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Journal of Cancer Research and Practice 3 (2016) 14e18

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Case report

Perivascular epithelioid cell tumor of the gastrointestinal tract

Tsung-Hao Liu a, Cher-Wei Liang b, d, Li-Chun Lu a, c, *

a Department of Oncology, National Taiwan University Hospital, Taiwanb Department of Pathology, National Taiwan University Hospital, Taiwanc Graduate Institute of Oncology, National Taiwan University College of Medicine, Taiwand Graduate Institute of Pathology, National Taiwan University College of Medicine, Taiwan

a r t i c l e i n f o

Article history:Received 5 June 2015Accepted 6 August 2015Available online 17 November 2015

Keywords:Perivascular epithelioid cell tumorPEComaGastrointestinalSarcomamTOR

* Corresponding author. Department of OncologyHospital, No. 7, Chung-Shan South Road, Taipei 10002

E-mail address: lichun@ntuh.gov.tw (L.-C. Lu).Peer review under responsibility of The Chinese O

http://dx.doi.org/10.1016/j.jcrpr.2015.10.0012311-3006/Copyright © 2015, The Chinese Oncology Screativecommons.org/licenses/by-nc-nd/4.0/).

a b s t r a c t

Perivascular epithelioid cell tumor (PEComa) is a rare subtype of soft tissue sarcoma that coexpressesmelanocytic and smooth muscle markers. We report a case of malignant PEComa arising from thegastrointestinal tract. Definitive diagnosis of malignant PEComa is based on pathological examinationand the standard treatment is complete surgical resection. Cytotoxic chemotherapy has limited efficacyin recurrent or metastatic malignant PEComa. Overactivation of the mammalian target of rapamycin(mTOR) pathway is observed in PEComa, and mTOR inhibitors have been recommended as an effectivesystemic treatment.Copyright © 2015, The Chinese Oncology Society. Production and hosting by Elsevier B.V. This is an open

access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

Perivascular epithelioid cell tumor (PEComa), a rare subtype ofmesenchymal neoplasm, is composed of perivascular epithelioidcells that coexpress myogenic and melanocytic markers onimmunohistochemical staining.1 Bonetti et al. initially describedthese distinctive cells in 1992.2 Currently, the family of PEComasincludes angiomyolipoma (AML), pulmonary lymphangioleiomyo-matosis (LAM), clear cell sugar tumor of the lung, extrapulmonaryclear cell sugar tumor, and clear cell myomelanocytic tumor.3

Although rare, PEComas have been reported in a variety ofanatomical locations and are considered to be ubiquitous.4 Theclinical behavior of PEComas is highly heterogeneous. Most arebenign and are cured by surgical resection,5 but aminority recurs ormetastasizes. Thus, various definitions of the malignant potential ofthese tumors have been proposed.1,3,6 PEComa patients have beentreated with conventional chemotherapy used in other types ofsarcoma. However, recognition of aberrantly activated mammaliantarget of rapamycin (mTOR) pathway in malignant PEComa led tothe use of mTOR inhibitors, such as sirolimus, for systemic therapy,and promising anti-tumor effects have been demonstrated.5 Here,

, National Taiwan University, Taiwan.

ncology Society.

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we report a rare case of PEComa arising from the gastrointestinaltract and review the literature regarding this rare subtype of softtissue sarcoma.

2. Case report

A 60-year-old woman was in her usual state of health until late2013 when she started to experience acid regurgitation and post-prandial fullness. Esophagogastroduodenoscopy showed onlymild reflux esophagitis. Her symptoms failed to respond to symp-tomatic treatments, including metoclopramide, antacids, and pro-ton pump inhibitors, and progressed to easy vomiting over twomonths and experienced unintentional weight loss of 4 kg in 1week. There was no tarry stool or change in stool caliber. She wasexamined at a local hospital, and initial examination with abdom-inal ultrasonography revealed a large intra-abdominal tumor.Computed tomography (CT) of the abdomen showed a12 � 12 � 9 cm irregular mass in the left abdomen, with hetero-geneous enhancement and mass effect on the adjacent structures.No ascites or enlarged lymph nodes were seen on the CT image(Fig. 1A). The results of all her laboratory tests were within thenormal range. A diagnosis of gastrointestinal stromal tumor (GIST),leiomyosarcoma, or adenosarcoma was suspected. Surgical resec-tion was suggested, and she was then referred to our hospital forfurther management.

The patient was admitted to our gastrointestinal ward inNovember 2013, and a follow-up abdominal ultrasonography

Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://

Fig. 1. (A) CT showed a large tumor, measuring up to 12 cm, in the left abdomen (B) Abdominal echo showed a heterogeneous and hypoechoic lesion with hypervascularity arisingfrom the small bowel wall.

