Case 2 -
Click on each slide thumbnail image for an enlarged view
A 2 year-old female was referred to the local hospital for failure to thrive. Family and personal
health history were negative. Ultrasound performed for suspected urinary infection showed a voluminous
abdominal mass. CT scan confirmed a solid lesion with necrotic areas in the right abdomen, extending to
the left and right iliac fossa, adherent to the liver, right kidney, vena cava and abdominal wall,
measuring 12x60 cm. An open biopsy was done and intraoperative examination confirmed a malignant
neoplasm. Histology was reviewed at the University of Padova, and the child received 2 courses of
chemotherapy (IVA2). Due to poor response to chemotherapy, the child underwent surgery and the mass was
resected with part of the omentum. Nodules on the anterior peritoneum, right iliac fossa, pelvis and
sigmoid colon were removed and gastric, and periduodenal and mesenteric lymph-nodes were biopsied. After
surgery a new chemotherapy regimen (Ifosfamide/Adriamicine) was given. Six months later, the tumor
recurred but a debulking operation was not considered possible. The child, who did not receive any other
treatment, is alive with progressive disease and multiple masses in the abdomen after 2 years. The
seminar slide originates from the primary resection.
Case 2 - Slide 1
Case 2 - Figure 1
The lesion is well circumscribed and focally surrounded by a thin fibrous pseudocapsule.
Case 2 - Figure 2
This highly cellular neoplasm is composed of spindle cells with a vaguely fascicular pattern. There is a complex vascular network, formed by small capillaries, mostly arranged longitudinally.
Case 2 - Figure 3
Foci of necrosis are present.
Case 2 - Figure 6
Areas with epithelioid cells, arranged in a nested pattern with a typical chicken-wire vascular pattern, are also seen.
Case 2 - Figure 7
At higher power the epithelioid cells are characterized by clear cytoplasm, and nuclei show mild variation in shape and size with frequent nucleoli.
The initial incisional biopsy was a tiny specimen of about 1.5 cm. The mass that was further
resected measured 13 cm in maximum diameter: it was multinodular, covered by peritoneum, with a
glistening surface and a prominent vascular network. The tumor had a fleshy appearance, with solid areas
exhibiting a whitish-pink color mixed with hemorrhagic and necrotic foci. The majority of the secondary
nodules were necrotic.
On microscopic examination, both the initial biopsy and the resected tumor consisted of spindle
cells with clear, elongated cytoplasm and distinct cell borders arranged in fascicles accompanied by a
complex vascular network. In some areas the cells exhibited a vaguely epithelioid morphology, had clear
to eosinophilic cytoplasm and were aggregated in nests, surrounded by thin blood vessels. Nuclei varied
in size and shape from oval to round with finely-dispersed chromatin, sometimes clumped, and
inconspicuous nucleoli, that occasionally became prominent. Neither adipocytes nor thick-walled blood
vessels were observed. Foci of necrosis and hemorrhagic areas were frequent, with focal hemosiderin
pigment. Mitoses were present, occasionally atypical. Mitotic rate was 15/50HPF. There were no
features of angiolymphatic invasion. At the periphery, the neoplasia appeared well circumscribed and
surrounded by a thin fibrous pseudo-capsule. Secondary nodules were mostly characterized by collections
of macrophages surrounding necrotic foci. One nodule showed a neoplasm with the same features as the
Immunohistochemically the tumor cells were strongly positive for HMB45, SMA and H-caldesmon. S100,
cytokeratins, EMA, and p53 were negative. Cyclin D1 was positive in more than 70% of nuclei.
Malignant PEComa, with features of m alignant clear cell myomelanocytic tumor of the falciform
Clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres (CCMT) was described by
Folpe et al in 2000 as a clinicopathologic entity, typically arising in the abdomen of young females,
with predilection for the ligamentum teres and falciform ligament of the liver . It shows a
distinctive morphology, characterized by spindle cells with clear or eosinophilic cytoplasm arranged in
fascicles or nests, and is part of the large family of PEComa
The term "PEComa" was first
coined by Zamboni et al in 1996 to identify a group of mesenchymal neoplasms originating from the
perivascular epithelioid cell (PEC)
. The PEC is a newly identified cell, with a not yet recognized
normal counterpart, characterized by morphologic variability, an intimate relationship with blood vessels
and a typical co-expression of muscular and melanocytic markers
The PEComa family includes
angiomyolipomas, lymphangio-leiomyomatosis, clear cell "sugar" tumor of the lung and a group of entities
variously reported in the literature as "clear cell
myomelanocytic tumor (CCMT) of the falciform ligament/ligamentum teres" and "abdominopelvic sarcoma
of perivascular-epithelioid cells"
The current case represents an example of malignant PEComa, with typical features of CCMT
tumor showed multiple peritoneal nodules. The main mass was poorly responsive to chemotherapy and
exhibited a rather monotonous morphology, characterized by elongated cells with clear cytoplasm and only
focal epithelioid features. Most of the secondary nodules had almost completely responded to therapy and
showed a collection of foamy macrophages.
