PEComas of the kidney and of the genitourinary tract

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Available online at www.sciencedirect.com

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PEComas of the kidney and of the genitourinary tract Guido Martignoni, MDa,b,n, Maurizio Pea, MDc, Claudia Zampini, MDa, Matteo Brunelli, MDa, Diego Segala, MDb, Giuseppe Zamboni, MDa,d, Franco Bonetti, MDa a

Department of Pathology and Diagnostics, University of Verona, P.Le L.A. Scuro n. 10, Verona 37134, Italy Department of Pathology, Pederzoli Hospital, Peschiera, Verona, Italy c Department of Pathology, Orlandi Hospital, Bussolengo, Verona, Italy d Department of Pathology, Sacro Cuore Hospital, Negrar, Verona, Italy b

article info

abstract

Keywords:

PEComas are mesenchymal tumors composed of histologically and immunohistochemi-

Pecoma

cally distinctive perivascular epithelioid cells that are characterized by the coexpression of

HMB45

muscle and melanogenetic markers. This group of lesions includes angiomyolipoma, clear

Cathepsin-k

cell “sugar” tumor of the lung and extrapulmonary sites, lymphangioleiomyomatosis, clear

mTOR

cell myomelanocytic tumor of the falciform ligament/ligamentum teres, and rare clear cell tumors of other anatomical sites. In the genitourinary tract, PEComas have been described in the kidney, bladder, prostate, testis, and urethra. Although most PEComas behave as benign tumors, some are potentially malignant, and criteria for malignancy have been suggested for both and renal and extrarenal lesions. Recently, the expression of cathepsin K has been demonstrated in a large number of PEComas and has been proposed as a relatively specific marker to distinguish these proliferations from the majority of human cancers. In addition, a distinctive subset of PEComas harboring TFE3 gene fusions has been reported, giving rise to a possible relationship between them and MiTF/TFE family translocation renal cell carcinomas. The genetic alterations of tuberous sclerosis complex that promote activation of the mTOR pathway have been identified in PEComas. Therapy with mTORC1 inhibitors has been shown to be effective in some cases. & 2015 Elsevier Inc. All rights reserved.

Introduction Perivascular epithelioid cells (PECs) show unique morphologic, immunohistochemical, ultrastructural, and genetic characteristics and are the defining cell type of a group of neoplasms including angiomyolipoma (AML), clear cell “sugar” tumor of the lung and extrapulmonary sites, lymphangioleiomyomatosis, clear Source of funding: Department of Pathology and Diagnostics. n Corresponding author. E-mail address: [email protected] (G. Martignoni). http://dx.doi.org/10.1053/j.semdp.2015.02.006 0740-2570/& 2015 Elsevier Inc. All rights reserved.

cell myomelanocytic tumor of the falciform ligament/ ligamentum teres, and rare clear cell tumors of other anatomical sites. PECs typically have an epithelioid appearance with a clear to granular cytoplasm; a round to oval, centrally located nucleus; an inconspicuous nucleolus; and a typical perivascular location.1 At present, PECs have no known nonneoplastic counterpart.