T.-H. Liu et al. / Journal of Cancer Research and Practice 3 (2016) 14e18 15

showed a large heterogeneous and hypoechoic lesion with hyper-vascularity arising from the small bowel wall over the left upperquadrant area (Fig. 1B). A tumor marker panel showed levels withinnormal limits, as follows: carcinoembryonic antigen (CEA), 1.25 ng/mL (normal range <5 ng/mL); CA 19-9, 6.34 U/mL (normalrange < 37 U/mL); CA 15-3, 6.8 U/mL (normal range 0e31 U/mL);and CA-125, 7.1 U/mL (normal range 0e35 U/mL). A small bowelGIST or leiomyosarcoma was suspected, and a general surgeon wasconsulted for further resection.

Fig. 2. (A) Epithelioid tumor cell radiating from staghorn-like vessels (100�). (B) Admixtuatypia (400�). (D) Spindle cells with mitoses (400�). (E) Tumor cells staining positive for s

The patient underwent surgery on December 2, 2013. A13 � 13 cm elastic lobulated yellowish tumor, arising from theupper jejunum with suspected local invasion into the transversecolon and mesentery, was detected intraoperatively. Thus, smallbowel segmental resection and left hemicolectomy were per-formed as radical treatment. Under gross examination by ourpathologist, the tumor was observed to arise from the jejunalmuscle layer with a focally jagged and infiltrative tumor border andthat it extended to the subserosa, serosa, and nearby mesocolon.

re of spindle cells and epithelioid cells (200�). (C) Epithelioid cells with mild nuclearmooth muscle actin (100�). (F) Tumor cells staining positive for Melan-A (100�).

Table 1Immunohistochemical results of two large series of PEComa.

PEComa of soft tissue/gynecologicalorigin (Folpe et al.1)

PEComa of GI tractorigin (Doyle et al.3)

Smooth MuscleActin

80% (20/25) 57% (20/35)

Desmin 36% (8/22) 74% (26/35)Caldesmon N/A 50% (4/8)HMB45 92% (22/24) 66% (23/35)Melan-A 72% (13/18) 68% (23/24)MiTF 50% (9/18) 60% (15/25)TFE3 29% (5/17) 15% (3/20)S-100 33% (8/24) 18% (5/27)CK N/A 6% (1/15)Vimetin 86% (12/14) N/AKIT (CD117) 5% (1/20) 8% (2/25)CD34 0% (0/7) N/A

N/A: not available.

Table 2Risk stratifications in PEComa.

Factors associated with recurrence or metastasesa

Folpeet al.1

Tumor size >5 cm, mitosis >1/50 HPF, necrosis, infiltrative growthpattern, high nuclear grade and cellularity, vascular invasion

Doyleet al.3

Mitosis >2/10 HPF, marked atypia, diffuse pleomorphism

Bleekeret al.6

Tumor size >5 cmb, mitosis >1/50 HPFb, age, necrosis, high grade,vascular invasion

a Statistically significant by Fisher's exact test or univariate analysis.b Significant by multivariate analysis.

T.-H. Liu et al. / Journal of Cancer Research and Practice 3 (2016) 14e1816

The muscle layer of the colon and the jejunal mucosa were bothuninvolved. The tumor was yellowish, elastic, and firm with areasof necrosis. Microscopically, spindle cells arranged in interwovenfascicles with occasional epithelioid cells were seen radiating fromstaghorn-like vessels. The spindle cells contained elongated nucleiand eosinophilic fibrillary or granular cytoplasm. The epithelioidcells contained a clear cytoplasmwith hyalinized stroma (Fig. 2A, B,C). Mild to moderate nuclear pleomorphism and 6mitoses/10 high-power field (HPF) were seen (Fig. 2D). The surgical margins werefree of tumor involvement. Immunohistochemical studies showedthat the tumor cells were diffusely positive for smoothmuscle actin(SMA) and h-caldesmon, focally positive for desmin and melan-A,occasionally positive for MiTF, and negative for HMB-45, cytoker-atin, CD117, DOG-1, S-100, CD34, CDK4, and MDM-2 (Fig. 2E, F).Taken together, the tumor cells were positive for both myogenicand melanocytic markers. A diagnosis of PEComa with spindle cellpredominance was confirmed. Considering the highmitotic rate (6/10 HPF) but limited cellular atypia and pleomorphism, the PEComawas identified as a low-grade malignant tumor. Adjuvant chemo-therapy or radiotherapy was not suggested owing to the lack ofevidence for clinical benefits.