PEComa family tumors typically occur in young woman and adults. To our knowledge, less than 20 cases
have been reported so far in childhood, mostly as single cases, and only one large series by Folpe
included 6 pediatric CCMT
Pediatric PEComa occur more frequently in females. Only one case has been reported in a male, as a
second neoplasm following neuroblastoma . The most frequent site is the
abdomen (falciform ligament,
omentum, bowel wall}, followed by the pelvis and kidney
The prognosis in
PEComa is not easily predictable and there are not strict histologic criteria for malignancy. Malignant
PEComa, even with typical features of CCMT, are being increasingly reported
to the WHO classification, tumors showing infiltrative growth, hypercellularity, nuclear enlargement and
hyperchromasia, high mitotic rate, atypical mitoses and coagulative necrosis are prone to malignant
behavior . Folpe et al have proposed a stratification of PEComas in three groups: malignant,
for tumors showing at least two unfavorable morphologic markers (size >5cm, infiltrative growth
pattern, high nuclear grade and cellularity, mitotic rate more than 1/50HPF, necrosis, vascular
invasion); benign, when tumors are devoid of any unfavorable marker; and uncertain malignant
potential, when only one unfavorable marker is found . According to these criteria, malignant
PEComas represent about 20% of the cases in adult patients . Only few clinically malignant PEComas
have been reported in childhood, mostly characterized by epithelioid morphology, all in the abdomen, and
with evidence of unfavorable prognostic features
The CCMT had been
originally described as a lesion with a favorable clinical course, but the low number of cases and short
follow-up were inconclusive . Among the 6 cases with CCMT morphology in the recent study by Folpe,
only 1 had aggressive behavior . The case reported here displayed more than two morphologically
unfavorable markers and shared many features with a CCMT of the broad ligament, with malignant histology,
described by Kim et al in a 12 year old girl . Both cases had multiple peritoneal nodules at initial
diagnosis. The term "PEComatosis" was used by Fadare et al  for a case of PEComa of the uterine
cervix associated with multicentric peritoneal nodules, in a female patient who had tuberous sclerosis
(TBS). PEComatosis has been described in few patients with TBS, but it has never been reported in
sporadic PEComas . A "field effect", probably related to the tuberous sclerosis, has been suggested
as a possible pathogenetic mechanism responsible of the propensity to develop multiple nodules in the
abdomen . Our patient had no underlying conditions and the nodules were regarded as metastatic
spread from the main mass.
The CCMT and PEComas in general may be confused with a variety of both benign and malignant tumors.
In a child with an abdominal mass adherent to the kidney, the differential diagnosis includes clear cell
sarcoma of the kidney
or a renal carcinoma associated with Xp11.2 translocation/TFE3 gene fusion
CCSK is positive for vimentin and negative for melanocytic markers and SMA . Differential
diagnosis from TFE3 renal cell carcinoma may be more difficult, especially in PEComas that exhibit an
epithelioid morphology. Some Xp11.2 renal carcinomas, such as those associated with t(6;11)(p21.1;q12)
or t(X;17)(p11.2;q23), may show a clear cell morphology with a nested architecture and an
immunohistochemical profile identical to PEComa, with scant or negative expression of epithelial markers,
and positive melanocytic markers such as melan-A and HMB-45
Moreover, some PEComas may show
TFE3 immunostaining . In both tumors it has been hypothesized that TFE3 is involved in the
inappropriate activation of some targets of MiTF, resulting in the expression of melanocytic markers
In fact PEComas and renal carcinomas expressing TFE3 are generally negative for MiTF, suggesting
that the TFE3 induces the melanocytic phenotype in those tumors that are MiTF negative. The differential
diagnosis between these two lesions is made possible by the different intensity of HMB45, only focal in
carcinoma, and negative SMA
Moreover, at light microscopy, some carcinomas show pink hyaline
globules corresponding to aggregates of basement membrane material .
The positive staining for melanocytic markers (HMB45, MiTF) may suggest the diagnosis of clear cell
sarcoma of soft parts (CCSSP) (the so-called melanoma of soft parts). Histological features may be
deceptive because CCSSP and PEComa share the same epithelioid or spindle cell morphology with clear
cytoplasm and nuclei with prominent nucleoli. Melanin and multinucleated cells may be present in both.
