What is the perivascular epithelioid cell? 1 Fig. 1 Renal angiomyolipoma: perivascular epithelioid cells arranged around a blood vessel; H&E ×20  13 13 55 126 11 118 2 3 13 107 Fig. 2 Diagram demonstrating the modulation of morphology and immunophenotye of PECs  Fig. 3 Hepatic angiomyolipoma: strong granular HMB45 immunoreactivity in perivascular epithelioid cells; HMB45 ×20  87 What is a PEComa? 37 102 104 105 106 119 81 80 111 We believe that AML, CCST and pulmonary lymphangioleiomyomatosis are composed of PECs in different stages of modulation, and these lesions, together with clear-cell myomelanocytic tumor of the falciform ligament/ligamentum teres, belong to the same family of tumors, the PEComas. 15 Moreover, in the past 10 years, the use of the term PEComa has permitted to report and describe numerous cases with the morphological and immunohistochemical features of this tumor permitting to start to understand the biology of this group of lesions. PEC and tuberous sclerosis 112 116 62 59 Similar findings were obtained analysing extrarenal PEComas. PEComa: the past 5 77 9 93 94 9 42 43 93 94 118 10 10 35 125 4 96 Fig. 4 Renal microhamartoma completely composed of perivascular epithelioid cells; H&E ×20  PEComa: the present PEComas have been described in different organs and are considered ubiquitous tumors. Kidney PEComas of the kidney include classic AML, microscopic AML (so-called microhamartoma), intraglomerular lesions, cystic AML, epithelioid AML, oncocytoma-like AML and lymphangiomyomatosis of the renal sinus. Classic angiomyolipoma 29 76 19 57 101 76 6 1 110 22 32 73 17 50 Microscopic angiomyolipomas (so-called microhamartomas) 13 20 Intraglomerular lesions 74 Cystic angiomyolipoma 25 33 5 33 Fig. 5 Cystic angiomyolipoma: strong positivity for actin in the solid extracystic component; SM ACT ×10  33 Epithelioid angiomyolipoma 28 72 74 84 96 Oncocytoma-like angiomyolipomas 75 Lymphangiomyomatosis of the renal sinus 74 78 Bladder and prostate 85 86 6 7 90 Fig. 6 Prostatic PEComa composed of epithelioid cells with clear cytoplasm arranged in nests; H&E ×4  Fig. 7 Bladder PEComa composed of epithelioid cells with clear cytoplasm arranged in nests, H&E ×4  120 Uterus 95 8 Fig. 8 Uterine PEComa composed of epithelioid cells with a clear cytoplasm and well-defined cell borders; H&E ×10  115 lymphangioleiomyomatosis 16 39 31 Ovary, vulva and vagina epithelioid angiomyolipoma 4 111 clear-cell “sugar” tumor 39 83 Lung clear-cell “sugar” tumor Lymphangioleiomyomatosis 9 9 11 18 113 Fig. 9 Pulmonary lymphangioleiomyomatosis composed of epithelioid cells arranged around a vascular channel; H&E ×20  LAM is usually sporadic; patients with TSC are frequently afflicted. 113 CCST 10 68 12 11 12 41 93 Fig. 10 Pulmonary clear-cell “sugar” tumor composed of epithelioid cells with a clear cytoplasm and well-defined cell borders. A prominent and vascular channel is present; H&E ×10  Fig. 11 Pulmonary clear-cell “sugar” tumor: HMB45 immunoreactivity in tumor cells; HMB45 ×20  35 Pancreas 125 12 Fig. 12 Pancreatic clear-cell “sugar” tumor: this tumor has overlapping features of the clear-cell “sugar” tumor of the lung: epithelioid cells, with a clear cytoplasm and with a nested or appearance; H&E ×4  The paper reported a tumor with overlapping features of the “benign clear-cell sugar tumor of the lung”. This finding was in our opinion consistent with the hypothesis that similar tumors could possibly arise in many if not all locations. Thus the term PEComa was introduced to include all similar lesions arising outside the lung. At the time, we believed this to be a unique case. However, in the following years we have observed other two cases of PEComa of the pancreas with overlapping morphological, phenotypical and clinical features. Thus, while still a very rare disease of the pancreas, PEComa is not an extraordinary finding in this location. The clinical aspects of PEComa of the pancreas are interesting because they are discovered incidentally during echography of the abdomen and then investigated usually with cyto-aspiration. The observation of clear epithelioid cells can understandably lead to the wrong diagnosis of clear-cell carcinoma of the pancreas and thus lead to duodenocephalopancreasectomy. angiomyolipoma 51 Liver angiomyolipoma 13 44 114 118 114 98 Fig. 13 Hepatic angiomyolipoma: solid component made of large epithelioid cells; H&E ×10  Other sites Lymphangioleiomyomatosis 78 angiomyolipoma 14 34 47 7 49 63 53 54 Clear-cell “sugar” tumor 26 40 45 66 8 111 111 61 Clear-cell myomelanocytic tumour of the falciform ligament/ligamentum teres CCMMT 36 38 79 PEComa: the future 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. 107 56 71 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. 