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LETTER TO THE EDITOR
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Pediatric perivascular epithelioid cell tumor of the thigh: A great mimicker


1 Department of Pathology, St. John's Medical College Hospital, Bangalore, Karnataka, India
2 Department of Pediatric Surgery, St. John's Medical College Hospital, Bangalore, Karnataka, India
3 Department of Pediatric Surgery, All India Institute of Medical Sciences, Bhuvaneshwar, Odisha, India

Date of Submission14-May-2020
Date of Decision15-May-2020
Date of Acceptance19-Oct-2020
Date of Web Publication07-Aug-2021

Correspondence Address:
Gnanapriya Vellaisamy,
Department of Pathology, St. John's Medical College Hospital, Bangalore, Karnataka
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_507_20

PMID: 34380859




How to cite this URL:
Vellaisamy G, Ananthamurthy A, Mahadevappa K, Mohanty S, Das K. Pediatric perivascular epithelioid cell tumor of the thigh: A great mimicker. Indian J Cancer [Epub ahead of print] [cited 2021 Sep 28]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=323437




Perivascular epithelioid cell tumors (PEComas) are a family of tumors that includes angiomyolipoma (AML), clear-cell “sugar” tumor of the lung, lymphangioleiomyomatosis (LAM), clear cell myomelanocytic tumor of the falciform ligament, and rare clear cell tumors of other sites. They are composed of histologically, immunohistochemically, and ultrastructurally distinctive perivascular epithelioid cells. Bonetti et al. first proposed the origin of this family of tumors from perivascular epithelioid cells (PEC).[1] Histologically, these cells are epithelioid, or spindle-shaped with pale eosinophilic to clear cytoplasm and is intimately admixed with blood vessels. Usually, they co-express myomelanocytic markers. Among the melanocytic markers, human melanoma black 45 (HMB45) is more sensitive than Melan-A.[2] PECs can modulate their morphology and immunophenotype.[3] When the tumor is composed of epithelioid cells, it often expresses HMB45 more commonly than actin; when it is composed of predominantly spindle-shaped cells, then actin expression is more common. Ultrastructurally, these cells contain microfilament bundles with electron-dense condensation, numerous mitochondria, and membrane-bound granules.

There is no normal counterpart for perivascular epithelioid cells. Their origin is still debated, and they are hypothesized to develop from undifferentiated cells of neural crest, myoblasts with the molecular alteration that confers myomelanocytic markers expression or from pericytes.[3],[4] PEComas, though rare, have been reported in almost all sites of the human body.[3] The ubiquitous nature of these neoplasms and their diverse morphology leads to a diagnostic dilemma especially when they occur in soft tissue locations in children. Here, we report a case of PEComa of the thigh and discuss the diagnostic difficulties.

An eleven-year-old girl presented with a solitary, progressively increasing swelling in the right thigh noticed for 2 months. The 5 cm × 4 cm mass in the medial aspect of the mid-right thigh was non-tender, non-pulsatile, and firm. Systemic examination findings were non-contributory. On ultrasonography, it was a well-defined hypoechoic lesion measuring 3.9 cm × 2.6 cm × 2.9 cm with multiple small calcific foci. It occupied the adductor canal and had internal and peripheral vascularity. On CECT (contrast-enhanced computed tomography), the lesion was well defined and heterogeneously enhancing in the arterial phase with numerous feeding vessels from the femoral artery. The provisional diagnosis included a soft tissue tumor or a hemangioma. Intraoperatively, it was a cystic vascular mass with hemorrhage, located within the adductor canal. The femoral artery was adherent densely to the posterolateral surface while the femoral vein was splayed on the posteromedial surface. Multiple feeding vessels were noted from the femoral vein. Complete excision was done.

Grossly, it was a well-encapsulated grey white lesion measuring 3.5 cm × 3 cm × 1.5 cm. On the cut surface, dark brownish-black areas were identified [Figure 1]a. Histologically, it was a well-encapsulated neoplasm composed of epithelioid cells arranged as lobules, nests, and pseudoalveolar pattern intimately admixed with a delicate network of capillaries. These cells exhibited round nuclei, conspicuous nucleoli, and abundant pale eosinophilic to clear cytoplasm. A few multinucleated giant cells were also noted. At places, the neoplastic cells showed the presence of intracytoplasmic brownish-black pigment which was positive for Masson-Fontana stain [Figure 1]b and [Figure 1]c. Mitotic figures were absent. No invasion, necrosis, or atypia was noted. Immunohistochemically, these cells showed diffuse positivity for HMB45, focal positivity for vimentin and desmin, and negative for MyoD1, myogenin, epithelial membrane antigen (EMA), Melan-A, S-100, smooth muscle actin (SMA), synaptophysin and cytokeratin (CK) [Figure 2]. The Ki-67 was less than 5%. The patient is well with no evidence of relapse/recurrence on follow-up for a year.
Figure 1: (a) Cut surface shows a well-encapsulated grayish neoplasm with dark brown areas (b)Epithelioid cells arranged in the form of lobules, nests and pseudoalveolar pattern (Original magnification 20×) (c) Epithelioid cells with melanin pigment (Original magnification 40×) (Inset- Masson Fontana)