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PECs co-express contractile proteins, mainly alpha-smooth muscle actin (alpha-SMA); melanocytic markers including microphthalmia-associated transcription factor (MiTF), gp 100 (HMB45), HMSA-1, and MelanA/Mart1;2,3 and estrogen and progesterone receptors, while immunoreactivity for vimentin is usually negative to inconspicuous. Ultrastructurally, PECs contain microfilament bundles with electron-dense condensation, numerous mitochondria, and membrane-bound dense granules.4,5 This cell type can modify its morphological and immunophenotypical appearance to show features of muscle with a spindle shape and a stronger positivity for actin than for HMB45, or it can have more epithelioid appearance with strong expression of HMB45 and a scanty, if any, reaction for actin. Cells may also become vacuolated, acquiring the features of an adipocyte. Progesterone receptor positivity can be seen in PECs with spindle morphology, suggesting a possible role in this form of morphologic transformation.6 Loss of chromosome 16p and TSC2 mutations have been demonstrated in PECs.7 In 2002, the World Health Organization defined PEComa as “a mesenchymal tumor composed of histologically and immunohistochemically distinctive perivascular epithelioid cells.”8 Nevertheless, we would recommend, for clarity of understanding that, the traditional terminology for some of these tumors continue in usage (i.e., AML and pulmonary lymphangioleiomyomatosis). We make this recommendation as well-established names serve to identify the clinical and morphological characteristics of these specific tumor types and are familiar to both clinicians and pathologists alike.9,10 Despite this, the use of the term PEComa over the past 20 years has led to an understanding of the morphological and immunohistochemical features of this tumor group, resulting in an evolution in our concepts regarding their pathogenesis and behavior. Initial studies indicated that some of the tumors within this group were potentially malignant. An important study that did suggest a malignant potential for these tumors was that by Folpe et al., who, in 2005, evaluated a series of uterine and extrauterine PEComas, suggesting criteria for malignancy that included tumor size 45 cm, infiltrative growth pattern, high nuclear grade, necrosis or vascular invasion, and mitotic activity 41/50 HPF. They determined that tumors could be grouped into 1 of 3 categories of benign, uncertain malignant potential, and malignant based on the presence of none, 1, or 2 or more of these 6 criteria, respectively.11 Cathepsin K, a papain-like cysteine protease,12 is the target of the MiTF transcription factor family and has recently been found to be highly expressed in pulmonary lymphangioleiomyomatosis,13 in the entire spectrum of PEC lesions of the kidney,14 and in many other extrarenal PEComas, including those arising in the lung, vertex subcutaneous tissue, uterus, abdominal wall, and liver.15 In these studies, cathepsin K has been demonstrated to be more useful than other commonly used immunomarkers for diagnostic purposes and specifically for distinguishing PEComas from the majority of human cancers. MiTF is 1 of 4 members of the microphthalmia-associated transcription factor family, which also includes TFEB and TFE3, to be overexpressed in non-PEComa tumors, including melanoma, clear cell sarcoma, alveolar soft part sarcoma, and

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translocation-associated renal cell carcinoma. This latter group of tumors, unlike other renal carcinomas, has also been found to express cathepsin K.16 These data and the discovery of a distinctive subset of PEComas harboring TFE3 gene fusions are intriguing findings that have led to speculation regarding a possible relationship between these entities. PEComas are related to the tuberous sclerosis complex (TSC) or, more specifically, to the genetic alteration of TSC, an autosomal dominant genetic disorder resulting from inactivating losses of TSC1 (9q34) or TSC2 (16p13.3) genes.17,18 This is characterized by mental retardation, seizures, and the development of neoplasms such as AML, subependymal giant cell tumors, cutaneous angiofibromas, cardiac rhabdomyomas, lymphangioleiomyomatosis and, pulmonary multifocal micronodular hyperplasia. Similar TSC gene alterations have been demonstrated in a significant number of PEComas, occurring both within the TSC and in sporadic cases. TSC genes play an important role in the regulation of the mammalian target of rapamycin (mTOR) pathway.19 TSC1 and TSC2 genes encode proteins that form a complex (TSC1/ TSC2) that functions to negatively regulate mammalian target of rapamycin complex1 (mTORC1).20 Thus, when the TSC1/TSC2 complex is disrupted, mTORC1 is inappropriately activated, and this plays a critical role in the regulation of protein translation and cell growth.21 For this reason, mTOR inhibitors have been proposed as a potential therapeutic option for PEC lesions.22-24 In the genitourinary tract, PEComas have been described as occurring within the kidney, bladder, prostate, testis, and urethra.

Kidney PEComas of the kidney include classic AML, microscopic AML (so-called microhamartoma), intraglomerular lesions, AML with epithelial cysts (AMLEC), oncocytoma-like AML, lymphangiomyomatosis of the renal sinus, and epithelioid AML. Classic AML is the most common mesenchymal tumor of the kidney. It is composed of a variable mixture of adipose tissue and spindle and epithelioid smooth muscle cells with abnormal thick-walled blood vessels (Figs. 1 and 2). AML highlights the capacity of PECs to modulate its morphology.25,26 It was initially viewed as a hamartoma rather than a true neoplasm, but the clonal nature of the tumor is now well established.27-29 In patients with TSC, renal AML is found in both females and males in the third and fourth decades of life. These tumors are usually asymptomatic, bilateral, small, and multifocal. Sporadic AMLs occur in older patients in the fourth to sixth decades of life, with a female predominance. They are usually solitary, unilateral, and larger than those associated with TSC.30 Classic AML is designated lipoma-like or leiomyoma-like AML if adipose or a spindle smooth muscle component predominates. Classic AML has a benign outcome. Multifocality and regional lymph node involvement can occur; however, this represents a multifocal growth pattern rather than metastatic disease.31,32 Three cases of sarcomatous transformation in