The evidence of positive SMA immunostaining, associated with negative S100, is an important diagnostic
feature, even if occasional PEComas may be SMA negative. Moreover CCSSP shows a typical translocation
Although in adult patients other soft tissue neoplasms have to be considered in the differential
diagnostic spectrum, such as gastrointestinal stromal tumors and leiomyosarcomas, these are very rare in
children and can be excluded by an adequate immunohistochemical panel, since GIST and leiomyosarcomas are
negative for melanocytic markers. Moreover GISTs are positive for CD117. Nevertheless, occasional CD117
reactivity in a PEComa may be misleading .
The nested architecture of PEComa may also simulate the typical zellballen pattern of paraganglioma,
a tumor which may also be pigmented. In paraganglioma, S-100 decorates sustentacular cells, and tumor
cell are positive for chromogranin, Synaptophysin, and neuron-specific enolase. The distinction between
alveolar soft part sarcoma and PEComa is aided by detection of PAS-positive diastase-resistant
crystalline structures in the cytoplasm. Also, the same t(X;17) translocation as in alveolar soft part
sarcoma, but unbalanced, has been found in a subgroup of TFE3 renal carcinomas .
The cytogenetic features of PEComa have not been extensively investigated. Loss of heterozygosity
for the TSC2 gene, on 16p13, which is the alteration most frequently found in both sporadic and tuberous
sclerosis-associated angiomyolipomas (AML), has been detected in PEComas, suggesting a relationship to
It is possible that the histogenesis of PEComas might be related to the role
of TSC in the negative regulation of the Wnt-beta catenin pathway that controls cell proliferation and
differentiation, but further investigations are required . A chromosomal loss of 17p, the region
corresponding to the TP53 oncosuppressor gene, has also been identified by CGH . Nevertheless, PCR
studies have failed to show mutations or allelic losses in TP53 gene, confirmed also by negative
immunostains for p53. Other genetic alterations reported include deletion of 1p, deletions on chromosome
19, and chromosomal gain on 12q, 2q, 3q, and 5 . The possible role of cyclin D1 in the pathogenesis
of PEComas has also been investigated . Cyclin D1 is only transiently expressed in normal cells, but
may be constitutively expressed in some tumors such as melanomas. Soucek et al  have demonstrated an
association of cyclin D1 abnormalities with loss of the TSC gene, and positive immunostaining has been
reported in some PEComas. Interestingly, Weinreb et al demonstrated negative staining for cyclin D1 in
an aggregate of cells distant from the main mass and with the same histological features, while the main
mass was strongly positive . They have suggested that these small nodules, called "PECosis", may
represent the precursor lesion of PEComa. The present case was immunoreactive for cyclin D1, but FISH
analysis failed to show abnormalities in number of copies or translocations of the gene.
In conclusion, PEComas are very rare tumors that occasionally occur in children. As in adults, some
cases may have malignant behavior. The recent prognostic classification based on morphologic criteria
proposed by Folpe et al.  helps to predict the clinical course. The challenge of the future is the
development of new and effective treatments. At this time, the treatment is based on complete surgical
excision, because radiotherapy and chemotherapy are not effective. Rapamicin is a promising drug. It is
an inhibitor of m-TOR, which is activated in sporadic AML and extrarenal PEComas. M-TOR activates the
protein kinase p70S6K and its isoform p85S6K, both detected by immunohistochemistry with cytoplasmic and
nuclear staining respectively. Perhaps in the future this will provide a basis for a targeted therapy in
aggressive unresectable tumors
Table: Differential Diagnosis of PEComa
