Hepatic perivascular epithelioid cell tumors: Benign, malignant, and uncertain malignant potential

Abstract

In 2013, the World Health Organization defined perivascular epithelioid cell tumor (PEComa) as “a mesenchymal tumor which shows a local association with vessel walls and usually expresses melanocyte and smooth muscle markers.” This generic definition seems to better fit the PEComa family, which includes angiomyolipoma, clear cell sugar tumor of the lung, lymphangioleiomyomatosis, and a group of histologically and immunophenotypically similar tumors that include primary extrapulmonary sugar tumor and clear cell myomelanocytic tumor. Clear cell tumors with this immunophenotypic pattern have also had their malignant variants described. When localizing to the liver, preoperative radiological diagnosis has proven to be very difficult, and most patients have been diagnosed with hepatocellular carcinoma, focal nodular hyperplasia, hemangioma, or hepatic adenoma based on imaging findings. Examples of a malignant variant of the liver have been described. Finally, reports of malignant variants of these lesions have increased in recent years. Therefore, we support the use of the Folpe criteria, which in 2005 established the criteria for categorizing a PEComa as benign, malignant, or of uncertain malignant potential. Although they are not considered ideal, they currently seem to be the best approach and could be used for the categorization of liver tumors.

Key Words: PEComas; Liver; Pathology; Malignant; Benign; Uncertain malignant potential

Core Tip: Perivascular epithelioid cell tumors are rare mesenchymal tumors for which the diagnostic criterion appears to be exclusively histopathological. They are characterized by a proliferation of perivascular epithelioid cells and the coexpression of markers for smooth muscle and melanocytes. They mainly affect females and occur in almost all organs. The incidence of benign and malignant perivascular epithelioid cell tumor of the liver is much lower than in other organs. It is necessary to reinforce the notion that there are malignant variants located in the liver, which are more frequently described along with their histologic and immunohistochemical features.

INTRODUCTION

In this editorial, we would like to comment on an article published in World J Gastroenterol 2021 by Zhang et al[1] titled “Hepatic perivascular epithelioid cell tumor: Clinicopathological analysis of 26 cases with emphasis on disease management and prognosis”, in which the typical features of these tumor lesions are described and a series that included all cases with predominantly benign features is shown.

We believe that in order to contribute to the discussion on this entity, we need to reinforce the idea that there may be malignant variants in the liver that are being described with increasing frequency along with their histologic, immunohistochemical, and molecular features.

PECOMA FAMILY TUMORS

In 2013, the World Health Organization defined perivascular epithelioid cell tumor (PEComa) as “a mesenchymal tumor which shows a local association with vessel walls and usually expresses melanocyte and smooth muscle markers”[2]. This generic definition seems to correspond better to the PEComa family, which includes angiomyolipoma (AML), clear cell sugar tumor of the lung, lymphangioleiomyomatosis, and a group of histologically and immunophenotypically similar tumors that include primary extrapulmonary sugar tumor and clear cell myomelanocytic tumor[1]. According to the latest edition (the 5^th edition) of the 2020 World Health Organization classification, the terms clear cell myomelanocytic tumor and sugar tumor of the lung are not recommended, and epithelioid AML is defined as a synonym for PEComa[3].

The diagnosis of a PEComa is based on its pathological features, including epithelioid cell forms with abundant clear to eosinophilic cytoplasm and in some cases arrangement around thick-walled blood vessels as well as immunohistochemical phenotypes, including melanocyte and smooth muscle markers. Typically, lesions are positive for HMB45, Melan-A, and smooth muscle actin (SMA) in decreasing order. It seems necessary to also evaluate immunoreactivity for TFE3, as a group of these tumors with this mutation has been described[1]. Some PEComa cases may be negative for Melan-A, emphasizing the importance of careful evaluation or melanocytic differentiation using HMB-45 and Melan-A. The ratio of α-SMA-positive cells was also inconclusive. In the figures in a report by Nie et al[4], there appeared to be partial α-SMA positivity (no diffuse positive pattern), suggesting that SMA positivity may be variable in PEComa cases[5].

In terms of molecular features, PEComas are characterized by mutations leading to activation of the mTOR pathway, such as biallelic inactivation of TSC1 or TSC2, fusion of the TFE3 gene, and truncating FLCN mutations[6]. This activation was first discovered while investigating the risk of developing lymphangioleiomyomatosis or AML in patients with tuberous sclerosis complex[7].

