Malignant Perivascular Epithelioid Cell Tumor of the Gallbladder A Case Report and Review of Literature Liena Zhao, MD, PhD; Karl H. Anders, MD

 Perivascular epithelioid cell tumors are rare mesenchymal neoplasms composed of histologically and immunohistochemically distinctive perivascular epithelioid cells. The perivascular epithelioid cell tumor family includes angiomyolipoma, clear cell sugar tumor of the lung, lymphangioleiomyomatosis, clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres, and rare clear cell tumors of other anatomic sites. Perivascular epithelioid cell tumors have been reported previously in various sites, but to our knowledge not in the gallbladder. We report here, for the first time, a malignant perivascular epithelioid cell tumor arising in the gallbladder. (Arch Pathol Lab Med. 2014;138:1238–1241; doi: 10.5858/arpa.2013-0092-CR)

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he World Health Organization defines perivascular epithelioid cell tumors (PEComas) as mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells.1 The PEComa family includes angiomyolipoma, clear cell sugar tumor of the lung, lymphangioleiomyomatosis, clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres, and rare clear cell tumors of other anatomic sites.2 Immunohistochemically, the perivascular epithelioid cells show positivity for melanocytic markers, such as HMB-45 and Melan-A, as well as smooth muscle markers, such as actin and myosin.1 Here, we report the first case of a malignant PEComa arising in the gallbladder. REPORT OF A CASE The patient was a 46-year-old woman who was diagnosed with high-grade invasive ductal carcinoma of the left breast showing left sentinel node metastasis in 2010. Both estrogen and progesterone receptor status were negative by immunohistochemistry. She received 4 cycles of preoperative chemotherapy, followed by left

Accepted for publication August 12, 2013. From the Department of Pathology and Laboratory Medicine, Foothills Medical Centre, University of Calgary, Calgary, Alberta, Canada. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Liena Zhao, MD, PhD, Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Room C1140, Foothills Medical Centre, 1403 29 St NW, Calgary, Alberta, Canada T2N 2T9 (e-mail: [email protected]). 1238 Arch Pathol Lab Med—Vol 138, September 2014

mastectomy and left axillary lymph node dissection. She then received adjuvant chemotherapy, as well as regional radiotherapy. In September 2012, the patient presented with right upper quadrant pain. An ultrasound of the abdomen suggested a primary gallbladder wall malignancy with regional nodal metastasis and possible hepatic invasion. A computed tomography scan of the abdomen and pelvis revealed a gallbladder mass extending into the pericholecystic fat and inseparable from the liver, with an enlarged portacaval lymph node measuring up to 3.3 cm with mild compression of the inferior vena cava (Figure 1, A). A computed tomography scan of the chest showed no evidence of distant metastatic disease. She subsequently underwent an open cholecystectomy in October 2012.

Macroscopic Examination The cholecystectomy specimen weighed 62.2 g and consisted of a previously opened gallbladder resected en bloc with its underlying 6.5 3 4.0 3 2.5-cm liver bed. The fixed gallbladder measured up to 11.0 cm. There was a large tumor mass within the lumen of the gallbladder that measured 5.5 3 4.5 3 3.3 cm (Figure 1, B). The tumor was arising in the fundic portion of the gallbladder and grossly did not extend closer than 4.0 cm from the cystic duct resection margin. The tumor invaded the wall of the gallbladder. Aside from this large tumor the gallbladder mucosa was otherwise normal. No calculi were identified.