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Figure 2: Diffuse positivity for HMB 45 (Original magnification 10×), focal positivity for vimentin (Original magnification 20×) and desmin (Original magnification 10×) and negative Melan-A (Original magnification 20×)

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The World Health Organization defines PEComas as “mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells”.[4] It is a rare tumor of adulthood and is uncommon in children too. In adults, there is a striking female predominance. In prepubertal children, there is equal distribution, but the female preponderance becomes apparent only during adolescence suggesting a hormonal influence. The most common site of PEComas in children is the gastrointestinal tract.[5] Soft tissue involvement of thigh is exceedingly rare and the only handful of cases are reported in the English literature.[2],[6] In the literature, 9% of cases occurred as a second malignancy;[7] this case had no such history. PEComas are related to tuberous sclerosis complex (TSC), an autosomal dominant disease characterized by loss of TSC1 or TSC2 genes.[8] Only a minority of soft tissue PEComas are associated with TSC.[2] In this case, the patient did not have any clinical features suggestive of TSC.

Microscopically, these tumors can have epithelioid and/or spindle cell morphology which are intimately admixed with thin-walled vessels. Melanin pigment may or may not be seen.[9] In this case, the tumor was well encapsulated and composed of only epithelioid cells arranged as nests and alveolar pattern with focal melanin pigment. Given the rare soft tissue location and epithelioid morphology, it can pose significant diagnostic difficulties in children. The differential diagnoses are broad and include alveolar soft part sarcoma, clear cell sarcoma, alveolar rhabdomyosarcoma, paraganglioma, and metastatic carcinoma. Among these, clear cell sarcoma and paraganglioma may be pigmented whereas the rest are not.[10],[11]

Alveolar soft part sarcoma (ASPS) is a rare soft tissue tumor that is common in this age group and location. It is a poorly circumscribed non-pigmented tumor and is composed of epithelioid cells arranged in a pseudoalveolar pattern. These tumors can have focal desmin positivity similar to this case and show diffuse TFE3 positivity. A majority of PEComas can show aberrant positivity for TFE3 and a subset may also show TFE3 gene rearrangements or amplification, making it difficult to distinguish them from ASPS based on TFE3 positivity alone.[12],[13] The subset of PEComas with TFE3 translocation has a predilection for the young, with the absence of association with TS, predominantly pseudoalveolar pattern and epithelioid cytology, minimal myogenic marker reactivity, and diffuse expression for TFE3.[13] This case had similar features except that TFE3 immunohistochemical expression and TFE3 gene rearrangements were not done. The presence of melanin pigment, expression of melanocytic markers, and absence of t(X;17) translocation are other features that help to differentiate PEComas from its close mimicker, ASPS. It is important to differentiate ASPS from PEComas due to its high-recurrence rate and metastatic potential.[14]

Melanotic tumors like clear cell sarcoma can also have epithelioid or spindle morphology with immunoreactivity for melanocytic markers and S-100. Focal S-100 positivity has been reported in a third of cases of PEComas; however, they never show diffuse staining for S-100 immunostain. In all those cases, myogenic markers were also positive.[2] Hence, if a tumor is positive for S-100 and negative for myogenic markers, PEComa is unlikely.

Alveolar rhabdomyosarcoma may mimic PEComas due to its pseudoalveolar pattern but are composed of small round cells with or without rhabdomyoblastic differentiation.[11] This will be distinguished based on the expression of myogenic markers for desmin, myogenin, and MyoD1. PEComas are generally positive for SMA and may express focal desmin positivity but are negative for the rest of the muscle markers.

Solid nests of cells with vascular stroma in PEComa may mimic a paraganglioma but are distinguished based on the lack of expression for chromogranin, synaptophysin, and S-100.[11]

Metastatic carcinomas may also be rarely considered in the differential diagnosis especially in the older age group. PEComas are generally negative for cytokeratin but 13% of gynecological and soft tissue PEComas may express cytokeratin focally.[2] Melanogenic and myoid marker expression may also help to exclude the same.

