87% of patients with lung cancer had STM. Although this proportion is much lower than that for lung, liver, bone, or brain metastases, STM of lung cancer are not exceptional. Importantly, a more widespread use of 18 F-FDG PET/CT may allow detection of previously undetected STM.
The median age and sex distribution in our study population was similar to that in previous studies [16,25] of STM of lung cancer, indicating that the disease is the most prevalent in middle-aged and elderly males. Further, existing literature [11,[14][15][16] suggests that STM mostly occurs in patients with lung adenocarcinoma, which is consistent with our findings. Muscle metastasis is reportedly more common than subcutaneous metastasis, with a ratio of 1.2-3.3:1 [7,8,14]) This was also observed in the current study; the overall incidence of skeletal muscle STM was 60%, while that of subcutaneous STM was 51.8%, i.e. a ratio of 1.2:1.
SUVmax is the most widely used parameter to measure the uptake of a radiolabeled tracer by tumor tissue [29]. In this study, the median SUVmax in STM was 6.12 (range 0.8-20.9); while that in skeletal should include a thorough examination of soft tissue [9,11,25,30,31].
Generally, STM are asymptomatic and easy to miss during clinical evaluation [9,13]. Indeed, most of our patients (80%) did not present with symptoms related to their STM, and if 18 F-FDG PET/CT had not been performed, the lesions would have likely remained undetected. If STM is the only metastasis, tumor staging and treatment might change dramatically. In 20% of the patients, the lesions were symptomatic, with local pain or swelling in muscle STM and painless masses in subcutaneous STM.
Thus, in patients with lung cancer, unexplained muscle pain or subcutaneous nodules should raise suspicion of STM, and comprehensive physical and imaging examination should be conducted [4].
STM may also be the initial manifestation of lung cancer, which was observed in 10 of our patients (11.8%). In such cases, in addition to active follow-up of medical history and physical examination, 18 F-FDG PET/CT imaging should be performed as soon as possible to locate the primary tumor and ensure optimal patient management.
STM, which was shown to have the same practical significance as other types of distant metastases of lung cancer, may be a manifestation of declining immunity and a sign of advanced-stage disease [7].
Most patients with STM of lung cancer display multiple organ and lymph node metastases, and since metastasis mostly occurs in patients with a high degree of malignancy, their prognosis is poor [5,7,8,11]. Thus, 18 F-FDG PET/CT detection of additional STM does not have a significant effect on the staging of lung cancer patients with extensive metastases, but it can help delineate the target area for local radiotherapy [15]. 18 F-FDG PET/CT could also guide biopsies of soft tissue lesions, which usually occur in superficial areas. Among the 85 patients in our study, 79 had extensive metastatic diseases, which led us to believe that STM is a sign of advanced lung cancer.
A small proportion of patients (7.1%) showed solitary STM on 18 F-FDG PET/CT, which was the only manifestation of metastatic disease. 18 F-FDG PET/CT results completely changed tumor staging, treatment plan, and prognosis of these patients.
Increased 18 F-FDG uptake in soft tissue may be caused by a variety of physiological and pathological factors, and differential diagnosis should take into account muscle hyperactivity, infectious/inflammatory processes, post-surgical reactions, primary soft tissue tumors, lymphoma, etc [14,32]. When 18 F-FDG PET/ CT of patients with lung cancer shows elevated 18 F-FDG uptake in soft tissue, especially in muscle tissue, and the above factors are excluded, the lesion should be regarded as suspicious STM even if there is no corresponding morphological abnormality on CT [8,14]. In addition, some factors might result in decreased 18 F-FDG uptake in soft tissue and lead to false negative results, such as small lesions, tumors with low metabolic activity, elevated blood glucose levels, etc.
The treatment of STM of lung cancer can vary depending on the patient's age, overall health, metastatic status, and expected goal. Treatment options include palliative radiotherapy, systemic chemotherapy, and supportive treatment; resection can be considered if the metastasis is isolated [3,4,11,[14][15][16]33]. Despite the different treatment strategies available, most patients diagnosed with STM die within months [34]. In this study, the median survival time was 5.0 months, which was similar to that reported in previous studies [7,33]. Therefore, we propose that STM is one of the strong predictors of lung cancer prognosis.

Limitations
First of all, our study was retrospective and only 17.6% of patients were confirmed to have STM by histopathology. While in line with patient care standards (most metastases do not need pathological diagnosis), the fact that not all lesions were verified by histopathology might have cause some deviation in the results [9,12,13].
Secondly, since the 4458 patients with no signs of STM on 18 F-FDG PET/CT were not followed-up in the same way as the 85 patients with STM, the actual incidence of STM in lung cancer may be higher than that observed in our study.
Thirdly, we performed low-dose CT scans, which have relatively low resolution and failed to detect lesions with small density changes.
In addition, the vast majority of our patients were scanned from the base of the skull to the middle upper thighs, which is not a true whole-body scan. Some studies have shown that a considerable proportion of STM may occur outside the scan range [8,12]. Missed diagnosis of limb metastases can underestimate the extent of STM, leading to under-staging and mis-management of the disease.
Newer PET/CT technology allows fast whole-body scanning without affecting imaging accuracy. In our future work, we will gradually adopt the whole-body approach to PET/CT imaging (from the top of the head to the soles of the feet) to prevent missed lesions.
STM in lung cancer are relatively rare, but not exceptional. Understanding their incidence and characteristics on 18

Consent for publication
Not applicable.

Data Availability
The datasets used and analyzed during the present study are available from the corresponding author on reasonable request.   The general condition of the patient was good, and no metastases were found in head MRI or thoracic and abdominal CT. The patient underwent surgical resection and received adjuvant chemotherapy after the operation. Three months later, the patient underwent 18F-