Primary retroperitoneal PEComa: an incidental finding
- Bárbara Monteiro Marinho ,
- António Gâmboa Canha ,
- Donzília Sousa Silva and
- José Davide Pinto Silva
- Department of Surgery, HEBIPA - Hepatobiliary and Pancreatic Unit, Hospital de Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal
- Correspondence to Dr Bárbara Monteiro Marinho; barbaramarinho_12@hotmail.com
Abstract
Perivascular epithelioid cell neoplasm (PEComa) is a rare type of tumour, and primary retroperitoneal PEComa is rarer still. Although pulmonary lymphangioleiomyomatosis (LAM), angiomyolipomas and clear cell ‘sugar’ tumours of the lung are well described, relatively little is known about other members of the PEComa family. We describe a case of an asymptomatic retroperitoneal PEComa, lymphangioleiomyoma type, which appeared in a previously healthy middle-aged woman as an incidental finding, in a CT scan performed in the context of spontaneous pneumothorax. The patient underwent surgical excision of the tumour and the histopathological and immunohistochemical analysis of the surgical specimen made the definitive diagnosis. Although rare, reports of isolated retroperitoneal lymphangioleiomyoma and primary retroperitoneal PEComas NOS (not otherwise specified) are described in the literature, normally associated with pulmonary LAM. The patient’s pulmonary imaging was normal. Short-term re-examination did not detect any recurrence. We also provide a literature review of this rare group of tumours.
Background
Perivascular epithelioid cell neoplasms (PEComas) are a family of rare mesenchymal tumours composed mostly of perivascular epithelioid cells (PECs). PECs simultaneously express differentiation markers for muscle cells and melanocytes. Under normal conditions, perivascular cells do not exist and its aetiology remains unknown. However, it appears to be related to the blood vessel wall since they are closely associated with these structures.1 Over the years, several hypotheses regarding its origin have been raised.2 3
The progressive enlargement of the PEComa family led the WHO classification of tumours to include PEComas as a distinctive entity in 2002 and to define them as: “mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells.”4 This very heterogeneous family, with differentiation and uncertain biological behaviour, includes angiomyolipomas, lymphangioleiomyomatosis (LAM), clear cell sugar tumours (CCST), clear cell myomelanocytic tumours of the falciform ligament, primary cutaneous PEComas and less well-characterised PEComas of a variety of other anatomic origins.1 4 The term PEComa NOS (not otherwise specified) has been proposed to describe the latter subgroup, a broad group of tumours with perivascular epithelioid differentiation, not qualifying for the remaining subgroups of the PEComa family.5
LAM is characterised by abnormal smooth muscle-like cells proliferation (LAM cells) leading to the formation of lung cysts and fluid-filled cystic structures (lymphangioleiomyomas) in the axial lymphatics. LAM, almost exclusively affects women in their reproductive years, is a rare systemic disease and the main manifestations are pulmonary.6 It can also affect extrapulmonary sites, such as the mediastinum, the retroperitoneum or the lymph nodes, although these locations are rare. A localised form of LAM can manifest as extrapulmonary lesions and this form is referred to as extrapulmonary lymphangioleiomyoma (e-LAM).7 An extrapulmonary manifestation or asymptomatic e-LAM lesions, preceding pulmonary disorders, are unusual but there are reported cases.7 8 A review of the clinicopathological features in 22 cases of e-LAM demonstrated that, in most patients, the diagnosis ofe-LAM preceded that of pulmonary LAM, usually by 1–2 years.8 The cases demonstrate the importance of appropriate LAM diagnosis and being aware of such disease in cases presenting with extrapulmonary extension of the disease.
Case presentation
A woman in her 30s, non-smoker, with no significant medical history or medication other than oral contraceptive, was admitted to the emergency room with a spontaneous pneumothorax (see figure 1). She presented with complaints of right posterior chest pain, with pleuritic features, and shortness of breath, with about 48 hours of evolution. The patient went first to primary care physician, who noticed a decreased respiratory sounds at the right lung base and referred her to the emergency department. She underwent a chest tube drainage procedure and was admitted to the pneumology unit. Four months later, the patient had a recurrence of the right-sided pneumothorax and was again hospitalised.
Chest X-ray showing a right-sided pneumothorax.
Investigations
After chest tube drainage, a CT scan was obtained. The scan showed a solid, retroperitoneal mass, with approximately 3.5 cm × 3 cm, located anteriorly to the middle third of the left kidney and contacting the adrenal gland. Apparently contiguous and inseparable from the posterior part of the pancreatic body/tail and with relatively similar enhancement (see figures 2 and 3). Serum levels of chromogranin A, adrenocorticotropic hormone, aldosterone and catecholamines were normal. After being discharged, she was referred to the cardiothoracic surgery department at another hospital. There, the patient was submitted to video-assisted thoracic surgery with apical resection and talc pleurodesis without complications.
