Multifocal PEComas are extremely rare lesions, which do not include malignant PEComa with metastasis. We reviewed PUBMED’s English literature from 2000 to 2020 and collected a total of 12 cases (Table 1). Our case is the second case of multiple PEComas involving the liver and pancreas. Because of its rarity, some of these cases had caused clinical diagnosis difficulties or even misdiagnosis, and the opinions of authors varied about whether multicentric or metastatic tumors. To explore the nature of the lesion, we analyze the clinicopathological characteristic of these cases. Of the total of 12 patients, there were 4 male patients (33%) and 8 female patients (67%). The age was range from 38–68, the median age was 47. The most common organs involved in multi-organ cases were the kidney and lung, and the latter was often involved in both lung fields. 2 cases involved more than 2 organs (case #8: kidney, spleen, and bilateral lung; case #10: liver, left kidney, and bilateral lung). Moreover, most cases had multiple foci in one organ. The lung was the organ most frequently affected by multiple foci, followed by the liver and kidney. Angiomyolipoma (AML) was the most common type in multiple PEComas. There was no evidence of pathological malignancy in all cases, except for focal cell pleomorphism (case #4), and epithelioid AML (case #12). Some authors believe that pure epithelioid PEComa has malignant potential, and is often related to younger patients, larger tumor sizes, and disease progression[2]. While the diagnostic criteria for malignant PEComa summarized by Folpe et al [3] based on soft tissue and gynecologic origin did not include epithelioid morphology. Most cases were treated surgically, and no recurrence or metastasis during the follow-up period. One case (case #1) was treated with mTOR inhibitor sirolimus 2mg/d, with reduction of multiple AML lesions in the lung and kidney in 8 months, while the lymphangiomyomatosis (LAM) lesions in the lung were unchanged. In some cases, multiple small lesions had not undergone any clinical treatment, but did not cause clinical symptoms for a long time. Overall, the prognosis of multifocal PEComas was good. Although some cases did not provide follow-up data or lost contact with the patients, the tumors in most cases remained stable for a long time, and the longest follow-up time recorded was 12 years.
There are different opinions on the pathogenesis of multifocal PEComa, and the exploration of its cause would help to determine the clinical treatment of such lesions. Although the clinical course of PEComa is benign or inert, some authors believe that because of the lack of clear criteria for the diagnosis of PEComa malignancy, multifocal PEComa cases, especially those unrelated to tuberous sclerosis complex (TSC), are potentially malignant and cannot be ruled out as metastatic disease[4]. There are also authors believe that multifocal PEComas are multicentric lesions[5], with benign characteristics.
About 20% of PEComa cases are associated with tuberous sclerosis complex (TSC), which were due to the germline mutations of TSC1 (9q3.4) and TSC2 (16p13.3) genes[6]. PEComas related to TSC often occur in young patients with bilateral or multifocal origin and a fast growth rate. According to the clinical diagnostic criteria of TSC proposed by the 2012 International Tuberous Sclerosis Complex Consensus Conference[7], the occurrence of ≥2 angiomyolipoma or lymphangiomyomatosis is one of the major features, respectively. Therefore, for multifocal angiomyolipoma or lymphangiomyomatosis cases, it is best to check for other TSC-related clinical evidence or perform genetic testing to assist in the diagnosis of TSC. Among the 12 collected cases, 2 cases were reported as clinically definite TSC (case #4 and #6). The two cases were both bilateral renal angiomyolipomas and multiple lymphangiomyomatosis in the lung. Two other cases (case #1 and #9)showed no mutations in the TSC1/2 gene based on genetic analysis, just like our case, and no other TSC-related clinical manifestations were mentioned in the report, indicating that multifocal PEComas were not always related to TSC. PEComas unrelated to germline mutations in the TSC1/2 gene are sporadic cases. Some of these cases also have somatic mutations in the TSC1/2 gene[8], and some have other genetic changes[9].
The study of Henske, E. P. suggested that PEComa cells could migrate with blood, rather than metastasis[10]. From the clinicopathological characteristics of these multifocal PEComa cases, several points support the opinion: 1) although PEComas exhibit a wide anatomical distribution, the most prevalent locations are blood-rich organs, such as kidney, lung, and liver. In multifocal PEComas, we found that the lung was the most involved organ (10 out of 12 collected cases). And in almost all metachronous cases (7 out of 8), the later onset tumors were always pulmonary PEComa (LAM or AML). Organs with abundant blood supply are conducive to the dissemination of tumor cells. 2) Multifocal PEComas can involve two or more organs or locations, and most cases (11 out of 12) have multi-foci within one organ. The growth pattern of multiple foci in an organ is also similar to that of metastatic tumors. 3) Angiomyolipoma, lymphangiomyomatosis, or other types of PEComa are rich in vascular lymphatic vessels and exhibit the characteristics of perivascular growth patterns. It is prone to the spread of tumor cells through the vasculature. 4) These multifocal PEComa cases have a chronic clinical course. The onset of the later tumor in the majority of metachronous multifocal PEComa cases (6 out of 8) was found years later (ranged from 5 to 26 years). From the above points, it seemed the pathogenesis of multiple PEComa involved tumor cells spreading by blood, which may be due to the operation performed for the first tumor or the close relationship with the blood vessel wall. During a long dissemination process, migrating cells encounter blood-rich organs, forming multiple tumors with similar cell morphology and immunophenotype. Therefore, the occurrence of multifocal PEComas is the result of distant migration of “angiotropic” tumor cells, which is a type of “benign” metastasis. However, this hypothesis that is inferred from the clinicopathological characteristics of multifocal PEComas must be supported by further molecular biology research.
In conclusion, multifocal PEComas, excluding metastatic cases of malignant PEComa, are benign or indolent tumors. The genesis of such tumors may be related to the blood dissemination of tumor cells that ultimately encounter distant organs. It is a benign dissemination process rather than metastasis. Therefore, radical treatment should not be performed for such tumors in clinical management. However, for large tumors, because of rich in blood supply, it requires early treatment for the risk of bleeding and other symptoms. In addition, although it is rare, for multifocal lesions occurring in organs such as kidney, lung, liver, and pancreas, the diagnosis of multiple PEComas should also be considered. And even cases of PEComa with benign pathological morphology should be monitored for a long time, because a second or a greater number of PEComa lesions may appear many years later.