Our study showed that 9 of 500 (1.8%) cancer patients had ST metastasis. Spencer et al. reported the prevalence of skin metastasis of any cancer type to vary between 0.75% and 9% [1]. Other studies in lung cancer patients revealed a lower and less variable cutaneous metastasis prevalence of 1.3% to 3.1% which is comparable to our findings [2, 3]. The most commonly reported primary carcinomas to result in clinically recognized ST metastasis are those of the lung, kidney, and colon [8]. Our study indicated that the prevalence of ST metastasis of lung carcinoma (2.3%) was much lower as compared to that of melanoma (9.8%) which is higher than is reported in the literature [8]. Our study showed that either in-transit or distant ST metastasis was associated with other distant metastasis, and was suggestive of poor prognosis as demonstrated previously [9, 10]. Of note, three of the four melanoma patients were older than 70 years. This observation might have prognostic significance as older individuals with melanoma have increased mortality as compared with younger ones [11]. However, this requires future evaluation in a larger cohort of melanoma patients. Two of 3 patients with available Breslow's depth showed lesion thickness greater than 4 mm (pT4) which is indicative of high risk neoplasms and may explain the widespread disease in these patients. Lymphoma has rarely been reported to have ST metastasis [8]. However, we found an equal number of cases with ST metastasis in the lymphoma and lung carcinoma cohorts (2 cases each). Among the lymphoma cases, one had a CD30 positive, anaplastic variant, diffuse large B-cell lymphoma potentially explaining the development of ST metastasis. The other patient had a grade III follicular lymphoma with a single subcutaneous lesion and limited lymphadenopathy. Additional research is needed to fully comprehend the prevalence and pattern of ST metastasis in lymphoma.
The most frequently reported locations for ST metastasis have been the back, chest wall, and abdomen [12]. These are the areas typically included in chest, abdomen and pelvis CT scans as well as the LWB PET/CT scans. In contrast, our study showed that ST metastasis occurred outside the typical LWB FOV in 46% of cases (19/41 lesions). Thus, previously reported prevalence and locations of ST metastasis may have been biased by the imaged FOV. ST metastasis has been reported as a common clinical presentation of occult malignancy and as an isolated metastasis in the patient with a known malignancy [8, 13]. Only a small percentage of ST metastasis has been reported to occur in the presence of disseminated disease [8, 14]. In contrast, our findings revealed that all patients with ST metastasis had widespread disease on PET/CT. Our study also indicated that ST metastasis can occur early during the course of the disease since 7 out of 9 patients developed ST metastasis within 12 months of diagnosis of their primary malignancy. It is likely that patients with advanced disease have been underrepresented in the literature as they neither present a diagnostic challenge nor have a curative therapy. Moreover, previous studies mostly revealed a referral bias as the reported patients had symptomatic ST lesions referred for further evaluation and management [8, 11].
Although magnetic resonance imaging (MRI) is not specific for soft tissue metastasis, it has been advocated as an indispensable tool for the diagnosis and treatment planning in patients with soft tissue malignancy [15]. However, a recent study showed that F-18 FDG PET/CT has higher sensitivity than MRI in detecting skin and ST metastasis [16]. This is supportive of the increasing role of F-18 FDG PET/CT in cancer patient management [4]. Nevertheless, there are undoubtedly false positives as seen in two cases (actinic keratosis, skin folding) of the studied population that need to be taken into account. FDG uptake and resulting increased tracer activity is not limited to neoplastic tissue. Recognizing the strengths and weaknesses of PET is important for the accurate interpretation of the PET/CT images. The diagnosis of ST metastasis in our study using combined PET/CT was relatively straightforward as most lesions had significant FDG uptake higher than that of the liver which is a widely accepted reference organ to distinguish benign from malignant lesions. Most PET facilities recommend at least 4 hours of fasting before the tracer injection as a standard. A longer fasting time may increase the detection of ST lesions; however, the standard protocol of at least 4 hours fasting was followed in this retrospective study. PET/CT protocol in cancer staging usually comprises a low dose, non-enhanced CT protocol [17, 18], which is sufficient for attenuation correction and anatomical information while keeping the radiation exposure to a minimum. Given the low-dose and non-contrast enhanced protocol, the CT portion of the study helped localize the lesions and increase the diagnostic confidence as ST metastatic lesions can appear hyperdense or hypodense as compared to the surrounding soft tissue.
