Perivascular Epithelioid Cell Tumor- PEComa

Executive Summary

Perivascular epithelioid cell tumor (PEComa or PEC tumor) is the family of rare tumors forming in the soft tissues of the stomach, intestines, lungs, female reproductive organs, and genitourinary organs. It includes angiomyolipoma (AML), clear cell/sugar tumor of the lung, lymphangioleiomyomatosis, and other histologically and immunohistochemically similar tumors (e.g., clear cell myomelanocytic tumor) that developed in various locations in the soft tissues and visceral sites. It is most commonly found in the uterus. It can also develop in the kidneys, bladder, prostate, lungs, pancreas, and liver, among other organs. These lesions are uncommon and difficult to detect compared to other liver tumors. It frequently occurs in young women than in young males, with a female-to-male ratio of 6:1. Ultrasound, CT and MRI scans are used to diagnose its tumors. Human melanoma Black-45 (HMB-45), melan-A, MITF, smooth muscle antigen, desmin, and caldesmon are used to make the final diagnosis after histological and immunohistochemical investigation of the excised tumor. Even in core needle biopsy, preoperative diagnosis is challenging. Surgery (lesion excision) is the only treatment for people with PEComa. Apart from surgical treatment, there is no traditional postoperative therapy, chemotherapy, or radiotherapy for malignant lesions. The study has a retrospective observational study conducted at the Medical University of Warsaw in two surgical departments. Patient medical records and internal computerized databases are used to acquire baseline characteristics, imaging study findings, and information on operational treatment and postoperative courses. Characteristic immunohistochemical results are presented. It is essential to distinguish it from HCC since it has a lot of arterial vascularization in radiological investigations. Surgery, or liver resection, is the preferred treatment. The definitive diagnosis is confirmed only after histological analysis of the resected specimen and many immunohistochemistry tests.

What is Perivascular epithelioid cell (PEComa) tumor?

PEComa (perivascular epithelioid cell tumor) is a relatively uncommon liver tumor. Currently, patient management decisions are based on a few tiny case studies. The goal of this study was to report the clinicopathological aspects of PEComa to help management, using our own experience as a supplement. Between 2002 and 2020, all patients with PEComa who underwent surgical therapy in two departments were included in this retrospective observational analysis. Following the histological investigation, 20 patients were identified with PEComa. The patients ranged in age from 21 to 73 years old. Women made up the vast majority of the patients (85%). The tumors mainly were unintentional in most cases.

PEComas with significant arterial vascularization has been described in diagnostic research. The therapy of choice was liver resection. There was only one problem after the surgery. Tumors were predominantly made up of epithelioid cells, with spindle cell components, thick-walled vasculature, and adipocytes in various proportions, as determined by histopathology. All tumors expressed melanocytic markers (HMB45, Melanie) and at least one smooth muscle marker. Three patients had characteristics that pointed to malignancy.

Finally, PEComa is an uncommon liver tumor that is discovered by chance. Tumors with significant arterial vascularization have been seen in radiological examinations. The treatment of choice is liver resection.

Introduction of Perivascular Epithelioid Cell Tumor- PEComa

Bonetti et al. were the first to describe a mesenchymal liver tumor arising from perivascular cells in 1992. Zamboni coined the term PEComa (perivascular epithelioid cell tumor) four years later. PEComas are mesenchymal tumors that are made up of perivascular cells that have a specific connection with blood vessel walls and exhibit melanocytic and smooth muscle markers ^​1​.

Until recently, PEComa tumors included angiomyolipoma (AML), clear cell/sugar tumor of the lung, lymphangioleiomyomatosis, and other histologically and immunohistochemically similar tumors (e.g., clear cell myomelanocytic tumor) that developed in various locations in the soft tissues and visceral sites ^​2​. The labels clear cell myo melanocytic tumors and sugar tumor of the lung are no longer suggested in the WHO 2020 classification (5th edition), and epithelioid AML is a synonym for PEComa.