CT scan (arterial phase) demonstrating a solid, retroperitoneal mass, with approximately 3.5 cm × 3 cm, located anteriorly to the middle third of the left kidney and contacting the adrenal gland. Apparently contiguous and inseparable from the posterior part of the pancreatic body/tail and with relatively similar enhancement.
CT scan showing the same mass as figure 2 but in venous phase timing.
For better clarification of the abdominal CT finding, an endoscopic ultrasound with biopsy was performed. A hypoechoic lesion, slightly heterogeneous and with well-defined contours, was observed in the retroperitoneum, between the gastric wall, the tail of the pancreas, the left kidney, the spleen and the adrenal gland. The starting point of the tumour remained unclear and cytology revealed spindle cells, showing mesenchymal origin (see figure 4). Although definitive characteristics of malignancy (necrosis, mitotic figures) were not observed, the benign nature of the mass could not be safely concluded.
The neoplasm is constituted by loosely arranged short fascicles of spindled cells.
Treatment
After a multidisciplinary assessment of the case, a surgical approach was proposed and the patient underwent a laparoscopic resection of the tumour. The pathological examination revealed a fusocellular mesenchymal neoplasm, with fascicular growth pattern, and the bundles in close relationship with the vascular spaces (see figure 5). The cells had clear, granular eosinophilic cytoplasm, with monomorphic nuclei and no evident nucleoli (see figure 6). Two mitoses were present per 50 high-power fields (HPF), while necrosis was absent. Immunohistochemistry was positive for smooth muscle actin (see figure 7), desmin, human melanoma black 45 (HMB-45) (see figure 7), oestrogen receptors, progesterone receptors and succinate dehydrogenase. The tumour cells did not show reactivity for CD117, S-100, CD34, ALK, DOG1 and MDM2. The final pathology referred a 4.3 cm retroperitoneal PEComa, lymphangioleiomyoma type, with uncertain malignant potential.
The fascicles of tumour cells are separated by small, slit-like vascular spaces.
The tumour cells are spindled, with eosinophilic granular cytoplasm and mildly atypical nuclei.
The cells are weakly positive for smooth muscle actin (A) and multifocally positive for human melanoma black 45 (B), confirming the typical myomelanocytic differentiation of perivascular epithelioid cell neoplasms.
Outcome and follow-up
The patient recovered well following surgery, without further treatment, and did not develop any other signs or symptoms, namely dyspnoea, chest pain, cough or cutaneous changes. Given the association with tuberous sclerosis, the patient underwent brain CT which was normal. The pulmonary imaging investigation, to assess the possibility of pulmonary LAM, showed no relevant alterations until 2 years of follow-up. At 25 months postsurgery, a chest CT revealed three air-filled infracentimetric cavitary lesions (pneumatoceles), two in the right lower lobe and one in the right upper lobe, and serum vascular endothelial growth factor-D (VEGF-D) levels were greater than 800 pg/mL, favouring the suspected diagnosis of LAM.
Discussion
PEComa tumours are more likely to affect women in the fourth and fifth decade of life, more specifically between the ages of 38 and 56,5 although cases have also been reported in children.9–11 They may be an incidental finding, which occurs in about 20% of cases, or present as pain or discomfort in the tumour area, weight loss, or other complaints related to the compression of adjacent structures.5 Medical imagiology, in accordance with clinical presentation, has no specific signs. Very few descriptions of the radiological appearance of PEComas exist to define specific diagnostic imaging characteristics.5 12
The most common locations for the development of PEComas are the uterus,13skin, liver14 and colon. Despite the majority of reported PEComas arise from retroperitoneal organs, there are only a few cases of primary origin in the retroperitoneum,15 16 as in the present study. In addition, several case reports of PEComas have been published in very different anatomical locations: the pancreas, stomach, ileon, greater omentum, mesentery, gall bladder, breast, femur, skull, heart, pericardium, the prostate, cervix, adnexa, vulva, broad ligament,17 nasal cavity, throat, orbit, urinary bladder, lung, the groin, anorectal region16 and more.1 18
PEComas are defined by the presence of PECs coexpressing both myogenic and melanocytic markers and are characterised by similar histological and immunohistochemical presentations. These tumours are generally composed of epithelioid or spindled smooth muscle tissue, dysmorphic blood vessels and mature adipose tissue. The coexpression of melanoma cells markers (HMB-45, Melan A, Microphthalmia transcription factor) and muscle cells markers (actin, myosin, caldesmon, calponin) is one of the main characteristics. In general, PEComas are grossly circumscribed, but some are histologically infiltrative into the surrounding soft tissue.18 19
Somatic inactivating mutations within the suppressor genes Tuberous Sclerosis Complex 1 (TSC1) or 2 (TSC2) genes, which encode proteins responsible for inhibiting the mechanistic target of rapamycin complex 1 (mTORC1) complex, are characteristic for this group of tumours. The excessive activation of the mechanistic target of rapamycin (mTOR) pathways leads to increased proliferation of cells and their differentiation into myocytes.20 Based on this, the use of mTOR inhibitors has been proposed in the treatment of patients with advanced PEComas.21 More recent molecular studies have identified another PEComa subgroup, characterised by rearrangements of the transcription Factor Binding To IGHM Enhancer 3 gene, also resulting in activation of the mTORC1 signal pathway. However, PEComas harbouring TFE3 gene rearrangements are thought to form a morphologically similar but biologically distinctive subgroup, as they lack the TSC2 alterations characteristic of the conventional ones.22
