Perivascular Epithelioid Cell Tumor (PEComa) of the Pancreas in a Patient with Ulcerative Colitis: A Case Report and Review of the Literature

Perivascular epithelioid cell tumors (PEComas) are mesenchymal tumors of peculiar cells that are focally associated with blood vessels, and generally have a distinctive bi-phenotypic expression of both smooth muscle and melanocytic markers. There are several entities in the PEComa family, including tumors that arise in the soft tissues and viscera. Frequently affected organs include the lungs (sugar tumors), uterus, broad ligament, colon, small bowel, liver, and pancreas. Ulcerative colitis (UC) has been associated with the development of tumors, especially colorectal and hepatobiliary carcinomas. Rare cases of UC have been reported in the PEComa family of tumors, but none in the pancreas. Here, we present a case study of a 27-year-old female patient with a history of UC who developed PEComa of the pancreas, a unique association that has not been previously reported. We also review reported cases of PEComas in the pancreas, as well as PEComas at all anatomic sites associated with UC.


Introduction
The concept of perivascular epithelioid cell (PECs) was introduced by Bonetti et al. (1992) as a novel cell type that was identified in renal angiomyolipoma (AML), clear cell "sugar" tumor of the lung (CCSTL), and pulmonary lymphangioleiomyomatosis (PLAM). They stated that PEC is an unusual cell type that is immunoreactive, with melanocytic markers, particularly HMB45, and exhibits an epithelioid appearance, a clear-acidophilic cytoplasm, and a perivascular distribution [1]. Furthermore, Bonetti et al. also documented a comparative study of three cases each of CCSTL and AML of the kidney. Morphological analysis showed that the CCSTL cells were identical to the perivascular epithelioid component of AML and expressed the melanosome marker HMB45. They concluded that both lesions belonged to the same family of lesions [2]. In a subsequent review article, these authors introduced PEC as a unifying concept for a family of tumors, including AML and its variants, PLAM, and pulmonary and extrapulmonary clear cell "sugar" tumors (CCSTs) [3]. The term PEComa was introduced by Zamboni et al. to describe a pancreatic tumor composed purely of the perivascular epithelioid cell component of this family of tumors [4]. Folpe et al. added another novel entity to the family of PEComa, namely clear cell melanocytic tumors of the falciform ligament and ligamentum teres of the liver [5]. As the name of this tumor implied, it showed immunohistochemical positivity for melanocytic marker (HMB45) and smooth muscle marker (smooth muscle actin). the liver [5]. As the name of this tumor implied, it showed immunohistochemical positivity for melanocytic marker (HMB45) and smooth muscle marker (smooth muscle actin).
PEComas have thereafter been reported in many anatomic sites, including the uterus [6], gastrointestinal tract [7,8], liver [9], soft tissue [10], bone [11], and skin [12]. Twentyeight cases of pancreatic PEComas have been reported [4,, mostly benign, without associated pancreatic or gastrointestinal disease. Herein, we report a unique case of pancreatic PEComa associated with ulcerative colitis, along with a review of the literature.

Clinical History
A 27-year-old non-smoker female with a known long-standing (11 year) history of ulcerative colitis, and maintained on mesalazine, 1000 mg PO TID, with regular follow up, was referred to our hospital, a tertiary care center, in April 2013, from a peripheral hospital where she was found to have a pancreatic tail mass on a computed tomography (CT) scan. Upon presentation at our hospital, she stated that she had an episode of acute severe central abdominal pain that started one month earlier, associated with vomiting, which led her to seek medical attention. She denied a history of fever, weight loss, loss of appetite, or recent changes in bowel habits. Physical examination and laboratory investigations were unremarkable.
On a repeat of CT-scans of the abdomen, pelvis, and chest, a well-defined, solid, ovalshaped, exophytic mass projecting at the pancreatic tail inferiorly, measuring 4 cm in maximum dimension, was found ( Figure 1). The mass was iso-attenuated with the pancreatic parenchyma. There was no observable fat plan involvement that could suggest infiltration. No other remarkable lesions, apart from a subserosal uterine fibroid and small bilateral fibroadenomas of the breast, were found on chest, abdominal, and pelvic CT scans.