3 14 16 32 39 52 66 67 70 85 96 99 109 121 124 27 73 89 100 1 Table 1 Reported cases of malignant PEComas in literature Reference Diagnosis Site Sex/age Outcome Comments 100 CCST Lung n.a./n.a. AWD at 10 years Hepatic metastases at 10 years 32 Epithelioid AML Kidney F/49 DOD at 5.5 months   3 Epithelioid AML Kidney F/21 DOD at 3 months   96 Epithelioid AML Kidney F/24 DOD at 1 year Pelvic and hepatic metastases 96 Epithelioid AML Kidney M/29 DOD at 18 months Pulmonary and hepatic metastases 21 Epithelioid AML Kidney M/42 AWD at 15 months   67 Epithelioid AML Kidney F/71 DOD at 2 years   36 PEComa Ligamentum teres falciform ligament M/29 DOC at 1 year Radiographically suspected lung metastasis at 3 months 73 Epithelioid AML Kidney F/50 AWD at 10 years Local recurrence at 7 years; pulmonary, pelvic and abdominal metastases at 10 years 14 PEComa Uterus F/41 ANED at 6 months Ovarian mass at presentation 14 PEComa Uterus F/19 AWD at 18 months Aggressive local recurrence at 1 month; lung and bone metastases at 11 months 14 PEComa Terminal ileum and cecum F/28 DOD at 28 months Hepatic metastasis 22 Epithelioid AML Kidney F/49 AWD at 6 months   99 CCST Kidney F/23 DOD at 1 year Retroperitoneal recurrence at 3 months 122 Epithelioid AML Kidney M/47 DOD DOD with spinal, lung and lymph node metastases (autopsy case) 27 PEComa Uterus F/61 AWD at 7 years Lung metastases 46 PEComa Uterus and pelvic side wall F/79 DOD at several months Pelvic and mesenteric recurrence at 2 years 63 Epithelioid AML Retroperitoneum M/29 ANED at 18 years Liver metastases at 9 years; thymus and lung metastases at 17 years 64 Epithelioid AML Kidney F/36 ANED Lymph node metastases 69 Epithelioid AML Kidney n.a./58 AWD Liver and lymph node metastases 82 Epithelioid AML Kidney F/74 AWD Adrenal metastases 85 PEComa Prostate M/46 DOD at 4 years Submitted to adjuvant chemotherapy; lung metastases at 3 years 109 Epithelioid AML Kidney F/40 DOD at 18 months Submitted to adjuvant chemotherapy; pulmonary metastases 109 Epithelioid AML Kidney M/44 DOD at 60 months Splenic and retroperitoneal metastases at 3 years; hepatic metastases at 60 months 123 PEComa Jejunum F/32 AWD at 25 months Pelvic wall recurrence/local metastases at 13 months; ovarian metastases at 25 months 24 Epithelioid AML Urach F/n.a. AWD Lymph node metastases 49 PEComa Soft tissue near knee M/87 AWD at 40 months Inguinal lymph node and lung metastases at 13 months 66 PEComa Skull base F/49 DOD at 3 months Paraspinal and lung metastasis at 6 weeks 16 PEComa Uterus F/59 DOD at 1 year Pelvic recurrence at 6 months 30 PEComa Rectovaginal space F/56 AWD Pulmonary metastases at presentation 39 PEComa Neck F/77 ANED at 6 months Re-excision and submitted to adjuvant radiotherapy 39 PEComa Forearm M/71 ANED at 10 months Re-excision and submitted to adjuvant radiotherapy 39 PEComa Broad ligament F/16 ANED at 18 months Re-excised 39 PEComa Falciform ligament F/15 ANED at 35 months Re-excised 39 PEComa Uterus F/56 AWD at 11 years Submitted to adjuvant radio and chemotherapy; lung and bone metastases 39 PEComa Pelvic soft tissue F/72 AWD at 15 months Local recurrence 39 PEComa Omentum M/40 AWD at 24 months Extensive intra-abdominal recurrence/local metastases 39 PEComa Uterus F/59 AWD at 30 months Submitted to adjuvant chemotherapy; liver and lung metastases at 30 months 39 PEComa Mesentery F/46 DOD at 27 months Submitted to adjuvant chemotherapy; extensive intra-abdominal recurrence and liver metastases at 22 months 39 PEComa Uterus F/36 DOD at 39 months Submitted to adjuvant chemotherapy; lung metastases at 12 months and liver metastases at 36 months 108 Epithelioid AML Kidney F/47 ANED at 5 months Recurrence at 3 months 124 Epithelioid AML Kidney F/12 DOD at 9 months Lymph node metastases; submitted to adjuvant chemotherapy 2 PEComa Ileum F/63 AWD at 14 months Abdomino-pelvic recurrence 60 CCMT Broad ligament F/12 AWD at 1 year Iliac fossa recurrence 70 PEComa Thigh M/56 DOD at 1 year Pulmonary and brain metastases 70 PEComa Thigh F/60 DOD at 1 year Pulmonary metastases 70 PEComa Groin M/46 DOD at 2 years Lymph node metastases 89 PEComa Liver F/60 AWD at 10 years Hepatic recurrence and pulmonary, pancreatic and muscular metastases at 9 years; bladder metastases at 10 years 91 PEComa Lung/Adrenal gland F/53 AWD Brain metastases at several moths 121 PEComa Colon F/43 DOD at 38 months Peritoneal dissemination at 20 months 48 Epithelioid AML Retroperitoneum F/80 AWD at 1 year Hepatic and rib metastases 52 Epithelioid AML Kidney F/78 DOD at 5 months   92 Epithelioid AML Kidney M/69 AWD at 8 months Hepatic and peritoneal metastases 92 Epithelioid AML Kidney F/46 AWD at 12 months Hepatic and lymph node metastases 120 PEComa Retroperitoneum F/49 AWD Brain and lung metastases ANED AWD DOC DOD n.a. 39 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. 59 14 Fig. 14 Hepatic angiomyolipoma: cytoplasmic signal in immunohistochemical reaction for p70S6K; p70S6K ×10  23 117 88 97 58 65 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.