PLC, as the only clinical manifestation of patients without a history of malignant tumors, is relatively rare, so it is easy to be misdiagnosed. However, literature survey showed that there are many case reports rather than system reviews or case series with a large number of patients so far.
To summarize the clinical characteristics of patient with PLC as the first manifestation and enhance the diagnostic awareness, we searched PubMed to screen PLC related literature from inception to 12 October 2020. No language restrictions were applied. We also manually researched the references for eligible articles. The included studies should contain at least the following clinical information: gender, age, chief complaint/pulmonary symptoms, diagnosis methods and definite/probable primary tumor. Published abstracts involving these data were also included. Case series were excluded if the above information had not been documented for each case. We finally identified 78 publications comprising 96 patients with PLC as the initial presentation by reviewing and assessing the searched articles, including 66 full-text studies [4–6, 8–70] and 12 abstracts [71–82]. The search strategy (Supplementary Table 1, Fig. 1) and flow diagram of the study (Supplementary Fig. 2) were shown in the supplementary information files. We then pooled data of 97 patients including our case to further analyze the clinical features of the patients. To evaluate the efficacy of antitumor therapy, we defined the treatment was effective if the patients survived after receiving 4 cycles of chemotherapy or an improvement was reported in the study.
Primary Site, Gender And Age
The mean age of the 97 patients was 48.3 ± 18.1 years (range 7 to 88 years) and the majority of the patients were males (n = 61, 62.9%). The top three common primary malignancy sites were stomach (n = 34, 35.1%), lung (n = 19, 19.6%) and prostate (n = 15, 15.5%) (Fig. 2, Table 1). More than half (50/97) of the primary tumors were originated from digestive system, while the live, gallbladder and choledochal cyst were relatively uncommon. The youngest patient was a 7 year-old boy with kidney cancer [71], and the oldest one was a 88 years old female with lung cancer [6]. 19.6% of the patients were found in 51–60 year age group which was most commonly affected, 70.1% were within the age of 60 years (n = 68) and 33% of the patients (n = 32) were under the age of 40 years. 61 patients were males, especially in cases with lung cancer (15/19, 78.9%), while gastric cancer was more common in females (19/34, 55.9%). In view of the primary sites, sex and age, PLC as an initial manifestation probably occurred in young patients with tumors originated from digestive system.
Symptoms and imaging features
Almost all the patients presented with progressive dyspnea. We further analyzed the chief complaints and imaging features of the cases with full-text. A total of 82 patients including our case were identified. The most common chief complaints were dyspnea (90.2%), dry cough (56.1%) and loss of weight (51.2%), while the most common chest imaging findings were thickened interlobular septa (95.1%), reticulonodular opacities (37.8%) and pleural effusion (36.6%) (Table 2).
The prognosis of PLC
Among all the patients, 47 cases received anti-tumor treatment including chemotherapy, surgery and endocrine therapy while 44 improved (Table 3). Of note, all the patients with prostate tumor were relieved after treatment. Moreover, we further summarized the PLC course of the patients with recorded prognosis (Table 4). Out of the 78 patients, 23 patients died within 2 months after the onset, 5 patients died within 1 month after PLC diagnosis with an overall survival time (OST) more than 2 months. Out of the 3 patients without a definite survival time, one patient died within 1 month after PLC diagnosis and the left two patients were diagnosed by autopsy.
The mechanism of PLC
Regrettably, there were few basic researches conducted on the pathogenesis of PLC. We only found one preclinical study which showed vascular endothelial growth factor-C (VEGF-C) facilitated the induction of lymphangiogenesis and expansion of already disseminated cancer cells throughout the lung tissue in vivo, moreover, the metastatic breast cancer cells in the lung expressed high levels of VEGF-C in patients with PLC. A clinical meta-analysis showed ALK-rearranged NSCLC was more likely to have PLC, pleural metastasis and pleural effusion compared with ALK/EGFR-negative NSCLC95. These data imply that there may be some regulatory factors in the occurred of the PLC. Taking together, there is a great gap between fundamental researches in particular molecular aspects and clinical practice on the mechanism of PLC.
In conclusion, PLC can an initial manifestation of the malignancy. The most common symptoms are dyspnea, dry cough and loss of weight, while the common imaging features are thickened interlobular septa, reticulonodular opacities and pleural effusion. PLC should be considered when patients present with the above clinical features and fail to response to the treatment base on the initial diagnosis, especially in the young males. Stomach, lung and prostate should be the focus area for identifying primary tumor. However, the prognosis of PLC is so far poor, but the patients with prostate cancer showed good response to the anti-tumor therapy. For future, detailed studies are required to find the underlying mechanisms and special intervention targets of PLC.