Microscopic Examination The tumor infiltrated through the full thickness of the gallbladder wall. It abutted the serosa, but the tumor cells were separated from the serosal surface by a thin strand of connective tissue. The neoplastic cells were epithelioid and characterized by clear to granular, lightly eosinophilic cytoplasm and small, centrally located, normochromatic, round to oval nuclei (Figure 2, A and B). The nuclei showed slight variation, and most demonstrated small nucleoli. The cells had fairly distinct cell borders and were arranged as nests and sheets. Scattered mitotic figures were noted. There was no evidence of necrosis or hemorrhage. Clearly defined lymphovascular space invasion was present. Aside from the fundic tumor, the remaining gallbladder mucosa, including cystic duct sections, was benign. There were small nodules of tumor in the liver with similar morphology, underlying the gallbladder, which did not involve the resected margin of the liver. Contiguous spread between the liver tumor and the gallbladder tumor was not seen, so these might have been seeded by lymphovascular spread. The liver was otherwise normal. Sections of the portal lymph nodes showed metastasis from the gallbladder primary tumor. A panel of immunohistochemical and histochemical stains revealed positive immunoreactivity for HMB-45 (Figure 2, C), Bcl2 (Figure 2, D) and CD68, as well as weak positivity for CD117, vimentin, and CD31. The tumor cells were negative for pancytokeratin, cytokeratin 7, PEComa of the Gallbladder—Zhao & Anders

Figure 1. A, A computed tomography scan of the abdomen and pelvis reveals a gallbladder mass (arrow) as well as an enlarged portacaval lymph node (arrowhead). B, Grossly, a large tumor mass is present within the lumen of the gallbladder. Figure 2. The gallbladder shows a tumor involving the mucosa (A). The neoplastic cells are epithelioid and characterized by clear to granular, lightly eosinophilic cytoplasm, and small, centrally located, round to oval nuclei. The nuclei show slight variation and most demonstrate small nucleoli (B). Tumor cells demonstrate strong and diffuse cytoplasmic positivity for HMB45 (C) and Bcl-2 (D) (hematoxylin-eosin, original magnifications 3100 [A] and 3400 [B]; original magnifications 3100 [C and D]).

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cytokeratin 20, mammaglobin, MOC31, PAX-8, estrogen receptor, TTF1, polyclonal carcinoembryonic antigen, CDX2, BerEP4, Hep Par 1, calretinin, synaptophysin, CD56, CD10, S100, Melan-A, desmin, actin, CD34, factor 8, and inhibin. Ki-67 showed a nuclear staining rate of about 15%. Prussian blue demonstrated focal iron within the tumor. Periodic acid–Schiff stain without diastase revealed glycogen within many of the cells that was removed by diastase digestion. The morphologic features and the immunohistochemistry profile were those of a PEComa. Expert consultation at the Cleveland Clinic (Cleveland, Ohio) concurred with the diagnosis of malignant PEComa.

COMMENT Perivascular epithelioid cell tumor of the gallbladder is an unusual epithelioid neoplasm. On a morphologic basis, the differential diagnosis would include hepatocellular carcinoma, renal cell carcinoma, granular cell tumor, adrenal cortical carcinoma, and malignant melanoma. However, the immunophenotypic profile (see above) was highly compatible with a diagnosis of a PEComa. The tumor behaved in a malignant fashion, with lymphovascular space invasion, portal nodal metastasis, and foci of metastatic tumor within the hepatic parenchyma. The patient’s prior breast carcinoma was reviewed and compared with the current neoplasm. The breast tumor was of classic ductal type and was very different in appearance from the current gallbladder primary neoplasm. Zamboni et al3 in 1996 first described the name PEComa for neoplasms composed of proliferation of perivascular epithelioid cells. The origin of the perivascular epithelioid cells is unknown. It has been hypothesized that these cells are derived from the neural crest cells, smooth muscle cells, or pericytes.2 Perivascular epithelioid cell tumors have been previously reported in a variety of sites including the heart,4 kidney,5 urinary bladder,6 prostate, esophagus,7 intestines,8 pancreas,3 liver, uterus,9 ovary, vulva, lung, palate, bone,10 falciform ligament, retroperitoneal soft tissue, thigh, groin, and skin.1,2,11 Perivascular epithelioid cell tumors typically display nested architecture and are composed of epithelioid cells with a radial arrangement around the vascular lumen and a clear to granular, lightly eosinophilic cytoplasm.1 The tumor cells typically have small, centrally located, normochromatic, round to oval nuclei with small nucleoli. Perivascular epithelioid cell tumors may also show fascicular arrangement of spindle cells with delicate, arborizing capillaries.1 A study of PEComas of soft tissue and gynecologic origin performed by Folpe et al12 proposed a classification of PEComas based on worrisome features including size greater than 5 cm, infiltrative border, high nuclear grade and cellularity, mitotic rate more than or equivalent to 1 per 50 high-power fields, necrosis, and vascular invasion. Benign PEComas show no worrisome features, whereas malignant PEComas have 2 or more worrisome features. Perivascular epithelioid cell tumors with uncertain malignant potential show either nuclear pleomorphism/multinucleated giant cells or a size greater than 5 cm. Recurrence and/or metastasis was strongly associated with median tumor size greater than 8 cm, mitotic activity greater than 1 per 50 high-power fields, and necrosis.12 Obviously a tumor with metastasis, such as our case, is malignant. The most sensitive immunohistochemistry marker for PEComas is HMB45 (92%), followed by Melan-A (72%) and MiTF (50%).12 Perivascular epithelioid cell tumors have also been shown to be immunoreactive to smooth muscle actin 1240 Arch Pathol Lab Med—Vol 138, September 2014