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Fig. 1 – Classic angiomyolipoma. The tumour is composed of a mixture of adipose tissue, smooth muscle cells, and abnormal thick-walled blood vessels. sporadic AML have been reported, while similar tumors have not been described as occurring in individuals with TSC.33,34 Both inherited and sporadic AMLs frequently demonstrate loss of heterozygosity (LOH) of chromosome 16p (TSC2) but not of the TSC1 gene.35,36 Recently, it has been found that sporadic renal AML frequently has mutations in TSC2, but not in TSC1 or RHEB, and further, that they have no other genomic changes as a group. This would indicate that TSC2 inactivation by mutation is a consistent and likely necessary genetic event in the pathogenesis of most of these tumors. It should be noted, however, that chromosomal translocations and gene fusion events have not been fully assessed.37 Microscopic AMLs (so-called microhamartomas) are small nodules often seen in kidneys containing one or more AMLs. They are not homogeneous in appearance and display all the heterogeneous histopathological features of AML, although they do not contain thick-walled blood vessels.1,38 Intraglomerular lesions with similar features of AML have been reported in patients with and without tuberous sclerosis and in the TSC2/PKD1 contiguous gene syndrome, a disease associated with a deletion disrupting both TSC2 and PKD1 (autosomal dominant polycystic disease gene).39 AML with epithelial cysts (AMLEC) is a recently identified variant of AML40-46 (Fig. 3). These lesions are characterized by

Fig. 2 – Classic angiomyolipoma. HMB45 immunoexpression.

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Fig. 3 – Angiomyolipoma with epithelial cysts (AMLEC). The tumour is composed of a mix of solid and cystic architecture. a mixed, solid, and cystic architecture being composed of epithelial cysts lined by cuboidal to hobnail cells. The tumors show a positive immunohistochemical reaction to cytokeratin, PAX2, and PAX8.42 There is also a compact subepithelial “cambium-like” layer of stromal cells that is positive for HMB45 (Fig. 4), Melan-A, cathepsin K (Fig. 5), CD10, and estrogen and progesterone receptors. In addition, the tumor has a solid extracystic component with the morphology of a smooth muscle-predominant AML associated with thickened and irregular blood vessels. Cells are positive for HMB45, estrogen and progesterone receptors, and smooth muscle actin and desmin. The subepithelial “cambium-like” layer is viewed as a manifestation of müllerian differentiation of PECs, and the epithelial cysts represent entrapped renal tubular epithelium. These entrapped cystically dilated renal tubules commonly herniate beyond the renal capsule. Of the 24 cases reported to date, only 2 had a history of TSC.41,42 Oncocytoma-like AMLs are rare tumors consisting of a homogeneous population of HMB45-positive polygonal cells with strongly eosinophilic cytoplasm. They have been described in patients with and without TSC. Recognition of this variant is important, as oncocytomas co-existing in the

Fig. 4 – Angiomyolipoma with epithelial cysts (AMLEC). HMB45 immunoexpression.

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Fig. 5 – Angiomyolipoma with epithelial cysts (AMLEC). Cathepsin-k immunoexpression. same kidney as AMLs have been reported on several occasions, and in patients with TSC, oncocytomas seem to occur more frequently than in the general population.47 Lymphangiomyomatosis of the renal sinus is a plaque-like mass that develops in the wall of the renal pelvis. All 3 cases reported to date also had renal AMLs. In these patients, postmortem examination of the lungs revealed pulmonary lymphangiomyomatosis in one case.39,48 Epithelioid AML (pure epithelioid PEComa of the kidney) is a rare variant of AML, which, by definition, should consist of at least 80–95% of epithelioid cells49-87 (Table 1; Fig. 6). In a recent study, He et al. identified 20 of these tumors among 437 (4.6%) AMLs.83 As for classic AML, epithelioid AML has been described in patients with or without evidence of TSC, as well as in the TSC2/PKD1 contiguous gene syndrome. LOH of TSC2 has been reported in occasional cases of sporadic epithelioid AML.39,88–91 Epithelioid AML can show 2 different morphological patterns. Some tumors are characterized by the presence of cells arranged in cohesive nests, broad alveoli, and compartmentalized sheets separated by thin vascular-rich septa. The cells are usually large and polygonal, with a dense, deeply eosinophilic cytoplasm and with atypical nuclei, having prominent nucleoli. Although the cytoplasm is often eosinophilic, occasional cells have clearing toward the periphery of the cells, while intranuclear inclusions are frequently seen. Some of these tumors have 2 or more mitoses/50 HPF, but the majority have no mitoses or at most 1 mitotic figure/50 HPF. The combination of prominent nucleoli with intranuclear inclusions, in large discohesive cells with eosinophilic cytoplasm, imparts a ganglion cell-like appearance to the tumor cells. A prominent capillary network can be present, and tumors with prominent clear cells can be mistaken for a clear cell renal cell carcinoma. Multinucleate giant cells with morphology similar to the atypical mononuclear cells of the tumor are frequently present. Variable amounts of necrosis and hemorrhage can be present in these tumors, and the overall pattern has been described as a carcinoma-like growth (Fig. 7). The other pattern of epithelioid AML consists of epithelioid and plump spindled cells arranged in diffuse and