Perivascular Epithelioid Cell Tumor- PEComa is most commonly found in the uterus. It can also develop in the kidneys, bladder, prostate, lungs, pancreas, and liver, among other organs. These lesions are uncommon and difficult to detect compared to other liver tumors. Because the clinical presentation is non-specific, these tumors are frequently discovered by chance ^​3​. There were no specific abnormalities found in laboratory tests in patients with PEComa. In situations involving significant PEComa lesions, symptoms such as abdominal pain, increased abdominal wall tension, constipation, or evidence of ileus are common.

Perivascular Epithelioid Cell Tumor- PEComa is more frequent in young women than in young males, with a female-to-male ratio of 6:1. These are usually single lesions; however, multifocality has been documented more commonly in cases of malignant tumors. Other liver tumors, such as hepatocellular carcinoma (HCC), hemangiomas, focal nodular hyperplasia, and liver adenomas, are differential diagnosis. The tumors are frequently mistaken as HCC during a liver ultrasound examination, computed tomography (CT), or magnetic resonance imaging (MRI) ^​4​. When the tumor resembles HCC, the alpha-fetoprotein (AFP) concentration is within normal ranges, and there is no history of viral hepatitis or cirrhosis. PEComa should be examined ^​5​.

PEComa tumors in the literature have mostly been benign until now; nonetheless, malignant tumors have been identified in a few patients. Recurrences or metastases were seen in individuals with tumors larger than 5–7 cm in diameter, with strong nuclear atypia, pleomorphism, a high mitotic index, necrosis, and infiltrative borders. Malignant PEComa developing in the liver can infect several abdominal organs simultaneously, including the omentum, leading to extensive peritoneal cavity haemorrhage.

PEComa is tumors with extensive arterial vascularization both inside and outside the tumor, so imaging investigations using intravenous contrast are more reliable in assessing this type of lesion. It is noted that the tumor’s echogenicity in ultrasound tests might be varied; nonetheless, these tumors are usually hyperechogenic. Power Doppler imaging shows that the lesion has a lot of vascularization. The lesion is enormously and heterogeneously increased in ultrasonography with intravenous contrast delivery, followed by fast contrast drainage into the venous channels.

Similarly, the critical hallmarks of these tumors on CT and MRI include significant enhancement in the arterial phase and contrast wash-out in the veno-portal and delayed phases due to abundant vascularization from hepatic artery branches. Only some PEComas, such as AMLs, have adipose tissue, which is simpler to identify on MRI. Furthermore, the tumor has no MR-specific characteristics; it is frequently hyperintense in T2-weighted images and hypointense in T1-weighted images, and it may show water diffusion limitation.

Clinical and laboratory information is critical for differential diagnosis because the complete radiological appearance, including probable fat content, is comparable to HCC or hepatic adenoma. PEComas without contrast “wash-out” have also been reported in the literature, coinciding with features of benign, well-vascularized tumors such as focal nodular hyperplasias (FNH) hemangiomas. These should not be confused with FNHs, which display highly homogeneous amplification. On the other hand, Hemangiomas show a classic blood pooling look, which differs dramatically from the PEComas’ heterogeneous enhancement.

Some overlapping may be seen with hepatic epithelioid hemangioendothelioma (HEHE); however, unlike PEComas, HEHEs are typically numerous and subcapsular, with capsular retraction and capillaries terminating at the lesions’ edges (the lollipop sign). Human melanoma Black-45 (HMB-45), melan-A, MITF, smooth muscle antigen, desmin, and caldesmon are used to make the final diagnosis after histological and immunohistochemical investigation of the excised tumor. Even in core needle biopsy, preoperative diagnosis is challenging.

Surgery (lesion excision) is the only treatment for people with PEComa, which is sufficient in the case of benign tumors (and PEComa, which affects the majority of patients). Apart from surgical treatment, there is no traditional postoperative therapy, chemotherapy, or radiotherapy for malignant lesions ^​6​.

Also Read: Integrative cancer treatment.

