Uterine PEComas is a rare entity, on which around 150 cases have been reported in English literature till now. There are two distinct pattern of identified in PEComas- first with epithelioid pattern (100% cases)-these are polygonal cells with clear to granular cytoplasm, and positive for melanocytic markers HMB45, Melan-A and MITF. The second being the spindle cell pattern (37% of cases), which consists of cells with less cytoplasm, arranged in fascicles like smooth muscle and are positive for SMA, desmin, caldesmon. HMB-45 is the most sensitive marker being positive in 100% cases. The diagnosis should always be differentiated from smooth muscle tumors of uterus and especially tumors which showed similar IHC like epithelioid smooth muscle tumor of uterus, high grade endometrial stromal sarcoma (HGESS), GIST, melanoma involving the uterus [10]. CD10, is diffuse and shows strong immunoreactivity in endometrial stromal tumors, GIST shows strong CD34 staining, as well as c-Kit positivity and negative for melanocytic marker. Metastatic melanoma and/or clear cell sarcoma shows strong S-100 protein immunoreactivity of the former and their muscle marker negativity.
PEComas with TFE3 gene rearrangement have predominant epithelioid morphology with clear cells and have strongly positive staining for melanocytic markers like HMB-45 and Cathepsin K and weak or negative expression of myoid markers. Their rare variant is TFE 3 gene mixed cell PEComa with both epitheliod and spindle cell pattern. Morphologically these showed clear to granular cytoplasm with eosinophilic cells and showed marked immune expression for HMB-45, TFE-3, Melan A and also positive for myoid markers [5].
These lesions either represent collision between PEComa and smooth muscle tumor or PEComa with smooth muscle differentiation, which can be answered only by molecular analysis (Bennet 2018). This rearrangement can be explained by TFE3 fusing with other genes or undergoing breakage at different points along the gene [5].
In general, PEComa shows favourable prognosis, [4] but TFE3 associated PEComas show aggressive behaviour (52%of cases) and poor prognosis during follow up [9, 11, 12]. Folpe et al., showed that TFE3 fusion PEComa has an invasive behaviour, local recurrence and metastasis rates of 8.7% and 20.3%, respectively [4]. Careful review of English literature revealed only 10 cases of uterine and cervix pecoma with TFE3 rearrangement. Table-1 shows its clinical profile, treatment and follow up status. Table-2 shows the immunohistochemical profile of uterine PEComas.
Table 1
Features of uterine TFE3 translocation associated PEComa
|
Year
|
Age(years)
|
Site
|
Clinical features
|
Past h/o
|
Size(cm)
|
Pathology
|
Treatment
|
Follow up
|
Outcome
|
1
|
Cho 2008
[13]
|
9
|
Uterus, lower uterine segment
|
Vaginal spotting, metastases to pelvic lymph nodes at presentation
|
None
|
5
|
Alveolar, epitheliod
|
TAH + pelvic LN dissection
|
ALL occured at 25 months
|
Died at 33 months because of ALL, no e/o recurrence of pecoma at time of death
|
2
|
Liu 2014
[14]
|
34
|
Cervix
|
AUB
|
None
|
9
|
Sheets/ alveolus/nests
|
Resection of cervical mass
|
5 months
|
Alive
|
3
|
Schoolmester 2015
[5]
|
53
|
Uterine corpus
|
AUB
|
None
|
17
|
Sheet like nested
|
Supracervical hysterectomy, RSO
|
2 months: cervix and metastases to omentum treated by radical trachelectomy, upper vaginectomy, omentectomy and adjuvant chemotherapy 11 months: small and large intestine and intraabomdinal cavity treated by debulking and adjuvant chemotherapy
|
Alive; intraabdominal recurrence led to diagnosis revision from high grade LMS to pecoma; recently started sirolimus regimen
|
4
|
Schoolmester 2015
[5]
|
49
|
Uterine corpus
|
Uterine mass
|
Hodgkin lymphoma treated with ABVD chemotherapy (6 years prior)
|
33
|
Nested
|
TAH-BSO
|
25 months
Recurrence -none
|
Alive, ned
|
5
|
Schoolmester 2015 [5]
|
47
|
Pelvis, site not identified
|
Pelvic pain
|
Morcellated supracervical hysterectomy with cellular leiomyomata (1 year prior)
|
8
|
Nested
|
Local excision of pelvic mass, radical trachelectomy, bso, pelvic and paraaortic lymphadenopathy, omentectomy, staging biopsies
|
57 months
Recurrence-urinary bladder treated by excision
|
Alive, ned
|
6
|
Schoolmester 2015
[5]
|
46
|
Uterine corpus
|
Unknown
|
None
|
1
|
Nested
|
Hysterectomy
|
1 month
Recurrence- none
|
Alive, ned
|
7
|
Choi 2016
[15]
|
67
|
Uterus
|
AUB
|
Ns
|
6
|
Spindle cells
|
TAH + BSO
|
Ns
Multiple metastasis in lung and liver
|
Ns
|
8
|
Bennet 2018
[6]
|
Ns
|
Uterus
|
Ns
|
Ns
|
Ns
|
Nested
|
Ns
|
19 months
|
Alive
|
9
|
Gianella 2020
[11]
|
45
|
Uterus
|
Cyclic abdominopelvic pain and chronic constipation
|
K/c/o breast cancer, treated with quadrantectomy, axillary dissection, and radiotherapy,
Followed by tamoxifen therapy for five years
|
4
|
Nested architecture with thin-walled vascular spaces and was
Composed of large cells with a clear to granular eosinophilic cytoplasm, round to ovoid nucleus, and
Prominent nucleoli
|
TLH with a bilateral salpingectomy.
