STM are defined as metastases to skeletal muscle and subcutaneous tissue [6–8]. 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, 20–24]. 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 [9–13]. 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 [3–5]. 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 [25–27]. If local tissue conditions are suitable, the cancer cells begin to divide and proliferate and gradually become metastatic foci [7].
18F-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 18F-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, 14–16] 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 muscle and subcutaneous metastases was 6.79 (range 2.1–20.9) and 5.36 (range 0.8–19.1), respectively. The vast majority of metastatic lesions (98.2%) had high FDG metabolism, and could be detected by visual inspection of PET scans. A total of 80 muscle STM (36.5%) were missed by CT, which was probably related to the low resolution of low-dose CT acquisition, and the isodensity of the lesions. The highest frequency of muscle metastases was in the hip, upper limb, and dorsal muscle, while subcutaneous metastases were mainly distributed in the chest, abdomen, and back. These findings are in line with those reported in the literature, and suggest that the staging of lung cancer 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 18F-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, 18F-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, 18F-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]. 18F-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 18F-FDG PET/CT, which was the only manifestation of metastatic disease. 18F-FDG PET/CT results completely changed tumor staging, treatment plan, and prognosis of these patients.
Increased 18F-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 18F-FDG PET/ CT of patients with lung cancer shows elevated 18F-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 18F-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, 14–16, 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.