PERIVASCULAR EPITHELIOID TUMOURS (PEComas) OF THE GYNAECOLOGICAL TRACT

Abstract

Perivascular epithelioid tumour (PEComas) of the gynaecological tract are rare tumours which were first recognised and diagnosed within the last twenty years. They represent a unique diagnostic challenge with regard to their accurate and reproducible distinction from more common entities such as smooth muscle tumours of the uterine corpus. In this review article we trace the development of the concept of the PEComa tumour family, highlight what is known about extra-gynaecological tract PEComa at an immunohistochemical, molecular and therapeutic level and then present a summary of all reported cases of gynaecological tract PEComa to date. In the summary, we highlight rare subtypes of gynaecological tract PEComa, and compare the performances of extant prognostic classification systems for malignancy in these tumours.

Demonstration of the expression of the melanocytic marker HMB-45 in angiomyolipoma (AML)^{1, 2} and clear cell “sugar” tumours (CCST) of lung³ led to the concept of PEComa as a family of tumours occurring at many sites and characterised by the presence of an epithelioid cell of mixed myo-melanocytic immunophenotype. This family included previously recognised entities such as AML, CCST, lymphangioleiomyomatosis (LAM) and clear cell myomelanocytic tumour of the falciform ligament/ligamentum teres (CCMT). Subsequently, sporadic HMB-45-positive clear cell tumours of other sites such as pancreas⁴ and uterus⁵ were described.

The cell-of-origin of PEComas has not been unequivocally established. Early reports speculated tumour origin from vessel walls,⁶ or from a “peculiar muscle cell” based on morphology and expression of myomelanocytic markers.³ Embryological and in vitro studies have provided evidence for origin from a neural-crest stem cell that is capable of myoid and melanocytic differentiation and which can occur in embryologic development and tissue repair.^7–11

Tuberous Sclerosis Complex (TSC) is characterised by the development of tumours at various sites, including brain, heart and kidney. Genetically, TSC is associated with mutations in TSC1 or TSC2 (located on 9q 34 and 16q13 respectively), leading to impaired production of the proteins hamartin and tuberin respectively. TSC1 and TSC2 interact as heterodimers that inhibit the mTOR pathway; their inactivation leads to increased cell growth and proliferation.¹² The prototypical PEComa associated with TSC is renal AML. While ~80% of patients with TSC have AML, <50% of all renal AMLs and <10% of extrarenal AML occur in patients with TSC.¹³ The majority of cases of PEComatosis (widespread multifocal macroscopic and microscopic nodules of PEComa cells involving multiple sites in the gynaecological tract and pelvis) occurred in TSC patients,^14–18 and the uterus of a single TSC patient harboured a subserosal AML, a sclerosing PEComa of lower uterine segment and diffuse LAM of the uterine corpus.¹⁹ Thus, TSC-associated loss of function of TSC1/TSC2 can lead to a phenotypic spectrum (classical AML-like, classical PEComa, sclerosing PEComa, LAM) that is also recognised in sporadic PEComas.

Histologically, PEComa is characterised by the presence of predominantly epithelioid cells with clear, granular or eosinophilic cytoplasm, arranged in nests or sheets, with little intervening stroma. Many PEComas have a low mitotic rate of ≤1 per 50 high power fields (HPFs). Areas of necrosis may be seen. PEComas demonstrate varying levels of nuclear pleomorphism, including multinucleate giant cells and “spider cells”, analogous to those seen in cardiac rhabdomyoma.²⁰ Other features include macronucleoli and intranuclear pseudoinclusions.²⁰ While most reported PEComas have been epithelioid, they show a cytological spectrum from purely spindled to purely epithelioid (and combinations of the two). Rare features include sex-cord-like features²¹ and prolactin secretion.^{22, 23}

Sclerosing PEComa occurs predominantly in the retroperitoneum of women, and rarely in the uterus and pelvis. They show cords of epithelioid cells within densely sclerotic stroma. Areas of intimate association between tumour cells and blood vessels are often identified.²⁴