|
2 years, no recurrence
|
Alive
|
10
|
Hu 2020
[16]
|
53
|
Uterine endom etrial polyp
|
Irregular menstruation
|
K/c/o ca breast, h/o MRM f/b tamoxifen x 4 years
|
2
|
Epitheliod cells with nested architecture
|
TLH
|
5months
|
Alive
|
Note- TAH- Total abdominal hysterectomy, TLH-Total laproscopic hysterectomy, RSO- right salpingoopherectomy, AUB- abnormal uterine bleeding, ALL- acute lymphocytic leukemia, LMS- liomyosarcoma, NS-not specified, MRM-modified radical mastectomy, BSO-bilateral salphingoophorectomy, NED-no evidence of disease |
Table 2
Immunohistochemical and Molecular Profile of Uterine PEComas
Case no
|
HMB 45
|
MELAN A
|
CATHEPSIN K
|
TFE 3
|
SMA
|
DESMIN
|
Caldesmon
|
Ki 67
|
FISH
|
1
|
positive
|
0
|
positive
|
positive
|
0
|
0
|
ns
|
-
|
Not done
|
2
|
3+
|
3+
|
-
|
3+
|
0
|
-
|
-
|
2+
|
+
|
3
|
4+
|
2+
|
4+
|
4+
|
0
|
0
|
0
|
|
+
|
4
|
4+
|
0
|
4+
|
4+
|
0
|
0
|
0
|
|
+
|
5
|
4+
|
1+
|
4+
|
4+
|
0
|
1+
|
0
|
|
+
|
6
|
4+
|
0
|
4+
|
4+
|
-
|
0
|
0
|
|
+
|
7
|
3+
|
+
|
-
|
3+
|
+
|
+
|
-
|
5%
|
Not done
|
8
|
4+
|
-
|
4+
|
4+
|
4+
|
-
|
-
|
|
PSF-TFE3
|
9
|
positive
|
ns
|
positive
|
positive
|
Focal positive
|
-
|
-
|
|
Not done
|
10
|
positive
|
positive
|
positive
|
positive
|
-
|
-
|
-
|
5%
|
+
|
Present case
|
4+
|
4+
|
-
|
3+
|
-
|
-
|
1+
|
30%
|
Not done
|
In all the above cases reported in literature, the pelvic tumors were managed by primary surgical resection. In maximum of the above mentioned cases, diagnosis was confirmed postoperatively. Most of the cases does not contain any information regarding follow-up and further management.
No effective therapy with TFE 3 rearranged PEComa in advanced extrarenal cases have been mentioned in the literature. Chemotherapy (CT) and radiotherapy (RT) have also been reported in literature with advanced PEComa cases. Since there is paucity of cases, poor results reported with variety of treatment modalities and no randomised trial conducted, no uniform consensus has been achieved in this regard.
Both neoadjuvant and adjuvant CT (dacarbazine, ifosfamide, doxorubicin, vincristine), has been reported, but heterogenous results were achieved regarding disease progression and survival free interval. Regarding targeted therapy, the use of mTOR inhibitors in conventional metastatic PEComas with TSC1 and TSC2 mutation has been reported in very few cases at other extrarenal sites with promising results, however, further prospective studies are needed [17]. TFE 3 rearranged PEComas do not involve TSC2 gene, thus biologically these tumors behave distinctly with conventional PEComa and do not respond to mTOR inhibitors[5].
Xu et al., has reported a case of gastrointestinal PEComa with TFE3 rearrangement which did not responded to Everolimus, hence they switched to anti-VEGFR2 and Apatinib, for which the tumor remained stable and the progression free survival lasted for about 7 months [18]. Another case of ovarian TFE3 reactive PEComa was reported, which did not responded to sirolimus and develop liver recurrence [19].
Although our case showed strong nuclear positivity for TFE3, due to non affordability, the patient refused for FISH analysis to look for genetic rearrangements. In spite of TFE3 reactivity, our patient responded very well with Everolimus, in contrast to other cases reported in the literature.
Prompt identification of TFE-3 PEComa is recommended before starting their management, since these tumors show different biological behaviour as compared to the conventional counterpart, which can lead to important insight into their management and the targeted therapies. Since very few cases have been reported in literature, further studies are needed to clearly define their clinical characteristics, prognosis and management. We have reported the first case of TFE 3 reactive PEComa which showed an appreciable response to Everolimus.