Malignant perivascular epithelioid cell tumor of the lung synchronous with a primary adenocarcinoma: one case report and review of the literature
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Perivascular Epithelioid Cell Tumors (PEComa) is an extraordinarily rare mesenchymal neoplasm especially the malignant type originating from the lung. To date, only 8 cases of malignant or malignant potential pulmonary PEComa had been documented. Firm diagnostic criteria for malignant pulmonary PEComa need urgently to be established.
We report a challenging case of malignant pulmonary PEComa combined with a primary adenocarcinoma in a 54-year-old man. The PEComa-like tumor showed strong Melan-A and weak transcription factor E3 (TFE3) protein expression but no TFE3 gene rearrangement. The carcinoma-like nodule was recognized as a poorly differentiated primary lung adenocarcinoma.
Discussion and conclusions
Our case report was the first case of malignant pulmonary PEComa synchronous with a primary adenocarcinoma and studied the dilemma of diagnosing benign versus malignant criteria for this uncommon tumor.
KeywordsPerivascular epithelioid cell tumor PEComa Malignant Clear cell tumor Lung Adenocarcinoma Diagnostic criteria
- 18F-FDG PET/CT
Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography
Anaplastic lymphoma kinase
Epidermal growth factor receptor
Epithelial membrane antigen
Kirsten rat sarcoma viral oncogene
Perivascular epithelioid cell tumor
ROS proto-oncogene 1
Transcription factor E3
Tuberous sclerosis complex
World Health Organization
α-smooth muscle actin
Perivascular Epithelioid Cell Tumor (PEComa) is a rare mesenchymal neoplasm which is thought to originate from perivascular epithelioid cells showing both melanocytic and myogenic differentiation . Although this tumor was first described as a benign lung tumor in 1971 by Liebow and Castleman, it is extraordinary rare especially the malignant type originating from the lung .
Most PEComas are thought to follow a benign behavior. Clear cell tumor, angiomyolipoma, lymphangioleiomyomatosis, sugar tumor of the lung are all synonyms for this morphologically and immuno-phenotypically similar lesions . Though malignant PEComa had been described and studied at numerous sites including soft tissue  and gynecologic Origin , retroperitoneum , gastrointestinal  and uterine [8, 9], the diagnostic criteria and treatment strategy of malignant pulmonary PEComa have not been firmly established.
To date, only 8 cases of malignant or malignant potential pulmonary PEComa had been documented. We herein report a case of a 54-year-old man who synchronously presented with a well-demarcated mass in the right middle lobe and a small solid nodule in the left lower lobe. Since our case not only had a PEComa-like nodule and showed another solid nodule, the pressure on surgical management and frozen pathologic diagnosis is to judge whether the two tumors are homologous or heterogenous. The next challenge is to find and give preliminary evidence of histological features that determining its malignant behavior. Therefore, we described the difficulties of diagnosing malignant pulmonary PEComa in frozen and routine paraffin sections, and the predicament of surgical management we confronted. In this article, clinical and pathologic features were evaluated, immunohistochemical analysis and molecular alteration was studied.
TFE3 gene rearrangement was not identified by fluorescence in-situ hybridization and reverse transcription polymerase chain reaction (RT-PCR). The results of targeted molecular gene alteration including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1(ROS1), kirsten rat sarcoma viral oncogene (K-ras) of these two tumors were all negative.
The patient underwent three courses of chemotherapy of combined paclitaxel (300 mg) and carboplatin (600 mg) after surgery. A follow up fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) obtained 12 months after chemotherapy showed no metastatic lesions elsewhere. At present, the disease is stable and the patient is followed-up regularly.
Discussion and conclusions
Conventional PEComas frequently harbor tuberous sclerosis complex (TSC) gene mutation . A distinct subset of PEComa carrying transcription factor E3 (TFE3) gene rearrangements were identified arising in the uterine corpus, vagina, and pelvic and pulmonary tumor . They typically are strongly positive for TFE3 and HMB45, with purely clear cell epithelioid cells and an alveolar architecture [12, 13, 14]. But it is still uncertain what the role of TFE3 is in malignant pulmonary PEComa. Recognition of this genetic abnormality may have critical therapeutic implications for aggressive tumor in future.