Materials and Methods

It was a retrospective observational study conducted at the Medical University of Warsaw in two surgical departments:

General, Transplant, and Liver Surgery and General, Gastroenterological, and Oncological Surgery. Between 2002 and 2020, patients with histologically confirmed PEComa who had surgical therapy were included. The national legislation did not require informed patient consent or ethical committee clearance because this was a retrospective study.

Patient medical records and internal computerized databases were used to acquire baseline characteristics, imaging study findings, and information on operational treatment and postoperative courses. Data on survival were gathered from a national database. The critical outcome indicators were postoperative complications. The secondary outcome measure was patient survival. It was defined as the period between the start of operational treatment and the patient’s death. At the time of the last follow-up visit, observations were suppressed. For this investigation, histopathological specimens were re-evaluated. The findings of immunohistochemistry analysis were recorded.

Results

Between 2002 and 2020, 20 patients were diagnosed with PEComa after histopathological examinations at the Independent Public Central Clinical Hospital of the Medical University of Warsaw’s Departments of General, Transplant, and Liver Surgery and the Department of General, Gastroenterological, and Oncological Surgery. The patients ranged in age from 21 to 73 years old. Women made up the vast majority (n = 17, or 85 percent). The tumor was discovered by chance in most patients during ultrasound exams performed for other reasons. An 8-cm-diameter lesion caused unbearable pain in the right costal arch in one patient.

There was no history of parenchymal liver disease in any of the individuals. The findings of the laboratory tests were normal. The amounts of serum AFP, carcinoembryonic antigen, and Ca 19-9 were all within normal limits. The therapy of choice was liver resection. The extent of resection was determined by the size and location of the lesions in the liver and included both anatomical and non-anatomical excisions. They were made up of mature adipose tissue, thick-walled blood arteries, and epithelioid cells that formed nests and trabeculae with abundant clear or eosinophilic cytoplasm. The proportions of the various components varied greatly. Adipose tissue was relatively sparse in two cases.

There was no fatty tissue in the remaining seven tumors. The tumors in both groups (AML/PEComa without adipocytes) were similar in size. There were no changes in mitotic activity, cytological atypia, or necrosis between the two groups. In 7/20 tumors, extramedullary hematopoiesis was seen. The spindle cell component was discovered in four tumors, but it was never dominant and had nothing to do with the other morphological traits. Characteristic immunohistochemical findings were present. At least one smooth muscle marker (HMB45, Melanie) and melanocytic markers (HMB45, Melanie) were expressed.

Positive immunohistochemistry staining with smooth muscle antigen and Melan A (a,b) is obserbed. Magnification of the objective is ten. At least three of the following features were detected in three cases: size less than 5 cm, high-grade atypia, mitosis more than 1/50 high-power fields, necrosis, infiltrative growth, and lymphovascular invasion. PEComa refers to the tumor’s infiltrative growth. Magnification of the objective is ten. Two patients died during the follow-up period, with survival estimates of 100%, 90.9%, 80.8%, and 80.8%, respectively, after one, three, five, and ten years.

Discussion about Perivascular Epithelioid Cell Tumor- PEComa

PEComa tumors of the liver have been reported in the literature for 28 years. The majority of reports are based on specific cases. Only two publications had a more extended series: the first had seven occasions, and the second had thirteen. Our research comprised 20 patients who underwent surgery at the Medical University of Warsaw’s two surgical departments, making it one of the studies with the largest sample size from a single institution.

Some of the problems highlighted in previous investigations were confirmed in our research. Both departments admitted patients who had no recognized diagnosis. On CT and MRI, the lesions resembled HCC in most cases. Even though they had healthy livers, no history of hepatitis, and no factors that affected the parenchyma, all patients treated at our centre acquired hepatic lesions. Other authors also noted these traits. Like those in other published trials, patients in our study were primarily female, with 85% of the sample being female.

