PEComas are a group of ubiquitous neoplasms sharing morphological, immunohistochemical, ultrastructural and genetic distinctive features.
There are some open questions about PEComas: the histogenesis and the normal/physiological counterpart of PEC, the definition of epithelioid AML and the identification of the histological criteria of malignancy.
The histogenesis and the normal/physiological counterpart of PEC are unknown, but some hypotheses have been proposed. One hypothesis is that PEC derives from undifferentiated cells of the neural crest that can express dual smooth muscle and melanocytic phenotype; a second hypothesis is that PEC has a myoblastic, smooth muscle origin with a molecular alteration that brings to expression of melanogenesis and melanocytic markers [107
]; a third hypothesis is that PEC has a pericytic origin. As regards PEComa’s histogenesis, the involvement of TSC pathway in these neoplasms can suggest some possibilities: it has been previously proposed that B-raf activity in cells lacking TSC2 may play a role in cell differentiation [56
]. Moreover, TSC pathway regulates negatively Wnt/beta-catenin pathway [71
] and beta-catenin regulates transcription of genes involved in cell proliferation and differentiation. Nevertheless, more cases should be analysed to better understand PEC origin and PEComa’s histogenesis.
The second issue regarding PEComas is which cases should be classified as epithelioid AML particularly in the kidney and liver, where AML occurs with higher frequency. We defined epithelioid AML as a neoplasm composed of purely epithelioid cells with melanogenesis markers immunoreactivity arranged in sheets, without adipocytes and abnormal blood vessels.
However, in otherwise classic AML, areas of epithelioid cells can be observed, raising the question how much they should be represented to call a tumor “epithelioid angiomyolipoma”. The collection of such cases and a consensus meeting could be useful tools to answer to this problem.
Malignant PEComa can be a very aggressive disease leading to multiple metastases and death as expected with a high-grade sarcoma [3
]. A few malignant PEComas metastasised after several years (7–9 years) [27
] (Table ).
Reported cases of malignant PEComas in literature
Recently, Folpe et al. [39
] reported 26 cases of PEComas of soft tissue and gynaecologic origin proposing criteria for the classification of these tumors as “benign”, “of uncertain malignant potential” and “malignant”. In this study, they observed a significant association between tumor size >5cm, infiltrative growth pattern, high nuclear grade, necrosis and mitotic activity >1/50 HPF and subsequent aggressive clinical behaviour of PEComas.
We think that this approach is the best available at the moment. While more cases with long follow-up are needed to verify the effectiveness of this prognostic classification, we believe that all cases of PEComa should be classified according to the criteria proposed by Folpe et al.
Another future challenge regarding PEComas is their management.
Surgery seems to be the only approach for aggressive cases, as chemio- and radiotherapy has not shown significant results. However, this derives from anecdotical cases as no therapeutic trial has so far been implemented. There are obvious difficulties to perform a therapeutic trial mainly due to the rarity of the disease. An international cooperative study is needed to address this problem.
A very different problem is posed by lymphangioleyomyomatosis. In fact, lymphangioleyomyomatosis is composed of a population of cells with no atypia. Mitotic activity is virtually absent or extremely low. In spite of this, the disease usually progresses inexorably towards lung-function impairment.
Recently, Kenerson et al. [59
] demonstrated TSC1/2 inactivation and m-TOR hyperactivation in non-TSC AMLs and in extrarenal PEComas using immunohistochemistry and Western blot analysis. In particular, m-TOR hyperactivation can be studied in such lesions using immunohistochemical detection of p70S6K. As we have previously mentioned, p70S6K is a protein kinase activated by m-TOR. Immunohistochemical reaction for p70S6K can stain both p70S6K, which gives a cytoplasmic signal (Fig. ), and a second isoform of kinase, p85S6K, which is also activated by m-TOR and which gives a nuclear signal.
Hepatic angiomyolipoma: cytoplasmic signal in immunohistochemical reaction for p70S6K; p70S6K ×10
Rapamycin is a specific inhibitor of m-TOR [23
] which is approved by the US Food and Drug Administration for immunosuppression therapy after renal transplant [117
], and it has recently been approved also for therapy of renal cell carcinomas and acute myeloid leukemia [88
]. Preclinical studies in animal models of TSC have shown significant in vivo response to rapamycin [58
As regards LAM, an innovative therapeutic trial is under way. Rapamycin seems to block signaling through the Akt cell growth and survival pathway (for up-to-date information, see http://www.thelamfoundation.org
A similar trial has already shown a positive effect on renal AML, and we can hope to see the same effect on LAM.
If this will be the case, this could provide the rationale for the use of the same drug in other lesions composed of PECs.