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densely packed sheets (Fig. 8). In these neoplasms, compartmentalization is conspicuously absent. Overall, these tumors have greater homogeneity of growth pattern when compared to carcinoma-like tumors. The tumor cells are relatively uniform epithelioid cells with clear-to-granular, feathery eosinophilic cytoplasm (Fig. 9). In a few cases, the cells have been found to have clearer cytoplasm. The cell size is smaller and the nuclei are relatively homogeneous and lack atypia throughout. The nuclear chromatin is vesicular and there are prominent nucleoli. Intranuclear inclusions are infrequently seen in this group of tumors. Multinucleate giant cells scattered singly or in groups, with morphology similar to the background uniform cells, can be present. These neoplasms usually have no mitotic activity. This pattern has been designated epithelioid and plump spindled cells with diffuse growth. Occasional neoplasms can show a combined carcinoma-like and diffuse growth pattern.72 The differential diagnosis of epithelioid AML is relatively large and includes clear cell renal cell carcinoma, chromophobe renal cell carcinoma, oncocytoma, renal cell carcinoma with sarcomatoid transformation, translocation-associated renal cell carcinoma, and metastasis from malignant melanoma.92-97 The approach to diagnosis usually involves a high index of suspicion for pure epithelioid PEComa when an unusual renal epithelial-appearing neoplasm is found, particularly in individuals below the age of 50 years. Occasionally, careful examination may show focal microscopic areas of adipocyte differentiation, suggesting the correct diagnosis. The presence of carcinoma-like growth, or epithelioid and plump spindled cells with a diffuse growth pattern, discohesive sheets of ganglion-like cells, and numerous giant cells should further raise suspicion for epithelioid AML. The diagnosis may be confirmed by an appropriate immunohistochemical panel including cytokeratins and S100 protein (negative), 1 or 2 melanogenic markers (HMB45, microphthalmia transcription factor, and Melan-A), cathepsin K (Fig. 10), and a smooth muscle marker (smooth muscle actin and muscle-specific actin). In occasional cases of epithelioid AML, molecular and genetic changes, in particular p53 mutation, have been investigated.49,98,99 A p53 missense mutation was described in the case report by Kawaguchi et al.98 This contrasts with the finding of no significant p53 mutation in 2 cases reported by Ma et al.99 and by Sato et al.49, who concluded that p53 mutations are not always associated with malignant transformation in epithelioid AML, despite immunoreactivity for p53. Recently, Bing et al. studied p53 expression and gene mutation in 8 pure epithelioid PEComas and in a group of classic AMLs using immunohistochemistry, single-strand conformation polymorphism, and direct sequencing investigating point mutations of exons 5–9.78 They found that pure epithelioid PEComas usually showed stronger p53 expression when compared with classic AMLs. They showed that pure epithelioid PEComas, but not classic AMLs, harbored p53 mutations at a genetic/molecular level in some cases. Independently, Li et al.77 confirmed a missense mutation of the p53 gene in a malignant renal epithelioid AML in a patient with pulmonary metastases. They concluded that a p53 gene

144

Table 1 – Reported cases of renal epithelioid angiomyolipomas (pure epithelioid PEComas) in the literature from 2008 to 2014. ws

Reference

Diagnosis

Sex/age

Size (cm)

Border

% Epithelioid

Nuclear grade

component

and cellularity

Mitosis

Necrosis

TSC

Outcome/

Comments

follow-up (months)

2008

Matsuyama

EAML

Sclerosing

M/36

20

I

495%

Severe

5/10 HPF

Present

Yes

Died 24 months after the

Invasion of the inferior vena cava; metastatic lesions

diagnosis

in the lung, liver,

(autopsy

diaphragm, and

F/56

2

W

n.a.

Mild

n.a.

n.a.

No

case) ANED
10

et al.50

EAML

Matsuyama

Sclerosing

F/44

13
7

W

n.a.

Mild

n.a.

n.a.

No

n.a.

et al.50 Moudouni

EAML EAML

F/31

10

n.a.