The behavior of these rare tumors is difficult to predict. In 2005, Folpe et al. proposed a classification of PEComa into three groups based on size >5 cm, infiltration, high nuclear grade and cellularity, mitosis >1/50 high-power field, necrosis, and vascular invasion.[2] If the tumors do not have any of these features, they are considered benign whereas if they have two or more of these worrisome features, they are malignant. If the tumor size is >5 cm or if there are nuclear pleomorphism/multinucleated giant cells only, it is grouped under uncertain malignant potential. In the present case, there were no such worrisome features.

Surgery is the mainstay of treatment; chemotherapy and radiotherapy have not shown good outcomes. Loss of TSC1 or TSC2 genes leads to mTOR hyperactivation in TS and sporadic cases. Hence, mTOR inhibitors have been tried in many cases and have shown varied results.[15]


  Conclusion Top


PEComa is a great mimicker of other childhood malignancies, particularly in the soft tissue. The pathologist must note the microscopic features including melanin pigment which helps suspect the diagnosis which can be confirmed with appropriate immunostains. It is important to differentiate PEComas from alveolar soft part sarcoma which has a grave prognosis. Focal desmin and TFE3 positivity may mislead the diagnosis in some cases but an intimate admixture with thin-walled vessels, presence of melanin pigment, and positivity for myomelanocytic immune markers will clinch an accurate diagnosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Bonetti F, Pea M, Martignoni G, Zamboni G. PEC and sugar. Am J Surg Pathol 1992;16:307-8.  Back to cited text no. 1
    
2.
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;29:1558-75.  Back to cited text no. 2
    
3.
Martignoni G, Pea M, Reghellin D, Zamboni G, Bonetti F. PEComas: The past, the present and the future. Virchows Arch 2008;452:119-32.  Back to cited text no. 3
    
4.
Folpe AL. Neoplasms with perivascular epithelioid cell differentiation (PEComas). In World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Soft Tissue and Bone. Edited by Fletcher CDM, Unni KK, Mertens F. Lyon: IARC Press; 2002. p. 221-2  Back to cited text no. 4
    
5.
Pizzi M, di Lorenzo I, d'Amore ES, D'Angelo P, Alaggio R. Pediatric gastrointestinal PEComas: A diagnostic challenge. Pediatr Dev Pathol 2014;17:406-8.  Back to cited text no. 5
    
6.
Weinreb I, Howarth D, Latta E, Ghazarian D, Chetty R. Perivascular epithelioid cell neoplasms (PEComas): Four malignant cases expanding the histopathological spectrum and a description of a unique finding. Virchows Arch 2007;450:463-70.  Back to cited text no. 6
    
7.
Alaggio R, Cecchetto G, Martignoni G, Bisogno G, Cheng L, Sperlì D, et al. Malignant perivascular epithelioid cell tumor in children: Description of a case and review of the literature. J Pediatr Surg 2012;47:e31-40.  Back to cited text no. 7
    
8.
van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997;277:805-8.  Back to cited text no. 8
    
9.
Rekhi B, Sable M, Desai SB. Retroperitoneal sclerosing PEComa with melanin pigmentation and granulomatous inflammation-A rare association within an uncommon tumor. Indian J Pathol Microbiol 2012;55:395-8.  Back to cited text no. 9
  [Full text]  
10.
Kosemehmetoglu K, Folpe AL. Clear cell sarcoma of tendons and aponeuroses, and osteoclast-rich tumour of the gastrointestinal tract with features resembling clear cell sarcoma of soft parts: A review and update. J Clin Pathol 2010;63:416-23.  Back to cited text no. 10
    
11.
Iyengar P, Deangelis DD, Greenberg M, Taylor G. Perivascular epithelioid cell tumor of the orbit: A case report and review of the literature. Pediatr Dev Pathol 2005;8:98-104.  Back to cited text no. 11
    
12.
Argani P, Aulmann S, Illei PB, Netto GJ, Ro J, Cho HY, et al. A distinctive subset of PEComas harbors TFE3 gene fusions. Am J Surg Pathol 2010;34:1395-406.  Back to cited text no. 12
    
13.
Agaram NP, Sung YS, Zhang L, Chen CL, Chen HW, Singer S, et al. Dichotomy of genetic abnormalities in PEComas with therapeutic implications. Am J Surg Pathol 2015;39:813-25.  Back to cited text no. 13
    
14.
Jaber OI, Kirby PA. Alveolar soft part sarcoma. Arch Pathol Lab Med 2015;139:1459-62.  Back to cited text no. 14
    
15.
Starbuck KD, Drake RD, Budd GT, Rose PG. Treatment of advanced malignant uterine perivascular epithelioid cell tumor with mTOR inhibitors: Single-institution experience and review of the literature. Anticancer Res 2016;36:6161-64.  Back to cited text no. 15
    


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