In the 234 cases analyzed in the review by Bleeker et al[8], genomic alterations were found in a small proportion of cases. In the vast majority of case reports, there was no information on molecular status (n = 98). TSC1/2 mutations and TFE3 translocation were determined in 26 and 14 of the cases, respectively. Both mutations were only found in 3 cases. TSC1/2 mutations with loss of function were detected in 50% (n = 13) of all cases examined. Five tumors had a mutation in the TSC1 gene, while eight had a mutation in the TSC2 gene.

Some PEComas are indolent, but others may show malignant development with a poor prognosis. For example, epithelioid AML, a variant of the classic form of AML, is a well-known aggressive tumor[9]. In 2005, Folpe et al[10] identified six tumor characteristics as poor prognostic factors to facilitate the assessment of tumor aggressiveness. Clear cell tumors with this immunophenotypic pattern have been described in their malignant variants as malignant PEComas, perivascular epithelioid cell sarcoma, malignant perivascular epithelioid cell tumor, and primary malignant extrapulmonary “sugar tumor”[5,11-13].

Even today, the natural history of metastatic PEComa is hardly known due to its rarity. Case reports and literature reviews have been published but were often focused on a particular primary location, which prevents conclusions about all PEComas. The last review article on a variety of primary PEComa not otherwise specified (“NOS”) was published in 2012 and proposed a more convenient, revised set of risk stratification criteria based only on tumor size and mitotic index[7].

LIVER PECOMAS

Hepatic PEComas are a rare entity. Until 2020, there were only 24 studies related to this tumor and about 33 reported cases, of which only 4 showed features of malignancy and even distant metastasis[14]. Maebayashi et al[2] also identified 40 cases with epithelioid AML from 17 articles. It has been shown that it is very difficult to make a radiologic diagnosis preoperatively, and most patients were diagnosed as hepatocellular carcinoma, focal nodular hyperplasia, hemangioma, or hepatic adenoma based on imaging findings. The diagnosis of PEComa should be considered if the tumor looks similar to hepatocellular carcinoma, the alpha-fetoprotein concentration is within normal limits, and there is no history of viral hepatitis or cirrhosis[15].

Since the definition is essentially histologic and immunophenotypic[16] and at least two of these tumor types have been clearly described in the liver, namely PEComas and AMLs, it is necessary to distinguish these two tumor types. Most reports of PEComas, with their usual morphology of epithelioid cells forms with abundant clear to eosinophilic cytoplasm and in some cases an arrangement around thick-walled blood vessels, lack the diffuse expression (most reports define it as focal) of muscle markers found in the vessels of AMLs[17].

In the referenced work, histological evaluation showed the following results. Microscopically, the tumor cells were clearly different from normal liver cells and consisted mostly of proliferating epithelioid cells and spindle cells embedded in trabeculae or lamellae. In most cases, the tumor cell nest was surrounded by capillaries. The tumor cells were arranged in a radial pattern around the thick-walled blood vessels. The tumor cells were polygonal, and the cytoplasm was translucent with heterogeneity evident and sparse chromatin. Some of the cells were heteromorphic, and mitotic figures were not common. Collagen fibers were observed in the interstitium, which were generally feathery, and a few fibers were accompanied by hemorrhage and necrosis. Of the 26 cases, 25 showed HMB45 (+), usually with multifocal or diffuse distribution and occasionally with scattered distribution, 23 Melan-A (+), 22 SMA (+), 20 VIM (+), and 12 S-100 (+). Only three cases showed focal staining (1%-5%) for TFE3. All tumors were desmin (-). The positive rate for Ki-67 was < 10%. All cases expressed at least one smooth muscle or melanocyte marker. Fluorescence in situ hybridization showed no abnormal TFE3 separation signal in 26 cases of hepatic PEComa[1].

It is noteworthy that the description of immunohistochemical features by these authors showed the presence of two markers that are positive in at least a percentage of cases (S100 and vimentin) in addition to the three previously described features. We believe that the review conducted by Zhang et al[1] clearly defined the histological features of this type of tumor in its predominantly hepatic and benign version. On the other hand, none of the cases evaluated in this work showed TFE3 alterations.

PECOMAS: MALIGNANT VARIANTS

It must be emphasized that reports of malignant variants of these lesions have increased in recent years. Therefore, we support the application of the Folpe criteria, which in 2005 established the criteria for classifying a PEComa of soft tissue and gynecologic origin as benign, malignant, or of uncertain malignant potential[10].

