Due to the glycogen accumulation and fat storage in the cytoplasm, cytoplasmic clearing to the hematoxylin-eosin staining is a distinguishing feature of PCCCL . Owing to the relative rareness, most studies regarding PCCCL have been case reports or small, single-institution studies, rendering the epidemiology, etiology, and pathogenesis poorly understood . To the best of our knowledge, the present study included the largest published cohort of PCCCL patients and was the first to characterize the clinicopathologic properties, demographic features, treatment outcomes, and prognostic factors.
PCCCL has previously been reported to have low mortality and incidence (< 10% of HCC cases) [12, 13, 21–23]. A morbidity of 8.7% has been observed in America . Additionally, PCCCL has been detected in 9.3% , and 6.7–13.3% [4, 24] of the HCC patients in Japan and China, respectively. As expected, our results confirmed the rarity of PCCCL; we found that, between 2004 and 2016, 33345 cases (data not shown) were diagnosed as single primary HCC with positive histology confirmation, and 349 of them (1.05%) were PCCCL.
In this study, the average age of PCCCL patients was 64.1 years (range: 18–94 years), which was older than those reported by Qing-Yu Liu et al  (52 years) and Jung Hee Lee  (58.8 years). Regarding sex, our study indicated a male-to-female ratio of 1.43, indicating that males were more prone than females. This observation is in agreement with previous reports  . Additionally, most patients (63.3%) were of white ethnicity, reflecting the race distribution of western population. We also observed that the tumors were mostly (68.1%) < 1 cm. This observation differed from the previous observations of the high prevalence of big tumors (> 2.1 cm  or 7.28 cm  on average). This difference was likely due to the relatively small numbers of cases in these two previous studies (20 cases per study). Furthermore, the observations of Kazutoshi Kida et al are in agreement with ours [12, 26].
In this study, more PCCCL patients were diagnosed as T1 (49.6%), N0 (95.2%), or M0 (85.9%) stage, in addition to more AJCC stage I (44%) or localized stage (61.3%) patients, in accordance with several studies that have shown that PCCCL tends to have less vascular invasion[4, 12], lymph node metastases , and extra- or intrahepatic metastasis . This may be attributable to the high incidence of tumor capsule formation [11, 27], presumably caused by the stable expression of type I and III procollagen [4, 28]. In line with this, our study showed that the patients without vascular invasion accounted for 61.3% of the sample size.
PCCCL has hitherto been considered a highly differentiated subtype of HCC . Our results were confirmative, showing that high and moderate differentiation were present in 16.1% and 34.3% of the patients, respectively.
The clinical prognosis of PCCCL patients remains disputed. Most studies have indicated that patients with PCCCL had better outcome than those with other subtypes of HCC [10, 22, 30, 31]. Zhisheng Liu et al  have reported that PCCCL patients had a 5-year OS rate of 39% and a median OS of 40 months. Wei XU et al  have suggested a good prognosis, with a 5-year OS and DSS of 58.5% of 48.6%, respectively, whereas another study  has estimated 35.9% and 28.1%. Even the spontaneous regression of primary and metastatic PCCCL lesions occasionally occur . Meanwhile, several studies have claimed that the prognosis of PCCCL is poor . However, the limited numbers of cases render these conclusions unreliable. Here, we observed a 5-year OS and DSS of 23.2% and 28.3%, respectively, and a median OS and DSS of 19 and 24 months. Accordingly, our findings support the former view that PCCCL patients have a bad clinical outcome. Although our results are inconsistent with the mainstream, we have included 248 cases of PCCCL patients in the cohort study, reinforcing the reliability of our conclusions.
Kaplan-Meier and Cox regression analyses revealed that the increased tumor size was independently correlated with low OS and DSS rates in PCCCL patients. This association agreed with the conclusion of Zu-Shun Chen et al  that tumor size was a prognostic indicator for OS, disagreeing with Wei XU et al , who have claimed that the Edmondson grade is the only independent risk. This difference may be attributable to the involvement of a small patient cohort (38 cases in the study of Wei XU et al), hindering an accurate estimation.