40–50%

Severe

n.a.

n.a.

Yes

n.a.

Bilateral; thrombus in the inferior vena cava; and

D

retroperitoneal lymph

I A G N O S T I C

et al.51

mesentery.

node metastases. EAML

F/79

3.3

W

Almost 95%

n.a.

2008

Limaiem et al.53

EAML

M/38

9

W

n.a.

2009

Kato et al.54

EAML

M/28

12
10
8

W

100%

Kato et al.54 Kato et al.54

EAML EAML

F/61 F/34

3.5
3.5 7
7

W W

Berglund et al.55

14/55 Cases of

n.a.

0.6–19 (All 55

2009

ANED
3

n.a.

n.a

Mild

o1/10 HPF

n.a.

n.a.

ANED
12

Severe

n.a.

n.a.

Yes

n.a.

100% 100%

Moderate Moderate

n.a. n.a.

n.a. n.a.

No No

ANED
24 ANED
24

n.a.

n.a.

n.a.

n.a.

n.a.

n.a.

n.a.

Mean ¼ 8.6 1–30

n.a.

10–100% Mean ¼ 51%

Diffuse: 6

Mean ¼ 1.1/

Present: 4

No: 11 Yes: 4

Mean ¼ 61 ANED
1–237

3
3
2.5

W

n.a.

Mild

1/10 HPF

n.a.

Probably

ANED
3 n.a.

EAML (25%)

cases) M:F ¼1:6.5 Mean ¼ 38.6

2009

Aydin et al.56

15 Cases of

2009

Fukunaga

Pigmented

2009

et al.57 Ooi et al.58

PEComa EAML

M/34

12
15

n.a.

n.a.

Variable

n.a.

n.a.

yes No

Ooi et al.58

EAML

F/19

6.5
5.5
4

n.a.

n.a.

n.a.

n.a.

n.a.

Yes

n.a.

Arrabal-Polo et al.59

EAML

F/47

4
3
3.5

n.a.

n.a.

Severe

High atypical

necrotic areas

No

ANED
12

EAML

Invasion renal vein. Invasion renal vein.

years F/57

10 HPF

Multiple hepatic metastasis at diagnosis.

2009

2009

Kato et al.60

EAML

M/54

15

n.a.

n.a.

Moderate-to-

2009

Astigueta

EAML

M/12

8
7
2.3

I

Predominant

mitotic

hemorrhage causing

activity

hypovolemic shock

n.a.

n.a.

No

n.a.

Severe

0–5/10 HPF

Present

Yes

n.a.

n.a.

n.a.

Present: 1

Yes: 2

ANED
1–80

severe et al.61

(% n.a.) F:M ¼ 1:1.5

2009

Tsai et al.62

5 Cases of EAML between 2000 and 2009

Mean ¼ 39.6 years

2.6–7.3

n.a.

n.a.

Debut: spontaneous retroperitoneal

(Wünderlich Syndrome). A classic AML

32 (2015) 140–159

1–2/10 HPF

A T H O L O G Y

Zanelli et al.52

P

2008

E M I N A R S I N

2008

Sato et al.

S

2008

49

2010

Peng et al.63

EAML

M/14

10
12

I

100%

Severe

420/50 HPF

n.a.

No

Died of bleeding

The tumor embraced the

9 months after surgery

right common iliac vessels to right internal iliac vessels. Unresectable: the patient underwent partial masswall resection and intratumoral decompression.

2010

Ingle et al.64

EAML with

M/61

8.5
7.5
6.5

W

atypical nuclear features 2010

Chen et al.65

EAML

Predominant

Moderate

2/10 HPF

(% n.a.) M/27

15.5
13

n.a.

Predominant

Areas of

n.a.

n.a.

necrosis with calcification Severe

n.a.

n.a.

Hilar node involved in contiguity.

No

(% n.a.)

Died 7 months

Debut: multiple masses in

after surgery

both the kidneys; bilateral

large mass arising in the left retroperitoneum and multiple lesions in the liver. 9 Cases of malignant

Mean ¼ 57.1 years

3–17.7

n.a.

Mean ¼ 98%

90%

2.9/10 HPF

Present: 7

n.a.

Progression: 29 (6–72)

I A G N O S T I C

Brimo et al.66

Mean ¼ 11.3

D

2010

M:F ¼ 1:0.8

EAML M:F ¼ 6.5:1

Mean ¼ 7

Brimo et al.66

21 Cases of benign EAML

Mean ¼ 38.6 years

1–23

n.a.