The patient was then regularly followed-up at our outpatientclinic. However, abdominal CT in May 2014 revealed a right pelvicmass measuring 3.46 cm. No other tumors were noted after therestaging work-up. She underwent right pelvic tumor excision onJune 16, 2014. Further pathological examination confirmed thediagnosis of a recurrent PEComa. The mitosis count was 23/10 HPFwith moderate to marked pleomorphism. Systemic treatment wasnot performed owing to the absence of residual tumors. Unfortu-nately, a new left lower abdominal mass near the psoas muscle wasnoted during subsequent follow-up. The tumor size was observedto increase on serial CT images, and it resulted in left hydro-nephrosis. A double J catheter was inserted accordingly. Because ofits unresectable status, systemic therapy with sirolimus (2 mg,daily) for the recurrent PEComawas initiated in April 2015, with noobvious adverse effects. Follow-up abdominal MRI on May 27showed enlargement of the left lower retroperitoneal mass (from7.2 cm to 9.8 cm), suggesting primary resistance to mTOR in-hibitors. Thus, sirolimus was discontinued, and palliative resectionwith local radiotherapy will be scheduled in the near future.

3. Discussion

PEComa is a rare subtype of mesenchymal tumor with charac-teristic expression of both myogenic and melanocytic markers. Itharbors a wide range of morphologic appearances with the mostcommon finding of clear to lightly eosinophilic cells arranged innested, fascicular, or sheet-like patterns. The tumor cells are pre-dominantly epithelioid, predominantly spindle-like, or an admix-ture of both types and are surrounded by a delicate arborizingcapillary network.1 These unique tumor cells were thus named“perivascular epithelioid cells” (PECs). The PEComa family of tu-mors includes AML, LAM, and PEComa. AML is commonly seen asan asymptomatic renal lesion with fat, muscle, and blood vessels.Pulmonary LAM presents predominantly in young premenopausalwomen with progressive multiple nodular and interstitial pulmo-nary lesions, which may lead to respiratory failure. PEComa is anepithelioid neoplasm typically arising in the gynecological tract,retroperitoneum, GI tract, and soft tissue with variable clinicalbehaviors.5,7

Definitive diagnosis of PEComa is mainly based on pathologicalexamination showing positivity for myogenic markersdincludingSMA, desmin, and caldesmondand melanocytic markersdinclud-ing HMB-45, melan-A, and MiTFdin the characteristic tumor cells(Table 1). Generally, PEComas are diagnosed in middle-aged and

predominantly female patients. In one large pooled analysis of 234cases of PEComa by Bleeker et al., the median age of PEComa pa-tients was 43 years, and 79% of patients were women. The mostcommonly reported tumor site is the uterus, followed by the skinand the liver.6 Dolye et al. reported 35 cases of PEComa in the GItract, which is the largest reported series of GI PEComas. In contrastto previous reports, PEComas in the GI tract do not exhibit genderpredilections, and over 90% of tumors are composed of purely orpredominantly epithelioid cells. The most common site for GI tractPEComa is the colon followed by the small intestine.3

Most PEComas follow a relatively benign clinical course, but asubset demonstrates aggressive behavior of local recurrence ordistant metastasis. Risk factors associated with recurrence or me-tastases were proposed by several studies (Table 2). Folpe et al.developed the first and most widely accepted classification utiliz-ing the identified six unfavorable features (tumor size > 5 cm,mitosis >1/50 HPF, necrosis, infiltrative growth pattern, high nu-clear grade and cellularity, and vascular invasion). MalignantPEComas are defined as tumors with two or more unfavorablefeatures; benign PEComas, those with no unfavorable features; andPEComas of uncertain malignant potential, those not fulfilling theabove conditions. The largest PEComa series reported by Bleekeret al. showed that only primary tumor size �5 cm and high mitoticrate (>1/50 HPF) were associated with recurrence.6 The series ofPEComas of the GI tract reported by Doyle et al. demonstrated thatmarked atypia, diffuse polymorphism, andmitoses�2/10 HPFwereassociated with metastasis.3 According to the above criteria, ourcase should be classified as a malignant PEComa and it harbors arisk of recurrence or metastasis.