The Folpe criteria proposed seven histologic criteria for evaluation, and a PEComa with two or more features is classified as malignant. The criteria were: (1) Tumor size > 5 cm; (2) High nuclear grade; (3) Hypercellularity; (4) Mitotic rate of > 1/50 high power field (HPF); (5) Necrosis; (6) Infiltration into the surrounding normal parenchyma; and (7) Vascular invasion. Tumors that show only nuclear polymorphisms or multinucleated giant cells or are > 5 cm in size are considered to have uncertain malignant potential[10]. In that description, the authors defined that given the rarity of PEComas, it has been unclear whether any of these tumors can be declared benign or whether all PEComas carry some risk of aggressive behavior. Their results suggested that a subset of PEComas can be tentatively classified as either “benign” or perhaps “very low risk for aggressive behavior.” These include cases that do not have worrisome features (e.g., large size, high nuclear quality and cellularity, necrosis, 0.1 MF/50 HPF)[10].

In 2012, Bleeker et al[8] presented their study in which they analyzed 234 cases of PEComa-NOS and extracted information on the following features: Diagnosis; treatment approaches; and treatment outcomes. After multivariate analysis of several variables in the lesions, they performed a pathologic examination to refine the pre-existing risk stratification criteria. The results showed that the only factors significantly associated with recurrence after surgical resection were primary tumor size ≥ 5 cm (P = 0.02) and a high mitotic rate (1/50 HPF) (P < 0.0001).

This review better defined the natural history of PEComa-NOS at various primary sites and emphasized the importance of long-term surveillance in the face of a number of cases of late recurrence[8]. Although not considered ideal, it appears to be the best approach at present and could be used to categorize liver tumors.

MALIGNANT PECOMAS IN THE LIVER

The vast majority of reported cases of hepatic PEComa show a benign course, although some malignant tumors have been reported as well. There are also some cases that show an invasive growth pattern with distant metastases or recurrences. To date, there is no uniform standard for assessing the degree of malignancy of liver PEComa[18].

In 2013, Shi et al[19] presented a series of 4 cases and used the following parameters to categorize the cases they described as malignant. The criteria for the diagnosis of primary malignant PEComa of the liver included: (1) The tumor mass was found only in the liver; (2) The tumor had definite recurrence or metastasis after the initial surgical excision; (3) The presence of epithelioid myoid cells with cellular atypia; and (4) The tumor cells were immunohistochemically positive for melanocytic markers (HMB-45 and/or Melan-A) and SMA. Grossly, the resected tumors appeared as solitary masses, firm and grey-white on the cut surface, with the largest diameter of 10 cm to 15 cm (mean of 12.5 cm). The tumors were demarcated from the surrounding liver. Hemorrhage and tumor necrosis were observed in all tumors. Mitotic activity was low, on average 2-3/20 HPF.

Immunohistochemically, the tumor cells were positive for vimentin (4/4, diffuse), HMB-45 (4/4, diffuse), Melan-A (4/4, 3 diffuse and 1 focal), S-100 (3/4, focal), SMA (4/4, 3 diffuse and 1 focal), and desmin (1/4, focal). The tumor cells were completely negative for Hepar-1, alpha-fetoprotein, Inhibin-A, cytokeratin AE1/AE3, CEA, CD10, and CD117 in all tumors. The proportion of Ki-67-positive tumor cells was not high in all cases (10%-20%). As we can see, the cases fulfilled the two parameters published by Bleeker et al[8], which are essential for the diagnosis of malignancy. Although they are not common tumors, they should be considered in the diagnosis of clear cell liver tumors as there are a large number of possible differential diagnoses with which we could confuse this entity.

MUTATED TFE3 VARIETY

TFE3 is a novel marker that is highly expressed in 15% of PEComas, indicating the presence of TFE gene rearrangement. PEComas containing TFE3 gene rearrangements stain strongly with HMB45 and TFE3, but the expression of Melan-A and smooth muscle markers tends to be focal or negative[20]. Patients with this abnormality are younger. Microscopically, the tumors have an alveolar pattern, are composed of epithelioid cells, and often do not express smooth muscle markers[3].

TREATMENT

Due to the rarity of the disease, attempting treatment is fraught with significant difficulties and the treatment of liver PEComa remains controversial[21]. Surgery is the treatment of choice for patients with primary liver PEComa and is effective. The number of postoperative complications is relatively low. Nevertheless, these patients require constant oncologic surveillance, similar to patients with cancerous tumors in the liver.

CONCLUSION

There are very few reports on the nonsurgical treatment of patients with liver PEComas. In rare cases, transarterial chemoembolization and ablation have been used[22]. These nonsurgical methods should be considered when there are contraindications to surgery. For disseminated malignant PEComas, chemotherapy becomes the treatment of choice considering the potential efficacy of mTOR inhibitors[23].