Mean ¼ 63%

50–60%

0.8/10 HPF

Present: 5

n.a

ANED
6–156

Nepple et al.67

EAML

M/53

35

W

Predominant

n.a.

n.a.

n.a.

n.a.

ANED
5

Predominant (% n.a.)

n.a.

n.a.

Piecemeal necrosis

n.a.

ANED
24

Debut: intra-abdominal lymph node metastasis.

Predominant

n.a.

n.a.

Central necrosis

n.a.

ANED
2

Tumor thrombus in the

P

(% n.a.) 2011

Cui et al.68

EAML

F/47

38
29
16

n.a.

2011

Luo et al.69

EAML

F/27

3
4
4

W

ipsilateralrenal vein extending into the vena cava.

2011

M/15

10

I

n.a.

Moderate

n.a.

n.a.

n.a.

n.a.

Debut: renal mass indenting

Rasalkar DD

Malignant

et al.70

pigmented clear

the right lobe of liver;

cell epithelioid cell tumor

hepatic masses and enlarged nodes present at the porta, celiac, aortocaval, and retrocaval regions, compatible with liver and nodal metastases. Multiple

32 (2015) 140–159

(% n.a.)

A T H O L O G Y

2010

E M I N A R S I N

performed; 3 months later, a

S

renal AML and a left nephrectomy was

thoracic and skin metastatic deposits; only biopsy of hepatic metastases. 2011

Wen et al.71

EAML

M/49 M:F ¼ 1:1

Mean ¼ 11.9

2011

Nese et al.72

41 Cases of

mean: 38.6

2012

Ohe et al.73

EAML EAML

2012

Mak et al.74

EAML

5.5
4
5

W

n.a.

Severe

n.a.

Focal necrosis

No

ANED
3

2–37

n.a.

Almost 100%

n.a.

0–13/50 HPF

Present: 24

Yes: 9

ANED
2–240

years F/57

2.5

W

n.a.

Mild-Moderate

n.a.

n.a.

No

ANED
18

F/68

8
7.5
6.4

W

Predominant

Mild

No

n.a.

No

n.a.

Severe

5/10 HPF

present

No

ANED
12

(% n.a.) 2012

Cao et al.75

EAML

M/52

13.5
11
7

I

n.a.

145

A clear cell renal cell carcinoma.

ws

Reference

Diagnosis

Sex/age

Size (cm)

Border

% Epithelioid

Nuclear grade

component

and cellularity

Mitosis

Necrosis

TSC

Outcome/

Comments

146

Table 1 (continued) ) follow-up (months) 2012

76

Yang et al.

Monotypic

F/21

2.5

n.a.

n.a.

n.a.

n.a.

n.a.

n.a

ANED
3

And a right retroperitoneal

F/55

7.5
7

n.a.

n.a.

Severe

Frequently

Frequently seen

No

n.a.

Pulmonary metastases;

PEComa 2012

Li et al.77

Malignant EAML

schwannoma. seen

diagnosis of renal cell carcinoma (RCC) was made without immunohistochemical examination.

2012

M/36 M/33

13.0 and 2.2 6

n.a. n.a.

n.a. n.a.

Moderate Mild

1/50 HPF No

Present No

No No

ANED
34 n.a.

Bing et al.78

EAML

M/56

n.a.

n.a.

n.a.

Severe

42/50 HPF

Present

No

ANED
105

Bing et al.78

EAML

M/36

27

n.a.

n.a.

Severe

2/50 HPF

Present

Yes

Died of complications after 3 months

n.a.

n.a.

Moderate

95/50 HPF

Present

Yes

n.a.

Chang et al.79

Heavily pigmented

F/37

3.5

W

n.a.

Large cells and pleomorph-

Rare mitotic figures

n.a.

No

ANED
12

n.a.

n.a.

Yes: 2 (Died

1 Case:

PEComa

ism only occasionally detected

2013

Xu et al.80

10 Cases of

M:F ¼ 1:0.4

Mean ¼ 8.2

Mean ¼ 43.6

2–15

n.a.

n.a.

n.a.

EAML

within

recurrence; 3

follow-up)

cases: metastasis (follow-up: 1–

Shrewsberry et al.81

EAML

F/24

9.5

n.a.

n.a.

n.a.

n.a.

n.a.

No

n.a.

2013

Esheba Gel

EAML

F/56

5.4

n.a.

Predominant

Focal nuclear

1/10 HPF

n.a.

n.a.

n.a.

et al.82

2013 2013

(% n.a.)