PEComas are defined by the immunohistochemical (IHC) co-expression of myoid markers (SMA, desmin, caldesmon) and melanocytic markers (HMB-45, Melan-A, MiTF). Expression varies with morphology: tumours with predominant spindle cell morphology show strong expression of muscle markers and limited expression of melanocytic markers; predominantly epithelioid tumours may strongly express melanocytic markers with limited muscle marker expression. Recently, cathepsin K, a transcriptional target of the MiTF family, emerged as a sensitive marker for PEComa.^25–27 However, cathepsin K is not specific for PEComa, and is commonly positive in melanoma, alveolar soft part sarcoma, and mesenchymal tumours, including leiomyosarcoma.²⁸

Renal and extrarenal AMLs/PEComas exhibit true melanocytic differentiation in the form of melanosomes at various stages of development,^{29, 30} and positive Masson-Fontana staining. Grossly and microscopically pigmented examples of PEComa have been reported.^31–34

Limited genomic studies have suggested that loss of heterozygosity (LOH) at the TSC2 locus may play an important role in sporadic PEComa tumourigenesis, similar to its role in TSC-related and sporadic renal AML^35–37 and sporadic pulmonary LAM.³⁸ Comparative genomic hybridization (CGH) on 9 PEComas (including one uterine case) showed multiple chromosomal imbalances, with 16p loss in 6 cases and X-chromosomal gains in 6 cases.³⁹ Malinowska et al⁴⁰ demonstrated loss of immunohistochemical expression of tuberin in 4 PEComas and LOH or allelic loss of at least one TSC2 microsatellite marker in two of those four cases. Kenerson et al⁴¹ reported immunohistochemical evidence of mTOR pathway activation (increased levels of phospho-p70S6K, reduced levels of phospho-AKT and loss of tuberin expression) in sporadic AMLs and extrarenal PEComas. Based on these limited studies, several clinical trials of mTOR pathway inhibitors in malignant PEComa have been initiated.

PEComa of the gynaecological tract

Uterine Corpus

To date, 78 cases of uterine corpus PEComas have been reported in the English language literature (Table 1).^{5, 16–20, 24, 39, 42–72}

TABLE 1.

Summary of clinico-pathological features of PEComas of the gynaecological tract

	Uterine corpus	Cervix	Vagina	Adnexa	Broad ligament	Vulva
N	78	11	7	6	5	1
Age at diagnosis median (range) [years]	47.5 (9–79)	46 (25–61)	28 (6–57)	49 (33–63)	25 (24–57)	20
Associations
TSC	5 (6%)	1 (9%)	-	2 (33%)	-
Other PEComa family tumors	LAM (n=3)	-	-	-	-
PEComatosis	4 (5%)	1 (9%)	-	-	-
Tumour size – median (range) [cm]	5cm (0.2–30cm) (n=67)	3.9 (1–12) (n=9)	3 (1.5–9) (n=5)	4.2 (2.5–15) (n=6)	11.5 (4–17) (n=5)	2
Morphology
Sclerosing PEComa	9 (12%)	0	0	2 (33%)	1 (20%)
Cell shape		-
Epithelioid	43/74 (58%)	6/10 (60%)	6/7 (86%)	3/6 (50%)	2/4 (50%)
Spindle	1/74(1%)	4/10 (40%)	-		1/4 (25%)
Epithelioid + spindle	30/74 (41%)		1/7 (14%)	3/6 (50%)	1/4 (25%)
Necrosis	31/74 (42%)	4/10 (40%)	1/5 (20%)	2/6 (33%)	3/4 (75%)	-
Nuclear atypia	Significant, severe or extensive in 25/62 (40%)	Moderate to severe in 7/10 (70%)	Severe atypia not seen (5/5, 0%)	“Severe”/“significant” atypia in 4/6 (67%)	Varying from none to severe	None
Mitotic activity	<=1 (38, 52%) Rare (7, 10%) 2–222 per 50HPF (28, 38%) (n=73)	“zero”, “rare” or ≤1/50HPF (8/9, 89%)	Absent or “rare” 4/5 (80%)*	Variable: ≤1 (3/6) to 97/50HPF		Rare
IHC	(see also Table 2)
HMB-45	71/72 (99%)	8/8 (100%)##	6/6 (100%)#	6/6 (100%)	4/4 (100%)	1/1 (100%)
Melan-A	21/46 (46%)	4/5 (80%)	1/4 (25%)	3/3 (100%)@	1/3 (33%)
MiTF	14/21 (67%)		0/1 (0%)	1/1 (100%)$
SMA	53/68 (80%)	5/8 (63%)	2/4 (50%)	4/5 (80%)	4/4 (100%)^
Desmin	39/62 (63%)	3/5 (60%)	0/2 (0%)	4/6 (67%)	1/2 (50%)^^	0/1 (0%)
Caldesmon	17/22 (77%)			2/2 (100%)
Cytokeratin	2/43 (5%)
ER	10/19 (53%)
PR	11/13 (85%)
PAX8	0
CD10	4/28 (14%)
CD34	0
Vimentin	11/18 (61%)
Inhibin	1/20 (5%)
Follow-up
Duration median (range) [months]	20 (1.5–168)	28 (9–42)	14.5 (3–54)	9 (4–72)	13.5 (11–18)	48
Died of disease	10/63 (16%)	1/9 (11%)78	-	1/4 (25%)	-	-
No evidence of disease	44/63 (70%)	8/9 (89%)	6/7 (86%)	3/4 (75%)	2/4 (50%)	1/1 (100%)
Alive with disease	9/63 (14%)	-	1/7 (14%)		2/4 (50%)	-