The management of PEComa follows the same treatment prin-ciples as other subtypes of soft tissue sarcoma. Surgical resectionremains the primary treatment modality. There is no consensus onthe administration of adjuvant treatment. Other treatment options,including chemotherapy and radiotherapy, have been utilized at

T.-H. Liu et al. / Journal of Cancer Research and Practice 3 (2016) 14e18 17

the discretion of physicians to minimize risk of recurrence. In orderto achieve complete surgical resection, neoadjuvant approacheswith chemotherapy or radiotherapy have also been performed.8

There is still no high-level evidence to support the clinical benefitof adjuvant or neoadjuvant therapy. Close surveillance plusrepeated resection remains one strategy. Long-term survival wasreported in a patient with recurrent PEComa receiving multipleresections.9

Patients with tuberous sclerosis complex orlymphangioleiomyomatosis-related AML were shown to harbormutations of tuberous sclerosis genes, including the harmatin gene(TSC1) and the tuberin gene (TSC2). The TSC1/TSC2 complex in-hibits the downstream Rheb-GTP, which can activate the mTORcomplex and lead to phosphorylation of S6 kinase, protein syn-thesis, and cell growth. Aberrations in TSC1 or TSC2 result in loss offunction of the complex and release of inhibition of Rheb-GTP,which then aberrantly overactivates the mTOR pathway.7,10 mTORinhibitors, such as sirolimus or temsirolimus, are thus hypothesizedto possess clinical activity in neoplasms with loss of TSC1 or TSC2expression. The pivotal study by Bissler et al. demonstrated theefficacy of sirolimus in reducing the size of AMLs and improvingpulmonary function in patients with pulmonary LAM.7 There is alsoevidence of mTOR pathway overactivation in PEComa,11,12 andsirolimus was shown to be effective against malignant PEComa.5

PEComa cells are usually immunohistochemically positive forphospho-S6 and phospho-p70S6K and negative for TSC2 andphopho-Akt.11 The level of phospho-S6 expressionwas proposed tobe a predictive marker of early tumor response to mTORinhibitors.13

In patients with malignant PEComa receiving sirolimus ortemsirolimus, the largest case series reported a response rate of upto 50% with a median treatment duration of 128 days. Treatmenttoxicity is generally mild and manageable, with oral mucositis asthe most commonly occurring adverse effect. The reported 1-yearsurvival rate was 78.8% with a median overall survival of 2.4years.14,15 Primary or secondary resistance to mTOR inhibitors wasreported, but the exact mechanism is largely unknown.16 Possibleresistance mechanisms, as seen in other tumors treated with mTORinhibitors, include mutations in mTOR, feedback loop activation ofthe PI3K/Akt pathway, increased activation of the alternative ERK/MAPK pathway, decreased expression of 4E-BP1, or overexpressionof downstream eIF4E.17

Conventional chemotherapy has little efficacy in malignantPEComa, despite reports of cases showing clinical response.18

Interestingly, expression of estrogen and progesterone receptorshas also been noted in PEComas with predominant spindlemorphology.16 Letrozole, an aromatase inhibitor, has been reportedto have a favorable and sustained effect in PEComa.19 In addition tosystemic treatments, aggressive local treatments, such as radio-therapy and surgical resection, may still play some roles in man-aging metastatic PEComa. Long-term disease control achieved byrepeated metastasectomy was also reported.9

TFE3 gene fusion has been demonstrated in several types ofneoplasia, including alveolar soft part sarcoma (ASPS) and pediatricrenal cell carcinoma.20 Recently, a subset of PEComa has also beenshown to harbor TFE3 gene rearrangement.21,22 This subset ofrearranged PEComa is distinctive from their non-rearrangedcounterpart in several aspects. They typically comprise pureepithelioid cells arranged in an alveolar pattern and stain stronglyfor TFE3 and HMB-45 while expressing minimal muscle markers.23

Their morphology bears a similarity to ASPS under light micro-scopy, and the differential diagnosis can be made on the basis thatASPS is negative for HMB-45 and Melan-A and harbors a uniqueASPSCR1-TFE3 translocation.23,24 TSC2 is not inactivated in thissubset of PEComa, which theoretically implies that treatment with

an mTOR inhibitor will not be effective.20,25 The presence of thissubset of rearranged PEComa may serve to partly explain the pri-mary resistance to mTOR inhibitors. However, the primary resis-tance seen in our case is unlikely to be explained by TFE3 generearrangement considering the tumor's positivity for musclemarkers and the predominant spindle pattern.

In summary, we report a rare case of PEComa arising from the GItract. The diagnosis of malignant PEComa is based on pathologicallyunique features. Localized PEComa should be completely resected.Overactivation of the mTOR pathway may be present in PEComa,and mTOR inhibitors are currently the recommended systemictreatment in unresectable or metastatic malignant PEComa.

Conflicts of interest

None declared.

Funding

This study was supported by grants from the Ministry of Scienceand Technology, Taiwan (MOST-103-2314-B-002-090).

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