Esheba Gel et al.82

EAML

M:F ¼ 9:11

Mean ¼ 8.7

He et al.83

20 Cases of

Mean ¼ 49.7

1–25

EAML 1 Out of 41

years n.a.

n.a.

M:F ¼ 1:8 Mean ¼ 42

Mean ¼ 7.7 1.4–22

84

Mehta et al.

F/48

5.6

atypia

I

Predominant (% n.a.)

Focal nuclear atypia

1/10 HPF

Present

n.a.

n.a.

n.a.

80–100%

Present: 20 80% of

1–5/10 HPF

Present: 10

n.a.

ANED
1–356

n.a.

n.a.

the tumor n.a.

n.a.

n.a.

n.a

n.a.

I: 2

Predominant

Nuclear

o1/10 HPF

Present: 2

Present: 2

ANED
1–45

0/10 HPF

Absent

n.a.

ANED
36

cases of EAML 2013

Froemming

9 Cases of EAML

et al.85

years

cases

(% n.a.)

pleomorphism evident, and in some cases, marked nuclear enlargement with macronucleoli

2013

Chen et al.86

Minimally fatcontained

M/40

6
6
5.2

W

30%

No atypical mitotic figures

32 (2015) 140–159

53 months) 2013

A T H O L O G Y

8.5

P

F/18

I A G N O S T I C

EAML

D

2012

Bing et al.78

E M I N A R S I N

EAML EAML

S

Bing et al.78 Bing et al.78

disease. Liver lesions were biopsied.

n.a.: not available; EAML: epithelioid angiomyolipoma; ANED: alive, not evidence of disease; W: well delimited; I: infiltrative; TSC: Tuberous Sclerosis Complex; HPF: high-power field.

and breast

no evidence of local

completely resected, with

metastatic disease? renal,

gastric, ileal, and mammarian tumors were stomach, ileum, liver,

in the kidney,

PEComa located Crocetti et al.87 2014

angiomyolipoma

F/48

n.a.

I

n.a.

n.a.

n.a.

n.a.

n.a.

n.a.

Multifocal tumors or

S

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I A G N O S T I C

P

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147

Fig. 6 – Epithelioid AML (pure epithelioid PEComa of the kidney), carcinoma-like growth. A tumour characterized by the presence of cells arranged in cohesive nests, broad alveoli, and compartmentalized sheets separated by thin vascular-rich septa. mutation might play a role in the malignant transformation of these tumors. Recently, a novel relationship between the role of TSC2/ mTORC1 and E-cadherin in epithelial to mesenchymal transition was reported by Barnes et al.100 They concluded that loss of the TSC2 gene results in the retention of E-cadherin in the Golgi apparatus. This leads to a paucity of membrane Ecadherin through activation of the mTORC1 pathway, which promotes epithelial to mesenchymal transition. Although Ecadherin expression was not investigated in this study, Wang et al. subsequently demonstrated immunoexpression of Ecadherin in 98% of AMLs in their study and further showed stronger membrane immunoreactivity in epithelioid cells than in spindle-shaped cells.101 Despite dramatic advances in our appreciation of the morphologic spectrum and molecular characteristics of renal epithelioid AML (pure epithelioid PEComa) prognostic factors are largely undetermined. These tumors were defined in the 2004 World Health Organization Classification as a potentially malignant mesenchymal neoplasm characterized by proliferation of predominantly epithelioid cells and closely related to triphasic (classic) AML.92 Despite this, there is an inconsistency in the literature for nomenclature and defining criteria. This, coupled with both short-term or incomplete follow-up data, has contributed to a limited understanding of the determinants of disease progression.72 The percentage of epithelioid cells that is required to make a diagnosis of epithelioid AML has not been defined, and several published studies have not documented the percentage of epithelioid component of the tumors in their series. On the basis of a literature review, the percentage of the epithelioid component of tumors, wherever specified, ranged from 10% to 100%, and the presence of at least 20% of cells showing an epithelioid morphology was associated with tumor recurrence, metastasis, or death.33,56,102,103 Aydin et al.56 defined epithelioid AML as tumors in which there was at least a 10% epithelioid component. Utilizing this definition, the rate of epithelioid AML in a review of all AMLs from a single institution was 7.7% (15 of 194 cases). In this

148

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Fig. 7 – Epithelioid AML (pure epithelioid PEComa of the kidney), carcinoma-like growth. The cells of the tumor are large and polygonal with a dense, deeply eosinophilic cytoplasm and with atypical nuclei, having prominent nucleoli.