(80%), desmin (36%), S100 (33%), vimentin (86%), pancytokeratin (13%), TFE3 (29%), and CD117 (5%).12 In addition, it has been reported that Bcl-2 is positive in epithelioid variants of renal angiomyolipoma,13 and in a case of malignant PEComa of the uterus with late renal and pulmonary metastases.14 Our case also showed positivity for Bcl-2. Bcl-2 is not an established marker for PEComas, and the significance of immunoreactivity to Bcl-2 in this group of tumors is unknown. Tuberous sclerosis complex is an autosomal dominant disorder caused by mutations in TSC1 or TSC2 genes encoding hamartin and tuberin, respectively.15 These proteins act as tumor growth suppressors that regulate cell proliferation and differentiation. Tuberous sclerosis complex is characterized by the development of multiple hamartomas and benign or rarely malignant neoplasms, especially in the brain, skin, retina, kidney, heart, and lungs. Tuberous sclerosis complex is associated with some tumors in the PEComa family, including cardiac rhabdomyomas,16,17 renal angiomyolipomas,18,19 and lymphangioleiomyomatosis.20,21 Our patient had no documented history of tuberous sclerosis complex or manifestations suggestive of tuberous sclerosis complex. Management of PEComas has been a challenge. Surgery is the major treatment option.22 Chemotherapy and radiation therapy have been administered in patients with locally advanced or metastatic PEComas, although the data are limited. Neoadjuvant and adjuvant chemotherapy have been described. Significant clinical response with an oral mTOR inhibitor, everolimus, has been demonstrated in a patient with metastatic retroperitoneal angiomyolipoma.23 Adjuvant interferon a immunotherapy has been given to a pediatric patient with PEComa of the ascending colon following surgery, with a good clinical outcome.8 Many thanks to Travis Ogilvie, MD, at the Foothills Medical Centre (Calgary, Alberta, Canada) for intradepartmental consultation, and John Goldblum, MD, at the Cleveland Clinic (Cleveland, Ohio) for external consultation. References 1. Folpe AL. Neoplasms with perivascular epithelioid cell differentiation (PEComas). In: Fletcher CDM, Unni KK, Epstein J, Mertens F, eds. Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France: IARC Press; 2002: 221–222. World Health Organization Classification of Tumours. 2. Martignoni G, Pea M, Reghellin D, Zamboni G, Bonetti F. PEComas: the past, the present and the future. Virchows Arch. 2008;452(2):119–132. 3. Zamboni G, Pea M, Martignoni G, et al. Clear cell ‘‘sugar’’ tumor of the pancreas: a novel member of the family of lesions characterized by the presence of perivascular epithelioid cells. Am J Surg Pathol. 1996;20(6):722–730. 4. Niu H, Wang FW, Zhang PJ, Bing Z. Cardiac epithelioid PEComa: report of two cases and review of the literature. Case Rep Med. 2012;2012:521678. 5. Fukunaga M, Harada T. Pigmented perivascular epithelioid cell tumor of the kidney. Arch Pathol Lab Med. 2009;133(12):1981–1984. 6. Yin L, Bu H, Chen M, et al. Perivascular epithelioid cell neoplasm of the urinary bladder in an adolescent: a case report and review of the literature. Diagn Pathol. 2012;7(1):183. 7. Fassan M, Cassaro M, Vecchiato M, et al. Malignant perivascular epithelioid cell tumor of the esophagus. Case Rep Pathol. 2012;2012:438505. 8. Park SJ, Han DK, Baek HJ, et al. Perivascular epithelioid cell tumor (PEComa) of the ascending colon: the implication of IFN-alpha2b treatment. Korean J Pediatr. 2010;53(11):975–978. 9. Bleeker JS, Quevedo JF, Folpe AL. Malignant perivascular epithelioid cell tumor of the uterus. Rare Tumors. 2012;4(1):e14. 10. Kazzaz D, Khalifa M, Alorjan M, Shaw M, Rezajooi K, Saifuddin A. Malignant PEComa of the lumbar vertebra: a rare bone tumour. Skeletal Radiol. 2012;41(11):1465–1468. 11. Armah HB, Parwani AV. Perivascular epithelioid cell tumor. Arch Pathol Lab Med. 2009;133(4):648–654. 12. Folpe AL, Mentzel T, Lehr HA, Fisher C, Balzer BL, Weiss SW. Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin: a clinicopathologic study of 26 cases and review of the literature. Am J Surg Pathol. 2005; 29(12):1558–1575.