Pathological Findings
On gross examination, the resected pancreas revealed a solid well-circumscribed, encapsulated, homogenous dark red mass, measuring 4.2 × 4.1 × 3 cm, involving the medial margin. The rest of the pancreas was unremarkable. The spleen weighed 130 g and was unremarkable. Microscopically, the tumor was encapsulated, and the cells were arranged in sheets, with vague nodularity, associated with high vascularity (Figure 2a.). The tumor

Pathological Findings
On gross examination, the resected pancreas revealed a solid well-circumscribed, encapsulated, homogenous dark red mass, measuring 4.2 × 4.1 × 3 cm, involving the medial margin. The rest of the pancreas was unremarkable. The spleen weighed 130 g and was unremarkable. Microscopically, the tumor was encapsulated, and the cells were arranged in sheets, with vague nodularity, associated with high vascularity (Figure 2a). The tumor cells were mainly spindle-shaped, with a component of epithelioid cells featuring clear to eosinophilic granular cytoplasm, and centrally located rounded uniform nuclei with inconspicuous nucleoli (Figure 2b,c). They were centered around the blood vessels.
Necrosis, significant mitosis, vascular invasion, and atypia were absent. The tumor reached the medial margin of the resection.
Healthcare 2023, 11, x 3 of 11 cells were mainly spindle-shaped, with a component of epithelioid cells featuring clear to eosinophilic granular cytoplasm, and centrally located rounded uniform nuclei with inconspicuous nucleoli (Figure 2b,c). They were centered around the blood vessels. Necrosis, significant mitosis, vascular invasion, and atypia were absent. The tumor reached the medial margin of the resection.  The patient was followed up at our outpatient clinic for seven years, and there was no evidence of tumor recurrence despite the positive medial margin of resection. However, the patient was admitted several times to our hospital because of exacerbations of chronic inflammatory bowel disease. She was evaluated retrospectively for tuberous sclerosis complex (TSC), but did not show signs of this complex either clinically or radiologically. The patient was followed up at our outpatient clinic for seven years, and there was no evidence of tumor recurrence despite the positive medial margin of resection. However, the patient was admitted several times to our hospital because of exacerbations of chronic inflammatory bowel disease. She was evaluated retrospectively for tuberous sclerosis complex (TSC), but did not show signs of this complex either clinically or radiologically.

Discussion
In the classification of tumors of the soft tissue and bone, the World Health Organization (WHO) has defined PEComas as mesenchymal tumors composed of distinctive cells that show a focal association with blood vessel walls, and usually express melanocytic and smooth muscle markers. The PEComa family includes AML, CCST, lymphangioleiomyomatosis (LAM), and a group of histologically and immunophenotypically similar tumors arising at a variety of soft tissue and visceral sites. PEComas other than AML and LAM are rare, with approximately 200 cases reported as of 2013. PEComas are more frequent in females, with a male to female ratio of 1:6 [39]. A subset of PEComas show aggressive behavior. In a study of 26 cases of gynecologic and soft tissue PEComas and a review of 61 additional cases from the literature, Folpe et al. proposed a three-tier classi-