The arterial phase of CT revealed intense saturation of the arteries on the tumor’s periphery, with a significant decrease in contrast in the portal and delayed phases. In MR investigations, a considerable intensity was evident in the T1 stage, but the T2 power dropped. In the literature, similar observations have been made. Patients were eligible for surgery based on the findings of their radiological test, which, although not providing a definitive diagnosis, suggested the necessity for surgery. The tumor’s location and size determined the extent of liver excision. There is no necessity for substantial liver resection, in our opinion.

The majority of patients had non-anatomical resections. However, oncological wholeness has always been a goal for us. In the patient with the most significant tumor (8 cm), the oncological margin was only 1 mm. This resection was done with such a small margin due to the magnitude of the malignancy. The non-expanded segments of the tumor that did not include cancerous cells that remained after the resection should be large enough to be roughly the patient’s body weight. Preoperative biopsy was not performed on any patients in the described series. The outcomes of the imaging studies were used to make the surgical choice.

We assumed that the patients’ tumors were resectable and that a biopsy would not change our minds. However, in another series, a biopsy was conducted. For example, the investigators did a fine-needle biopsy on two of the seven treated patients, finding cells suggestive of PEComa. The results did not change their minds, and they proceeded with the liver resection. While non-anatomical resection is sufficient for individuals with PEComa, in the case of HCC diagnosis, anatomical resection may be superior to non-anatomical resection. Individuals with PEComa, on the other hand, usually have no underlying liver disease, making them more like patients with HCC in a healthy liver.

In the latter, achieving an R0 resection status seems to be of the most importance. Histopathological diagnosis of PEComa is based on morphological and immunohistochemical features that allow differentiation of the tumor from other focal lesions in the liver, including HCC. PEComa, as a neoplasm with myomelanocytic differentiation, typically expresses both melanocytic (HMB-45, Melanie, Mitf) and myogenic markers (actin, myosin, calponin) with variable intensity and distribution of staining. TFE3 is a new marker strongly expressed in 15% of PEComas, indicating the presence of TFE gene rearrangement.

Perivascular Epithelioid Cell Tumor- PEComa with TFE3 gene rearrangements stain strongly with HMB45 and TFE 3, while Melanie and smooth muscle markers have a focal or negative expression pattern. Patients with this condition are in their early twenties. The tumors have an alveolar pattern, are made up of epithelioid cells, and do not always show smooth muscle markers. PEComas have minimal molecular genetic data. However two unique molecular groupings have been identified recently: PEComas with TSC2 mutations and tumors with TFE3 fusions (TFE3-translocation associated with PEComas).

TP53 mutations have also been discovered in 63% of TSC2 mutated Pecomas. The first category of patients (those diagnosed with malignant tumors) may benefit from focused therapy with mTOR inhibitors. Other rearrangements reported in PEComas include RAD51B fusions and HTR4-ST3GAL1 fusions. One investigation described a lesion in the liver that was distinct from original lesions. The case study above involves a young man who had surgery for a rectal tumor later diagnosed as a PEComa after histological investigation.

Surgery was used to treat the patient, and an anterior low rectal resection was performed. A tiny metastatic lesion in the liver was discovered four years later. After the number of lesions had increased to three and the size had increased, the patient agreed to surgery four years later. The patient underwent non-anatomic liver resection with proven PEComa metastases, followed by a successful postoperative course.

Surgery is the preferred and successful treatment for people with primary liver PEComa. The number of problems following surgery was relatively low. Nonetheless, these individuals must be closely monitored by oncologists at all times. 

Given the possible efficiency of mTOR inhibitors, chemotherapy has become the treatment of choice for disseminated malignant PEComas. There are limited studies on the non-surgical management of people with PEComas in the liver. Transarterial chemoembolization and ablation have been used in rare cases. If surgery is contraindicated, these non-surgical options should be investigated.

Conclusion

Perivascular Epithelioid Cell Tumor- PEComa is an uncommon liver tumor often discovered by chance. It’s important to distinguish it from HCC since it has a lot of arterial vascularization in radiological investigations. Surgery, or liver resection, is the preferred treatment. The definitive diagnosis is confirmed only after histological analysis of the resected specimen and many immunohistochemistry tests.

References