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13. Cho NH, Shim HS, Choi YD, Kim DS. Estrogen receptor is significantly associated with the epithelioid variants of renal angiomyolipoma: a clinicopathological and immunohistochemical study of 67 cases. Pathol Int. 2004;54(7): 510–515. 14. Armah HB, Parwani AV. Malignant perivascular epithelioid cell tumor (PEComa) of the uterus with late renal and pulmonary metastases: a case report with review of the literature. Diagn Pathol. 2007;2:45. 15. Tomasoni R, Mondino A. The tuberous sclerosis complex: balancing proliferation and survival. Biochem Soc Trans. 2011;39(2):466–471. 16. Benyounes N, Fohlen M, Devys JM, Delalande O, Moures JM, Cohen A. Cardiac rhabdomyomas in tuberous sclerosis patients: a case report and review of the literature. Arch Cardiovasc Dis. 2012;105(8–9):442–445. 17. Madueme P, Hinton R. Tuberous sclerosis and cardiac rhabdomyomas: a case report and review of the literature. Congenit Heart Dis. 2011;6(2):183–187.

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18. Budde K, Gaedeke J. Tuberous sclerosis complex-associated angiomyolipomas: focus on mTOR inhibition. Am J Kidney Dis. 2012;59(2):276–283. 19. Dixon BP, Hulbert JC, Bissler JJ. Tuberous sclerosis complex renal disease. Nephron Exp Nephrol. 2011;118(1):e15–e20. 20. Henske E. Tuberous sclerosis complex and lymphangioleiomyomatosis: miles to go, promises to keep. Ann Intern Med. 2011;154(12):840–841. 21. Muzykewicz DA, Sharma A, Muse V, Numis AL, Rajagopal J, Thiele EA. TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex. J Med Genet. 2009;46(7):465–468. 22. Bleeker JS, Quevedo JF, Folpe AL. ‘‘Malignant’’ perivascular epithelioid cell neoplasm: risk stratification and treatment strategies. Sarcoma. 2012;2012: 541626. 23. Gennatas C, Michalaki V, Kairi PV, Kondi-Paphiti A, Voros D. Successful treatment with the mTOR inhibitor everolimus in a patient with perivascular epithelioid cell tumor. World J Surg Oncol. 2012;10:181.

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Malignant perivascular epithelioid cell tumor of the gallbladder: a case report and review of literature.

Perivascular epithelioid cell tumors are rare mesenchymal neoplasms composed of histologically and immunohistochemically distinctive perivascular epit...
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