Optimal treatment for PEComas is not well established at this time. Radical resection is the mainstay of treatment for primary PEComa at presentation as well as for local recurrences and metastases.3 Metastasectomy of metastatic foci (lung, kidney, liver) allowed long-term control of the disease in several cases described.23 Chemotherapy, immunotherapy and radiotherapy appear to have little efficacy.3 There are no published prospective clinical trials or sufficiently large retrospective case series regarding the role of these therapies, including conventional chemotherapy or other biological agents (ie, antiangiogenic agents), in their therapeutic approach. Thus, the role of adjuvant and neoadjuvant therapy remains unclear but, so far, its importance has not been proven and it is currently not recommended, with the exception of clinical research protocols and application in reference centres.1 3
Because of frequent genetic perturbations causing an increase in the activity of the mTOR pathway, the use of mTOR inhibitors in patients with locally advanced or metastatic PEComa has been studied and seems promising. In spite of promising responses, cases of resistance to mTOR inhibitors have also been described.21 24 There also appears to be a potential benefit in the use of angiogenesis inhibitors in advanced disease, but only a very small percentage of objective responses have been achieved. Regarding systemic therapy in patients with advanced/metastatic PEComa, mTOR inhibitors appear to be the most active agents. Antiangiogenics and chemotherapy with gemcitabine-based regimens or anthracycline-based regimens are options in further line, but with a lower response rate and median progression-free survival.25
The biological behaviour of PEComas remains unclear. Among PEComa NOS tumours, both benign tumours and poorly differentiated malignant tumours, with an aggressive clinical course and disease dissemination, are observed. Folpe et al 26 proposed to classify PEComas into three categories, according to the risk of malignancy. The classification is based on the presence of six recognised high-risk characteristics: tumour size ≥5 cm, mitotic rate >1/50 HPF, infiltrative growth pattern, high nuclear grade and cellularity, presence of necrosis and vascular invasion.27 Based on a review of 34 retroperitoneal PEComas, about 45% of retroperitoneal PEComas have malignant potential. Thus, retroperitoneal PEComas are not as indolent as they were supposed to be, since 20%–21% of all reported cases presented with or developed metastases in the course of the disease. These findings should be taken into consideration in designing therapeutic strategies and surveillance.3
The major target organs for metastasis are the lungs—there are cases of pneumothorax caused by tumour infiltration,28 the liver and bones. However, metastases have been described in many other places, such as central nervous system, skin, intestinal wall, ovary, stomach, peritoneum, adrenal glands and lymph nodes.29 This requires a complete evaluation of the staging when a malignant PEComa is diagnosed. As metastases can occur even up to 10 years after resection of the primary tumour, and the predictive markers for their development are not known, a long period of surveillance for these tumours after initial surgical treatment is necessary. An optimal routine follow-up policy for PEComa cases is not available and it has been proposed to follow the sarcoma guidelines for follow-up.3
In the present clinical case, since the analysis of the surgical specimen revealed a lymphangioleiomyoma-type PEComa, the patient had two spontaneous pneumothoraces, and the vast majority of e-LAM cases end up with pulmonary LAM (usually within 1–2 years), clinical and imaging surveillance were performed to detect lung manifestations of LAM as early as possible, and serum VEGF-D levels were also obtained. As we know, the key treatment for parenchymal lung disease due to sporadic LAM is inhibition of the mTOR signalling with sirolimus. However, as the patient did not have abnormal lung function, substantial disease burden or problematic chylous effusions, we chose not to start the drug and keep surveillance.
Learning points
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Primary retroperitoneal PEComa is a rare type of tumour and its diagnosis remains difficult given the non-specificity of the clinical presentation and imaging findings.
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The biological behaviour of PEComas is variable and difficult to predict, and retroperitoneal PEComas are not as indolent as initially thought, with radical surgical excision being the treatment of choice.
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Regarding treatment options for disseminated disease, mTOR inhibitors constitute the most promising therapy.
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Prospective clinical trials or larger retrospective case series are necessary to better clarify the imaging characteristics of PEComa tumours and the methods for their diagnosis and treatment.
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We should always consider the association between isolated PEComas, especially lymphangioleiomyomas and angiomyolipomas, with lymphangioleiomyomatosis and tuberous sclerosis.
Ethics statements
Patient consent for publication
Footnotes
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Contributors Supervised by JDPS. Patient was under the care of AGC and DSS. Report was written by BMM.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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