| ||PEComa ||Melanoma ||CCSSP ||CCSK ||ASPS ||TFE3-RC ||Paraganglioma|
|Histology || || || || || || |
|Spindle/Epithelioid cells ||+/+ ||+/+ ||+/- ||+/- ||+/- ||+/- ||+/-|
|Clear cytoplasms ||+ ||+ ||+ ||+ ||+ ||+ ||+|
|Prominent nucleoli ||+ ||+ ||+ ||+ ||+ ||+ ||+|
|Multinucleated cells ||+ ||+ ||+ ||+ ||+ ||+ ||+|
|Nested pattern ||+ ||+ ||+ ||-/+ ||+ ||+ ||+|
|Cytoplasmic inclusions ||- ||- ||- ||- ||+ ||- ||+|
|Melanin ||+ ||+ ||+ ||- ||- ||- ||+/-|
|Immunophenotype || || || || || || |
|Vim ||+ ||+ ||+ ||+ ||+ ||+ ||+|
|CK ||- ||- ||- ||- ||- ||50%+ ||-|
|EMA ||- ||- ||- ||- ||- ||50%+ ||-|
|S-100 ||-/rare+ ||+ ||+ ||- ||- ||- ||+ *|
|HMB45 ||+ ||+ ||+ ||- ||- ||+ ||-|
|MiTF ||50% ||+ ||+ ||- ||- ||- ||-|
|SMA ||+ ||- ||- ||- ||- ||- ||-|
|Cromogranin, Syn ||- ||- ||- ||- ||- ||- ||+|
|TFE3 ||30% ||- ||- ||- ||- ||+ ||-|
|Molecular Characterization ||- ||- ||t(12;22) ||- ||t(X;17) ||t(X;17) |
CCSSP= Clear cell sarcoma of soft parts; CCSK= Clear cell sarcoma of the kidney; ASPS= Alveolar soft
part sarcoma; TFE3-RC= Renal carcinoma associated with Xp11.2 translocation/TFE3 gene fusion. Vim=
vimentin; CK= cytokeratins; MiTF= microphthalmia transcription factor; SMA= smooth muscle actin
*in sustentacular cells
Take Home Messages
- Beware of tiny biopsies: lesions with unusual
morphological features may be misleading
- The prognostic categorization of some
mesenchymal lesions remains controversial and is an area for future investigation
- When in doubt about the interpretation of lesions unexpected for the patient's age,
remember: tumors do not read medicine books.
- Folpe AL, Goodman ZD, Ishak KG, et al. Clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres: a novel member of the perivascular epithelioid clear cell family of tumors with a predilection for children and young adults. Am J Surg Pathol. 2000 Sep;24(9):1239-46.
- Folpe AL, McKenney JK, Li Z, Smith SJ, Weiss SW. Clear cell myomelanocytic tumor of the thigh: report of a unique case. Am J Surg Pathol. 2002 Jun;26(6):809-12.
- Hornick JL, Fletcher CD. PEComa: what do we know so far? Histopathology. 2006 Jan;48(1):75-82.
- Martignoni G, Pea M, Reghellin D, Zamboni G, Bonetti F. PEComas: the past, the present and the future.Virchows Arch. 2007 Dec 14; [Epub ahead of print]
- Zamboni G, Pea M, Martignoni G, Zancanaro C, 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):722-730
- Bonetti F, Pea M, Martignoni G, Zamboni G. PEC and sugar. Am J Surg Pathol, 1992 (16):307-308
- Martignoni G, Pea M, Reghellin D, Zamboni G, Bonetti F. Perivascular epithelioid cell tumor (PEComa) in the genitourinary tract. Adv Anat Pathol. 2007 Jan;14(1):36-41.
- 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. Series: WHO Classification of tumours. IARC Press, Lyon, 2002: 221-222
- Folpe AL, Mentzel T, Lehr HA, et al. 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 Dec;29(12):1558-75
- Kim HJ, Lim SJ, Choi H, Park K. Malignant clear-cell myomelanocytic tumor of broad ligament--a case report. Virchows Arch. 2006 Jun;448(6):867-70
- 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 Jan-Feb;8(1):98-104.
- Ong LY, Hwang WS, Wong A, et al. Perivascular epithelioid cell tumour of the vagina in an 8 year old girl. J Pediatr Surg. 2007 Mar;42(3):564-6.
- Mhanna T, Ranchere-Vince D, Hervieu et al. Clear cell myomelanocytic tumor (PEComa) of the duodenum in a child with a history of neuroblastoma. Arch Pathol Lab Med. 2005 Nov;129(11):1484-6.
- Yu W, Fraser RB , Gaskin DA , et al. C-Kit-positive metastatic malignant pigmented clear-cell epithelioid tumor arising from the kidney in a child without tuberous sclerosis. Ann Diagn Pathol. 2005 Dec;9(6):330-4
- Rigby H, Yu W, Schmidt MH, Fernandez CV. Lack of response of a metastatic renal perivascular epithelial cell tumor (PEComa) to successive courses of DTIC based-therapy and imatinib mesylate. Pediatr Blood Cancer. 2005 Aug;45(2):202-6.