^*A single TFE3-translocation-associated case had a mitotic count of 5 per 50HPF

^#Strong or diffuse in 3/3 cases;

^##Strong or diffuse in 6/6 cases

^@focally weakly positive in 2 of 3 cases, and was strongly positive in 1 of 3 cases

^$weakly positive in less than half of tumour cells

^{^}focally positive in 2 tumours;

^{^^}focally positive

Tumour morphology was described in 74 cases (Table 1). A summary of the reported IHC findings is presented in Table 2. A mixed myo-melanocytic phenotype, with positivity for at least one melanocytic and one muscle marker, was confirmed in 66/73 (90%) cases. The remaining tumours^{44, 45, 48, 71} (including 3 TFE3-translocation-associated PEComas⁷¹) were HMB45-positive but negative for multiple muscle markers.⁷¹ On ultrastructural examination, 7/11 (64%) tumours^{5, 42, 48, 52, 59, 70} showed evidence of melanocytic differentiation (presence of premelanosomes or melanosomes).

TABLE 2.

Expression of myoid and melanocytic immunohistochemical markers in uterine corpus PEComas

IMMUNOHISTOCHEMISTRY RESULT			EXTENT OF POSITIVITY
IHC	n	POSITIVE (%)	n	<50% OF CELLS	≥50% OF CELLS
HMB45	72	71/72 (99%)	57	31/57 (54%)	26/57 (46%)
Melan-A	46	21/46 (46%)	20	13/20 (65%)	7/20 (35%)
MiTF	21	14/21 (66%)	12	5/12 (42%)	7/12 (58%)
S100	48	5/48 (10%)
Tyrosinase	3	0/3 (0%)
SMA	68	53/68 (80%)	39	16/39 (41%)	23/39 (59%)
Desmin	62	39/62 (63%)	18	7/18(39%)	11/18 (61%)
Caldesmon	22	17/22 (77%)	5	3/5 (60%)	2/5 (40%)
Cathepsin	12	12/12 (100%)
Myosin/MSA	4	2/4 (50%)

Reported chromosomal copy number alterations include trisomy X (n=1)⁶¹ and multiple gains and losses including 16p11.1-p13.3, which contains the TSC2 locus (n=1).³⁹ Conversely, no evidence of LOH at the TSC1 or TSC2 loci were identified in another PEComa.⁵²

Twelve patients had evidence of tumour metastasis at the time of diagnosis.^{20, 42, 44, 54, 55, 58, 60, 69} Median survival for those who died of disease was 20 months (Table 1).