ST metastasis can be present in many muscular and subcutaneous sites across the body with a ratio higher than 1.5:1 [8]. In our study, the ratio was 1.2:1, suggesting that subcutaneous ST metastasis may have been under-reported in the literature. One explanation for this may be that subcutaneous lesions tended to be smaller than muscular ones, although our findings did not reveal a statistically significant difference in these lesions' size (p = 0.106). Another potential reason is that 5/19 (26%) of the subcutaneous lesions in our study were 1 cm or less in size which may represent a diagnostic limitation for diagnostic CT and MRI scans.
Certainly, the prognosis in the presence of ST metastasis should be considered when weighing the merits of the findings. Seven out of nine studied patients died of their disease within 1–22 months after ST metastasis was diagnosed. This correlates with the reported median survival ranging from less than 5 months to no greater than 19 months after the diagnosis of ST metastasis [8].
We acknowledge the limitations of our retrospective study. We also realize that at many institutions, a TWB imaging is frequently performed in melanoma patients and probably would have detected the in-transit metastasis in two of the four melanoma patients (scalp, thigh). We intended to evaluate a cohort of 500 consecutive cancer patients with TWB PET/CT imaging and tried to delineate the extent of ST metastasis in this population. PET/CT is a relatively new technology that has already been shown to benefit the management of a number of cancers [18, 19]. A recent literature-based evidence review reported an average of 15% improvement in staging and restaging accuracies of PET/CT over PET or CT alone in different cancers [4]. The superior ability of F-18 FDG-PET/CT in the detection of metastatic disease can help provide an easily accessible biopsy site and avoid unnecessary invasive diagnostic procedures as it was the case in 4 of our 9 patients (44%). This can result in less invasive procedures performed, decreasing morbidity and cost.
LWB PET/CT scanning is typically performed from the skull base to the pelvic floor [5, 6] because most FDG avid lesions are expected to be within this field of view excepting cerebral metastasis which can be found in at least 20% of cancer patients during their life-time [20]. However, the sensitivity of F-18 FDG PET is suboptimal in detecting brain metastases due to the intense physiologic background uptake in the brain and the hypometabolic nature of some brain metastases [21]. Because of the higher sensitivity and specificity of contrast-enhanced MRI for cerebral metastasis [21], the use of F-18 FDG PET/CT to diagnose brain metastasis has become less desirable. Despite multiple reports in the literature, the prevalence of distant metastasis to the extremities is rare [1, 2, 4, 8, 12, 22, 23]. This is most likely why the extremities are usually not included in the field of view unless there is a clinical suspicion for cancer in the extremities. In our study, LWB scanning would have under-diagnosed all lesions outside LWB FOV. We found that 19/41 (46%) of ST metastatic lesions were detected outside the LWB FOV, i.e. could only be detected by TWB scanning.
A decision whether a TWB scanning should be used in cancer patients depends on the overall prevalence of distant metastasis outside the LWB FOV which is not limited to ST metastasis alone. The added value of TWB scan over LWB scan is beyond the scope of this manuscript. However, analyzing the same patient cohort of the current study, we found that distant metastasis occurred outside of LWB FOV in 28/500 (5.6%) patients [24]. The detection of such lesions had direct patient management in about 50% of the patients because of upstaging (unpublished data). The tumors with the highest prevalence (> 10%) of distant metastasis outside the LWB were melanoma and lung cancer. Therefore, TWB imaging for malignant melanoma and lung cancer would be a reasonable option and most beneficial for these two malignancies. However, metastasis outside of LWB in other cancers has the potential pitfall of a low overall prevalence of distant metastasis outside the LWB FOV. Of note, TWB imaging requires additional several minutes of image acquisition which can be uncomfortable for the patients and results in decreased scanning throughput; however, the time required for TWB image acquisition will continue to decrease with advancements in both hardware and software technology in newer PET/CT scanner designs that would allow increased scanning throughput without compromising imaging accuracy in an economical sense. For example, the recently installed PET/CT scanner at our institution is capable of acquiring a TWB scan in a patient with a normal body mass index in less than 18 minutes.