- I-Yu-Chen, Sheau-Fang Yang, Fang-Ming Chen et al. Abdominopelvic perivascular epithelioid cell tumor with overt malignancy: a case report. Kaohsiung J Med Sci 2005;21:277-81
- Bonetti F, Martignoni G, Colato C, Manfrin E, Gambacorta M, Faleri M, Bacchi C, Sin VC, Wong NL, Coady M, Chan JK. Abdominopelvic sarcoma of perivascular epithelioid cells. Report of four cases in young women, one with tuberous sclerosis. Mod Pathol 2002 (14):563-568
- Agaimy A, WŁnsch PH. Perivascular epithelioid cell sarcoma (malignant PEComa) of the ileum.Pathol Res Pract. 2006;202(1):37-41
- Parfitt JR, Bella AJ, Izawa JI, Wehrli BM. Malignant neoplasm of perivascular epithelioid cells of the liver. Arch Pathol Lab Med. 2006 Aug;130(8):1219-22
- Yamamoto H, Oda Y, Yao T, et al.Malignant perivascular epithelioid cell tumor of the colon: report of a case with molecular analysis. Pathol Int. 2006 Jan;56(1):46-50
- Weinreb I, Howarth D, Latta et al. Perivascular epithelioid cell neoplasms (PEComas): four malignant cases expanding the histopathological spectrum and a description of a unique finding. Virchows Arch. 2007 Apr;450(4):463-70
- Fadare O, Parkash V, Yilmaz Y, et al. Perivascular epithelioid cell tumor (PEComa) of the uterine cervix associated with intraabdominal "PEComatosis": A clinicopathological study with comparative genomic hybridization analysis. World J Surg Oncol. 2004 Oct 19;2:35.
- Liang SX, Pearl M, et "Malignant" uterine perivascular epithelioid cell tumor, pelvic lymph node lymphangioleiomyomatosis, and gynecological pecomatosis in a patient with tuberous sclerosis: a case report and review of the literature. Int J Gynecol Pathol. 2008 Jan;27(1):86-90.
- Argani P. Landanyi M. Renal carcinomas associated with Xp11.2 translocations/TFE3 gene fusions. In: Eble J, Sauter J, Epstein J, Sesterhenn (eds) Pathology and genetics of tumours of the urinary system and male genital organs. Series: WHO Classification of tumours. IARC Press, Lyon, 2004
- Argani P, Hawkins A, Griffin, et al. A distinctive pediatric renal neoplasm characterized by epithelioid morphology, basement membrane production, focal HMB45 immunoreactivity, and t(6;11)(p21.1;q12) chromosome translocation. Am J Pathol. 2001 Jun;158(6):2089-96
- Argani P, Lui MY, Couturier J, et al. A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2;q23). Oncogene. 2003 Aug 14;22(34):5374-8
- Reeves BR, Fletcher CD, Gusterson BA. Translocation t(12;22)(q13;q13) is a nonrandom rearrangement in clear cell sarcoma. Cancer Genet Cytogenet.1992;64: 101-103
- Uppal S., Aviv H, Patterson F et al. Alveolar soft part sarcoma-reciprocal translocation between chromosome 17q25 and Xp11. Report of a case with metastases at presentation and review of the literature. Acta Orthop Belg 2003; 69:182-187
- Martignoni G, Pea M, Rigaud G et al. Renal angiomyolipoma with epithelioid sarcomatous transformation and metastases: demonstration of the same genetic defects in the primary and metastatic lesions. Am J Surg Pathol. 2000 Jun;24(6):889-94
- Martignoni G, Pea M, Bonetti et al. Carcinoma-like monotypic epithelioid angiomyolipoma in patients without evidence of tuberous sclerosis: a clinicopathologic and genetic study.Am J Surg Pathol. 1998 Jun;22(6):663-72.
- Pan CC, Chung MY, Ng KF, Liu CY, et al. Constant allelic alteration on chromosome 16p (TSC2 gene) in perivascular epithelioid cell tumour (PEComa): genetic evidence for the relationship of PEComa with angiomyolipoma. J Pathol. 2007 Dec 11; [Epub ahead of print]
- Pan CC, Jong YJ, Chai CY, et al. Comparative genomic hybridization study of perivascular epithelioid cell tumor: molecular genetic evidence of perivascular epithelioid cell tumor as a distinctive neoplasm. Hum Pathol. 2006 May;37(5):606-12.
- Mak BC, Takemaru K, Kenerson HL, et al. The tuberin-hamartin complex negatively regulates beta-catenin signalling activity. J Biol Chem, 2003 (278):5947-5951
- Soucek T, Pusch O, Wienecke R, et al. Role of the tuberous sclerosis gene-2 product in cell cycle control. Loss of the tuberous sclerosis gene-2 induces quiescent cells to enter S phase. J Biol Chem. 1997 Nov 14;272(46):29301-8
- Kenerson H, Folpe AL, Takayama TK, et al. Activation of the mTOR pathway in sporadic angiomyolipomas and other epithelioid cell neoplasms. Hum Pathol 2007 (38):1361-1371