Different socioeconomic factors, such as marital status, have increasingly been identified as having obvious impacts on oncologic prognosis [32, 33]. Marriage has been shown to be correlated with improved clinical outcome in testicular , colon , and epithelial ovarian  cancers. However, the association between marital status and PCCCL prognosis has never been validated. Here, we found that marriage was independently associated with significant improvement in the OS and DSS. Accordingly, the clinical significance of this study is that it highlights the impact of marriage on the survival of PCCCL patients. Therefore, our study results may draw public attention to increase the social support for vulnerable populations, such as widow(er)s, thereby markedly maximizing the survival.
Insurance status is another important socioeconomic factor affecting the prognosis of cancer patients. Receiving a continuous and high-quality treatment by means of insurance significantly improves the survival of patients with cancer, such as small intestine adenocarcinoma  and colorectal cancer . To our knowledge, this is the first study that has explored the correlation between PCCCL outcome and insurance status in a population-based study. We found that the patients without insurance but with any medicaid had worse outcome than those with insurance. Similarly, Na Wang et al  have reported that patients with small intestine adenocarcinoma with insurance coverage have a significantly better OS than those with medicaid or without insurance. Moreover, Rosenberg AR et al  have suggested that patients uninsured or under medicaid coverage had 2.4 and 3.2 times higher risks to present stage IV disease, respectively, than insured patients. Accordingly, this study highlights the significance of governmental support on health insurance coverage.
Surgery may be the most important factor affecting the survival. Since PCCCL is more prone to forming capsules, surgical resection is an effective way to eliminate lesions containing intact capsules, thereby improving the survival . Surgery has been suggested to provide a long-term survival for PCCCL patients . Here, we found that the PCCCL patients who received no surgery had a shorter survival (median OS: 7 months; median DSS: 9 months) than those who underwent surgeries. We observed that total proctectomy and colectomy combination offered the longest survival (median OS: 124 months) for the PCCCL patients, followed by local tumor excision (median OS: 55 months; median DSS: 56 months), and wedge or segmental resection/partial proctosigmoidectomy (median OS and DSS: both 34 months). Therefore, surgical interventions should be used as the first-line treatment.
Although surgical resection is effective in treating PCCCL, adjuvant treatments, such as radiation therapy, has increasingly been receiving attention. Radiation therapy has been reported as an important clinical application in various tumors . However, our results showed that radiotherapy had no significant effect on the prognosis of PCCCL patients. This observation may be due to the special pathological type of PCCCL. Similarly, traditional chemo- and radio-therapy are largely ineffective in treating any renal cell carcinoma subtype, and the underlying mechanistic reasons need to be further explored .
In this study, we also reported a correlation between the pathological grade and AJCC stage of PCCCL. Kaplan-Meier analysis results showed that a higher AJCC stage or pathological grade was associated with decreased survival. Moreover, the grade I PCCCL patients were found more likely to present with AJCC stage I, implying that the patients with higher pathological grades should receive a systemic examination for metastases.
Similar with other retrospective studies using data from the SEER database, there are some limitations in our research. Firstly, the detailed chemotherapy information was not available in the database. Lack of these data is not conducive to our understanding of the treatments for PCCCL. Secondly, the patient data mainly illustrated the clinical characteristics of PCCCL in America and might not be globally applicable. Thirdly, we failed to collect the data about the proportion of clear cells and capsule formation. However, most studies indicated that capsule formation or high proportion of clear cells is beneficial to prolong the survival time . Fourthly, there are no data about any PCCCL-related genetic abnormalities in the SEER database. As known, oncogenic mutations or DNA abnormalities play an important role in the progression and chemo- and radio-sensitivities of various tumors . Aggressive morphologic features and aneuploidy have been reported to be associated with the prognosis of PCCCL . Clear cell HCC shows a higher frequency of IDH1 mutation, which is associated with shorter survival times . Lack of such information limits our full understanding of PCCCL.
In conclusion, in our exploratory research on PCCCL patients, we used the SEER dataset to characterize the demographic, clinical, survival, and therapeutic features of PCCCL patients. Our study showed a poor outcome of PCCCL, which was more common in males and prone to be localized. Moreover, insurance, tumor size, and marital status were independent prognostic factors for the OS and DSS of the PCCCL patients, whereas race was only correlated with the OS. Surgery intervention could improve the outcome; however, radiotherapy failed to lengthen the survival time. Additionally, grade I PCCCL patients were found more likely to present AJCC stage I.