Cervix

Eleven cervical PEComas have been reported.^{28, 33, 53, 73–79} One tumour demonstrated X polysomy and rearrangement of TFE3,³³ while another tumour showed bi-allelic somatic deletion of TSC1.⁷⁸ One patient (11%) recurred locally within 4 months, but had no evidence of disease at 19 months post-diagnosis (Table).⁷⁹

Vagina

Seven vaginal PEComa have been reported^{20, 53, 67, 71, 80–82} (Table 1). Three patients were aged less than 18 years.^80–82

Adnexa

6 adnexal PEComas have been reported to date.^{20, 32, 83–85} (Table 1). A mixed myo-melanocytic immunophenotype was demonstrated in 5 cases.^{20, 84, 85} TFE3 rearrangement was identified in one tumour.³² A 63-year-old patient who died of disease at four months had a 15cm sclerosing PEComa.⁸⁴ While the presence of severe atypia was noted, the presence of necrosis and mitotic rate were not recorded.

Broad Ligament

Five PEComas of the broad ligament have been reported^{27, 31, 34, 53, 86} (Table 1). A mixed myo-melanocytic immunophenotype was demonstrated in all 4 tested tumours.^{27, 31, 34, 86} Ultrastructural studies in a single tumour showed pre-melanosomes, consistent with melanocytic differentiation.³¹

Vulva

There is a single case report of a vulval/perineal PEComa (Table 1).⁸⁷ Ultrastructural studies were negative for pre-melanosomes.

Subtypes of PEComa in the Gynaecological Tract

PEComatosis

Six cases of PEComatosis have been described in the gynaecological tract.^{16–18, 66, 76, 88} Median patient age was 43.5 (range 29–70) years. Four (67%) patients had TSC.^{16–18, 66} The dominant tumour mass was located in the uterine corpus (n=4),^{16–18, 66} vaginal remnant post-hysterectomy (n=1)⁸⁸ and cervix (n=1).⁷⁶ Other sites involved by PEComatosis included ovary (n=4), lymph nodes, broad ligament, omentum, peritoneum and small bowel wall. Dominant tumour size ranged from 0.8 to 6 cm (mean 2.9cm).

The dominant tumours showed mixed epithelioid and spindled morphology (3/4 tumours), while one tumour was wholly spindled.¹⁶ Necrosis was present in 1/5 cases,¹⁸ and mitoses ranged from “rare” and ≤1 to 20 per 50 HPF. Atypia was noted in four tumours (moderate in 3). HMB-45 was positive in 5/5 cases (“strongly” positive in 3/4 where extent/intensity was reported), while Melan-A was strongly positive in 3/3 cases. SMA was positive in 6/6 cases (3/3 strongly positive), while desmin was positive in 3/4 cases. No ultrastructural studies have been reported in PEComatosis. One case showed balanced chromosomal studies.⁷⁶

Follow-up information was reported in 4/6 cases;^{16, 66, 76, 88} 3/4 patients had no evidence of disease after 12 to 168 months of follow-up. One patient was alive with disease at 12 months.⁸⁸

Sclerosing PEComa

Reported case involved the uterine corpus (n=9),^{16, 19, 24, 43, 64} adnexa (n=2)^{84, 85} and broad ligament (n=1).²⁷ Two patients had TSC,^{16, 19} and one patient had PEComatosis.¹⁶ Median patient age (n=11) at diagnosis was 46 (range 29–63) years. Mean tumour size (n=10) was 3.75cm (range 0.8–15cm). Four tumours were purely epithelioid, 1 was spindled and 1 was mixed epithelioid-spindled. No necrosis or atypia were identified (n=6) and no mitotic activity was seen (n=5).

IHC for HMB-45 was positive in 9/9 tumours (“strong” or “diffuse” positivity in 6/8). Melan-A was negative in 5/6 cases while MiTF was negative in 5/5 cases. SMA was strongly and/or diffusely positive in 8/8 tested tumours, while 7/7 tested tumours were positive for desmin (6/7 “strong” or “diffuse”). No ultrastructural evidence of melanocytic differentiation was seen in a single tumour.⁴³

Nine patients had no disease recurrence with a median follow-up of 19.5 months (range 12–168 months).^{16, 19, 24, 43, 64, 84} One patient died of her disease four months after diagnosis.⁸⁴