Including six cases in the English literature and two cases documented in the Chinese literature, a total of 8 aggressive or malignant PEComas of the lung have been reported [15, 16, 17, 18, 19, 20]. These documents illustrated the invasive clinical behavior of the tumor from a series of angles, including tumor size, infiltrative growth pattern, nuclear grade, necrosis, and mitotic activity. According to most literatures, malignant PEComa of the lung also appeared radiologically as a solitary, well-defined nodule like benign clear cell sugar tumor, without cystic changes and calcification. Only one recently reported case showed spindle cell morphology and significant calcification.
Histopathologically, PEC tumor should be differentiated from primary clear cell pulmonary carcinoma, a variant of adenocarcinoma according to 2015 World Health Organization (WHO) classification of tumors of the lung, carcinoid, metastatic renal clear cell carcinoma, paraganglioma, primary intrapulmonary meningothelial neoplasm and malignant melanoma.
As with more and more recognized cases at numerous sites, diagnostic criteria for malignant PEComa continue to evolve. Firm diagnostic criteria for malignant pulmonary PEComa also need to be urgently established. Therefore, we put forward some suggestions for reference in diagnosis of malignant lung PEComa according to our experience and retrospective literature analysis. The primary diagnostic criteria include: prominent coagulative tumor necrosis; infiltrates and invade adjacent pleura or viscera; distant metastasis of homology; pathological mitotic figure≥1/50HP. Secondary diagnostic criteria are as follows: tumor size≥3 cm; spotty necrosis; high mitotic index≥5%; multinucleated tumor giant cell≥5/50HP; marked hyper-cellularity; nuclear atypia and pleomorphism; numerous intranuclear pseudoinclusion.
The criteria for the diagnosis of malignant lung PEComa that we recommend are that the tumor meets 1–2 major diagnostic criteria and/or one more secondary diagnostic criteria. If the tumor satisfies only 2 or more secondary diagnostic criteria, we suggest the diagnosis of lung PEComa with malignant potential.
Scope of surgical resection and lymph node dissection and subsequent medical treatment of malignant PEComa is another challenge. Complete surgical resection is probably the most effective treatment at present. As for the need for combined chemotherapy, it should be considered the degree of histologic differentiation and whether the tumor is associated with a primary malignant tumor. In our case, the middle lobe lesion was successfully removed from normal surrounding parenchyma and a wedge resection of left lower lobe was carried out. The right middle lobectomy and lymph node dissection were finally performed. Three courses of toxic chemotherapy were performed targeting for lung adenocarcinoma after operation, and we speculated that the prognosis of malignant PEComa may benefit from the strategy. Postoperatively, follow up 18F-FDG PET CT showed no evidence of residual tumor or metastatic lesions elsewhere.
Pulmonary malignant PEComa associated with a primary poorly differentiated adenocarcinoma has not been described previously. TFE3 gene mutation was not identified in this case. Due to this tumor’s uncommon occurrence, the diagnostic criteria of this entity are not widely known and may lead to misdiagnosis. Therefore, its malignant characteristics may be multifaceted and need to be addressed from different angles and more examples.
This work was funded by Intelligent Medical Research Project of Shanghai Municipal Health Commission (2018ZHYL0213 ).
Availability of data and materials
The datasets used during the current study are available from the corresponding author on reasonable request.
YCH and JKZ designed the study. JKZ and LZ performed the experiments and HHT interpreted the pathologic and imaging data. RYZ and HHT completed the molecular analysis. WJD and KKY guaranteed the technical support. JZ provided conceptual advice and participated in the revision of the article structure, as well as the discussion of the diagnosis. JKZ and LZ wrote the manuscript. YCH supervised the entired project. All authors and contributors read and approved the final manuscript.
Ethics approval and consent to participate
The Ethics Committee of Shanghai Chest Hospital of Shanghai Jiao Tong University approved this study. The patient agreed to participate in the study with all relevant data. And written informed consent was obtained from the patient.
Consent for publication
Written informed consent for publication of the clinical details and clinical images was obtained from the patient.
All authors declare that they have no competing interests.
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