Discussion
In the classification of tumors of the soft tissue and bone, the World Health Organization (WHO) has defined PEComas as mesenchymal tumors composed of distinctive cells that show a focal association with blood vessel walls, and usually express melanocytic and smooth muscle markers. The PEComa family includes AML, CCST, lymphangioleiomyomatosis (LAM), and a group of histologically and immunophenotypically similar tumors arising at a variety of soft tissue and visceral sites. PEComas other than AML and LAM are rare, with approximately 200 cases reported as of 2013. PEComas are more frequent in females, with a male to female ratio of 1:6 [39]. A subset of PEComas show aggressive behavior. In a study of 26 cases of gynecologic and soft tissue PEComas and a review of 61 additional cases from the literature, Folpe et al. proposed a three-tier classification; namely, benign, of uncertain malignant potential, and malignant. They postulated the following "worrisome" features to differentiate between these categories: size > 5 cm, infiltrative margins, high nuclear grade, cellularity, mitotic rate > 1/50 HPF, necrosis, and vascular invasion. The presence of two or more of these features classifies the tumor as malignant [10]. The tumor in our patient did not exhibit any criteria suggestive of malignancy or malignant potential.
Fine needle aspiration cytology and biopsy (FNAC and FNAB) were performed using endoscopic ultrasound (EUS) guidance in 19 patients (65.5%). In four patients, no surgical resection was performed [33][34][35], including one malignancy that was treated using sirolimus, an mTOR inhibitor [35]. The role of EUS-guided FNAC has been emphasized in several studies [14,22,24,31,34,36]. Sangiorgio et al. reported a series of three hepatic and two pancreatic PEComas diagnosed preoperatively using US-guided FNA. All patients were females (aged 28-70 years), had no history of tuberous sclerosis complex (TSC), and presented with a single, localized, painless mass. Rapid on-site evaluation (ROSE) of cytological samples was performed in all cases to evaluate for cellular content and adequacy of specimens. Direct smear and cell block preparations revealed sheets and nests of epithelioid cells with eosinophilic or vacuolated cytoplasm. Immunohistochemical staining showed these neoplastic cells co-expressing both melanocytic and smooth muscle markers. The study indicated that a correct diagnosis could be achieved with the help of immunohistochemistry and good quality cytological samples obtained via FNA. This is particularly important for planning an adequate surgical strategy and avoiding overtreatment [34].
In 24 patients, surgical procedures were performed to excise the tumors. Depending on the location of the tumor, a variety of surgical procedures were performed; for example, distal pancreatectomy (DP) was performed in eight patients, including splenic-preserving distal pancreatectomy (SPDP; n = 1), middle pancreatectomy (MP; n = 1), pancreaticoduodenectomy (PD; n = 6), and pylorus-preserving pancreaticoduodenectomy (PPPD; n = 5). In five patients, the exact surgical procedure was not specified (Table 1).
Follow-up data were available for 23 patients for durations ranging from 3 to 144 months, with an average of 27.3 months. Of the four cases of malignant PEComa, two had developed liver metastases at 39 months [19] and 6 months [23] follow-up. The third patient had no metastasis 13 months after receiving chemotherapy [32]. The fourth patient had a marked reduction in the size of the tumor 42 months after treatment with sirolimus [34].
Of the members of the PEComa family of tumors, renal AML is highly associated with tuberous TSC, a group of autosomal dominant genetic disorders caused by germ-line mutations in TSC1 or TSC2, located on chromosomes 9q and 16p, respectively, which encode the proteins hamartin and tuberin, respectively. In addition to AML, patients with TSC frequently develop symptomatic lesions in the central nervous system, including cerebral cortical tubers, as well as distinctive skin lesions, cardiac rhabdomyomas, and LAM, another member of the PEComa family [40]. However, of the 28 cases of pancreatic PEComas, only one had stigmata of TSC. In this unique case, the patient was clinically diagnosed with TSC at 6 months of age when she developed infantile spasms. Brain MRI showed multiple cortical tubers and subependymal nodules. At 8 years of age, she underwent resection of a subependymal giant cell astrocytoma. Facial angiofibroma, hypopigmented macules, and an ungual fibroma were also identified, providing further evidence of TSC. Bilateral renal AML necessitated radiographic surveillance studies. In 2006, a CT scan with contrast identified an 8-mm cyst in the body of the pancreas; it enlarged to 5.8 cm by 2013. Distal pancreatectomy was performed, and pathological examination showed a 6.5 × 4.5 × 4.5 cm oligolocular cyst in the tail of the pancreas that was histologically diagnosed as a mucinous cystic neoplasm (MCN) with low-grade dysplasia. Three wellcircumscribed lesions, measuring 0.6, 0.2, and 0.12 cm, were also identified, and confirmed to be PEComas. Additionally, four well-circumscribed lesions, measuring 0.9, 0.25, 0.1, and 0.05 cm, were identified and confirmed to be neuroendocrine tumors (NET). Such a unique association of pancreatic epithelial MCN, multiple PEComas, and multiple NETs has not been previously reported [29].
In a review of the histology and genetics of PEComas, Thway and Fisher emphasized the mesenchymal nature of these tumors, which are composed of distinctive epithelioid or spindle cells that are immunoreactive for both melanocytic and smooth muscle markers. They stated that PEComas have a spectrum of behavior and outcome ranging from benign to malignant, and histological criteria have been proposed to assess malignant potential. Their differential diagnoses include carcinomas, smooth muscle tumors, clear cell neoplasms, and fatty neoplasms. They constitute a genetically diverse group that includes neoplasms harboring TEF3 gene rearrangements and those with TSC2 mutations, indicating alternative tumorigenic pathways. This can influence future management protocols [41].
Our patient had long-standing ulcerative colitis (UC). It is well known that UC can be associated with the development of colorectal dysplasia and adenocarcinoma [42] with prevalence rates of 4% and 7%, respectively [43]. UC is also associated with primary sclerosing cholangitis, which can predispose a patient to dysplasia that can progress to hepatobiliary carcinoma [44]. Additionally, iatrogenic Kaposi sarcoma and lymphoma can occur in patients with UC following treatment with immunosuppressive drugs [45,46].
Over 60 published inflammatory bowel disease (IBD) susceptibility loci have been discovered and replicated, of which approximately a third are associated with both ulcerative colitis and Crohn's disease (CD), although 21 are specific to UC and 23 to CD. Notably, genes implicated in mucosal barrier function (ECM1, CDH1, HNF4a, and laminin B1) confer risk of UC; furthermore, E-cadherin is the first genetic correlation between colorectal cancer and UC [47]. These genes have not been observed in PEComas.
We searched the literature for cases of UC associated with tumors of the PEComa family. We found four tumors, and our case was the fifth. These cases are presented in Table 2. They included two liver tumors, one kidney tumor, and one tumor in the cecum, in addition to the pancreatic tumor reported herein [34,[48][49][50]. All five tumors, except the present case, were labelled as AML. We speculate that the association of UC and PEComas could be a coincidental fortuitous occurrence, without any shared genetic susceptibility or underlying etiology.

Conclusions
In conclusion, we have reported a rare case of pancreatic PEComa of the pancreas in a young female with a history of ulcerative colitis. The tumor was resected, and the patient was followed up for seven years with no evidence of recurrence.