TFE3 translocation-associated PEComa

Transcription factor E3 (TFE3) is a member of the microphthalmia-associated family of transcription factors (MiTF). Translocations involving the TFE3 locus at Xp11.2 have been reported in epithelioid clear cell tumours such as alveolar soft part sarcoma and Xp11.2 translocation-associated renal cell carcinoma. In recent years, 18 cases of TFE3 translocation-associated PEComa have been reported in kidney,^{25, 89} bladder,⁹⁰ colon,^{91, 92} pelvic soft tissue,²⁵ ovary,³² vagina,⁷¹ and uterus.^{58, 71, 91} These tumours appear to be characterised by predominantly epithelioid morphology without pleomorphism, and immunohistochemical positivity for HMB-45, TFE3 and Cathepsin K, and negativity for MiTF,^{91, 92} SMA and desmin.^{25, 32, 71, 91, 92} This suggests that TFE3-positive PEComa may represent a distinct subgroup within the PEComa family.⁷¹ Activation of the mTOR pathway may not necessarily play a role in these tumours, which has implications with respect to patient entry into clinical trials of mTOR pathway inhibitors.⁴⁰

PEComas associated with TFE3 translocations are immunoreactive for TFE3, but the converse is not necessarily true; for example, 3 gynaecological tract PEComas which were TFE3-positive on IHC were negative for TFE3 translocation on FISH.⁷¹ Since TFE3 is ubiquitously expressed at a low level in many cell types, the use of sensitive immunohistochemical techniques may yield positive IHC results in tumours which lack TFE3 translocations.⁹¹ Therefore, weak IHC staining for TFE3 on should be interpreted with caution. At present, our approach to TFE3-immunoreactive tumours is to perform FISH to confirm the presence of the translocation.

Assessment of Malignancy in Uterine PEComa

Folpe et al's⁵³ prognostic system, based on retrospective analysis of 26 PEComas of multiple sites, divided PEComas into benign, uncertain malignant potential (UMP) and malignant groups based on histologic criteria (Table 3). Subsequently, some deficiencies in this system became apparent. While the categorization of cases with no worrisome features (benign) or two or more worrisome features (malignant) is straightforward, it is unclear how to categorize those PEComas with a single worrisome feature such as elevated mitotic count, necrosis or infiltrative growth pattern.

TABLE 3.

Folpe criteria for prognosis in PEComa (from Folpe et al⁵³)

	Criteria	Percentage Fulfilling Criteria With Aggressive Behavior	Comment
Benign	No worrisome features (<5 cm, non-infiltrative, non-high nuclear grade and cellularity, mitotic rate ≤1/50HPF, no necrosis, no vascular invasion)	0 of 22 (0%)
Uncertain malignant potential	Nuclear pleomorphism/multinucleated giant cells only or	0 of 6 (0%)	“Symplastic” PEComa probably benign, but few reported cases
	Size >5 cm only	2 of 17 (12%)	Large tumors should be extensively sampled to exclude areas with other worrisome features
Malignant	Two or more worrisome features (>5 cm, infiltrative, high nuclear grade and cellularity, mitotic rate ≥1/50HPF, necrosis, vascular invasion)	12 of 17 (71%)

Recently, Schoolmeester et al²⁰ applied the Folpe criteria to 16 gynaecological tract PEComas and proposed a revised system (Table 4) which set a higher threshold for malignancy (≥4 worrisome features) and yielded greater specificity and positive and negative predictive values for subsequent malignant behaviour without sacrificing sensitivity. In addition, they combined the benign and UMP categories into one group, in which no malignant behaviour was observed during the limited follow-up period of the study.

TABLE 4.

Schoolmeester criteria for prognosis in PEComa (from Schoolmeester et al²⁰)

	Criteria	Cases with known metastasis meeting criteria	Cases without known metastasis meeting criteria
Benign or uncertain malignant potential	Tumors with <4 features: gross size ≥5cm, high-grade nuclear features, necrosis, vascular invasion, or a mitotic rate ≥1/50HPF	0 of 9 (0%)	7 of 7 (100%)
Malignant	Tumors with 4 or more features	9 of 9 (100%)	0 of 7 (0%)

We extracted all reported histologic and outcome data from 78 uterine PEComas in order to compare the Folpe and Schoolmeester systems. In an attempt to rectify the deficiencies in the Folpe system outlined above, we tested a modification of the Folpe criteria (Folpe-modified), wherein tumours with a single “worrisome” features such as maximum dimension of ≥5 cm, infiltrative edge or mitotic count >1/10HPF are considered benign. It was not possible to define an upper limit to tumour size or mitotic count due to the small number of reported tumours with a single worrisome feature, but pending data from additional cases, clinicians may use their judgment and move the tumour to the UMP category if they consider the mitotic count or tumour size worryingly high (criteria arbitrarily used in this analysis were tumour size >10cm or mitoses >3/10 HPF). Tumours with isolated marked atypia, maximum dimension >10cm or mitotic count >3/10 HPF in the absence of other worrisome criteria should be considered UMP tumours due to the lack of available data.

For our analysis, it was necessary to discard “cellularity” as a criterion as it is poorly defined and is not assessed in most reports. Furthermore, features such as “infiltrative edge” and “lymphovascular invasion” (LVI) were not explicitly reported in many papers. We assumed that LVI was not identified if it was not explicitly stated as being present. Tumours in which the nature of the advancing edge was not reported were considered non-assessable using the Folpe and Schoolmeester criteria (unless the tumour reached thresholds for malignancy based on other worrisome features).

Using both Folpe and, no benign or UMP tumour behaved in a malignant fashion, although the Folpe-modified criteria allowed more tumours to be categorised and recognised as benign (Table 5). The Schoolmeester criteria showed superior specificity and positive predictive value (with all sixteen tumours categorised as “malignant” showing metastasis or local recurrence) than the Folpe and Folpe-modified systems, but seven of 47 tumours (15%) classified as benign/UMP behaved in a malignant fashion (Table 5).

TABLE 5.

Comparative analysis of PEComa classifications

Classification	Benign		UMP		Malignant		Not assessable
	Cases	Malignant behaviour	Cases	Malignant behaviour	Cases	Malignant behaviour	Cases
	N	N (%)	N	N (%)	N	N (%)	N
Folpe	10	0 (0)	5	0 (0)	42	29 (69)	21*
Folpe-modified	24	0 (0)	5	0 (0)	42	29 (69)	7
Schoolmeester	51	7 (14)			17	17 (100)	10

^*14 due to Folpe criteria deficits

The Folpe and Folpe-modified criteria show greater sensitivities and negative predictive values than the Schoolmeester criteria. However, tumours meeting the more stringent Schoolmeester definition of malignancy frequently recurred early. Until data from larger numbers of tumours are available, the Folpe-modified criteria may be used first to categorize tumours, with subsequent application of the Schoolmeester criteria to help identify malignant tumours at high risk of early recurrence.

Challenges in Diagnosis of gynaecological tract PEComa – the PEComa/Smooth Muscle Tumour (SMT) Morphologic Spectrum

The differential diagnosis of uterine PEComa versus LMS is an area of diagnostic controversy. The diagnosis of uterine PEComa is particularly challenging because of the relative frequency of smooth muscle tumours (SMTs). By middle age, up to 80% of women are believed to have uterine leiomyomas (LM).^{93, 94} PEComas express a myoid immunophenotype and may have spindled morphology and therefore, it is unsurprising that they share many features with common SMTs such as LM and leiomyosarcoma (LMS).

While evidence of a myo-melanocytic immunophenotype was initially considered a discriminatory feature in favour of PEComa, at least focal positivity for melanocytic markers such as HMB-45, Melan-A and MiTF has been demonstrated in uterine SMTs.^95–97 In 5 LMS with spindled and epithelioid morphology, the majority of HMB45-positive areas exhibited clear cell morphology, but some HMB45 positivity was also demonstrable in spindled areas.⁹⁶ Evidence of the phenotypic plasticity of LMS is illustrated by a report of the development of a clear cell, diffusely HMB45-positive, predominantly SMA-negative metastasis from a HMB45-negative primary epithelioid LMS.⁹⁵ Cathepsin K was recently promoted as a useful IHC marker for the differential diagnosis between PEComa and LMS, but further study has demonstrated cathepsin K expression in a proportion of LMS.⁹⁸

Although the uterus is now the most commonly reported extrarenal site for PEComa,^{14, 15} there has been some controversy as to whether uterine PEComa is a distinct entity.^{14, 15, 21, 95–97, 99} Evidence from four TSC patients with uterine PEComa, in whom the uterine tumour developed in the context of PEComatosis involving multiple gynaecological sites^{16–18, 88} appears to confirm the existence of uterine PEComa. However, it is unclear whether a subset of tumours currently diagnosed as sporadic uterine PEComas actually represent uterine SMTs with variant histological and/or immunohistochemical features.

There are several reasons for caution when considering a diagnosis of uterine PEComa. Firstly, there is overlap between the histological and IHC features of PEComas and uterine SMTs. While features such as epithelioid appearance, vascular architecture and the presence of spider cells, multinucleate giant cells and macronucleoli are proposed as being characteristic of PEComa,²⁰ their utility in distinguishing PEComa from uterine SMTs has not been validated. While classical spindled uterine LMS is a straightforward diagnosis in most cases, purely epithelioid LMS (rare) and, more commonly, mixed spindled and epithelioid LMS frequently pose diagnostic dilemmas due to their histopathological overlap with PEComas. As a result, there is variation between pathologists in the diagnosis of PEComa.

Secondly, criteria for malignancy in uterine LMS are well established, but much less so for PEComa. As discussed, the prognostic system for PEComa is in evolution as it is based on retrospective analyses of small tumour cohorts.^{20, 53} A uterine tumour on the morphologic spectrum between SMT and PEComa which demonstrates features such as infiltrative margin and mitotic count >2/10 HPF may be labelled as benign or malignant, according to the classification of the tumor as a SMT or PEComa, respectively. This has major implications for the patient in terms of the risk of overtreatment, inappropriate treatment (eg mTOR pathway inhibition) and psychological morbidity.

Thirdly, there is little available molecular data. While several small studies of both TSC-associated and sporadic renal AML have confirmed the importance of TSC2 loss-of-function, it has been shown in only 3 uterine PEComas.^{39, 40}

Four patients with gynaecological PEComa have been reported to have received mTOR inhibitors (sirolimus and temsirolimus);^{69, 78, 100} follow up is available on 2 patients, who died of their disease, at 9 and 10 months respectively. In none of these four cases was LOH or mutation of TSC2 demonstrated, nor was activation of the mTOR pathway confirmed. In our opinion, due to inter-pathologist variation and uncertainty in the diagnosis of uterine PEComa, all tumours accepted into clinical trials of mTOR pathway inhibitors should have molecular analysis to confirm loss of TSC2 and/or loss-of-function of tuberin with mTOR pathway activation.

What is the practicing pathologist to do when faced with a mixed spindled/epithelioid gynaecological tract tumour with mixed myoid and melanocytic marker expression? Fadare⁹⁹ proposed that morphologically-conventional SMTs be labelled as such, even if they focally express melanocytic markers (this should be noted in the report), while classical PEComa should also be diagnosed as such. He proposes that non-classical epithelioid mesenchymal tumours should be labeled as epithelioid tumours of uncertain malignant potential (UMP). In our opinion, it would be helpful to include a note in the pathology report explaining the basis for diagnostic uncertainty when using this term. For PEComas, the use of the Folpe-modified and Schoolmeester criteria may provide additional prognostic information to aid patient management. While these guidelines may help in the majority of cases, the ultimate question remains as to what constitutes a PEComa of the gynaecological tract outside of the setting of TSC, and how it can be reproducibly differentiated from SMTs. It is likely that molecular genetic studies will give us greater insight into the nature of gynaecological tract PEComa and its relationship to uterine SMTs, and help resolve this ongoing diagnostic dilemma.

Figure 1.

Morphologic features of uterine PEComa. A: Sheets of epithelioid cells without intervening stroma. B: Cells with abundant eosinophilic, fibrillary cytoplasm, prominent nucleoli and occasional nuclear pseudoinclusions. C & D: Perivascular cuffing by tumor cells.

Figure 2.

Malignant PEComa of uterus. A: Pleomorphic tumor with necrosis (upper left). B: Multinucleate tumor cells with macronucleoli.