Fig. 9 – Epithelioid AML (pure epithelioid PEComa of the kidney). Epithelioid and plump spindled cells arranged in a diffuse and densely packed sheets. The tumour cells are relatively uniform with clear-to-granular feathery eosinophilic cytoplasm.

study, there were 3 cases with 480% epithelioid morphology. Although there were 2 pure epithelioid PEComas in the series, no case showed metastasis or recurrence (mean follow-up ¼ 5.1 years). In this study, however, no detailed information relating to the follow-up of cases with pure or predominant epithelioid histology was reported. Meta-analysis of studies to date, excluding that by Aydin et al.,56 shows the presence of an epithelioid component in AML to be an adverse prognostic sign. In the tumors in which an epithelioid histology was not predominant or pure, prognostic factors contributing to disease progression are uncertain. There are reports of only 5 cases with triphasic and epithelioid AML morphology within the same tumor that have been associated with disease progression. Two of these were cases of sarcomatous (leiomyosarcoma and liposarcoma) transformation rather than being bona fide renal epithelioid PEComas.34,104 In 2 other reports, the percentage of epithelioid cells in each tumor is not specified, but it is noted that the tumors contained areas of classical AML.102,103 In a separate case report by Cibas et al.,33 a patient with multiple bilateral AML, with 1 resected tumor containing 30% epithelioid morphology, had liver metastasis. Experience

from these 5 cases suggests that tumors with sarcomatous transformation and patients with multiple AML and epithelioid PEComa (suggestive of TSC) have a potential for disease progression. Belanger et al.105 reported 3 cases of sarcomatoid transformation in epithelioid PEComa in a retrospective review of sarcomatoid renal cell carcinoma and sarcomas of the kidney from their archives. Nese et al.72 suggested that pure epithelioid PEComas with the presence of TSC and/or concurrent AML, tumor size 47 cm, carcinoma-like morphologic pattern, involvement of perinephric fat and/or renal vein, and the presence of necrosis were associated with disease progression, recurrence, metastasis, or death. The authors developed a prognostic parameter-based risk stratification model and divided tumors into low-rick (0–1 parameters), intermediaterisk (2–3 parameters), and high-risk (4 or more parameters) categories. There was a 15%, 64%, and 100% risk for disease progression among these groups, correspondingly, while for patients with 3 or more adverse parameters, 80% had disease progression. Data from a recent study of 6 cases where the epithelioid component varied from 70% to 100%, when combined with that derived from a literature review, showed that tumors with an unfavorable outcome exhibited marked

Fig. 8 – Epithelioid AML (pure epithelioid PEComa of the kidney). Epithelioid and plump spindled cells arranged in a diffuse and densely packed sheets.

Fig. 10 – Epithelioid AML (pure epithelioid PEComa of the kidney). Cathepsin-k immunoexpression.

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cytologic atypia and extensive tumor necrosis.106 In a further recent study of 40 cases of “renal epithelioid AML with atypia,” where the epithelioid component ranged from 5% to 90%, older age, large tumor size, higher percentage of epithelioid component, severe atypia, higher percentage of atypical cells, higher mitotic count, necrosis, lymphovascular invasion, and renal vein invasion were associated with malignancy.66 These studies reinforce the concept that epithelioid PEComas that do not show pure epithelioid histology do have malignant potential and that this seems to increase with an increase in the percentage of the epithelioid component.

Bladder Until now, just 17 cases of PEComa of the bladder have been reported in the English literature.107-121 Despite this, the bladder remains the second most common site of origin of this neoplasm in the genitourinary tract. Nine of these tumors occurred in females and 8 in males, with the age of the patients ranging from 16 to 55 years. None of the patients reported to date have shown the stigmata of TSC (Table 2). PEComas have been described as arising from any region of the bladder wall without any specific anatomical preference (Fig. 11). All but one of these tumors119 were solitary lesions, although multifocal lesions have been documented in other locations.122 Tumors ranged in size from 3 to 9.2 cm. Eight of 14 cases exhibited an infiltrative growth pattern, whereas the remaining 6 were well-demarcated lesions. Microscopically, all tumors showed the classical features of PEComas, with admixture of epithelioid and spindled cells arranged radially around blood vessels (Fig. 12). The mitotic activity was low in all cases, ranging from 1 mitosis/50 HPF to 2 mitoses/10 HPF, while the multifocal tumor was o3 mitoses/50 HPF.118 Necrosis was present in 5 of 14 tumors, although the necrosis in one of these cases was attributable to prior embolization.112 Immunohistochemistry showed all lesions to exhibit co-expression of melanocytic and smooth muscle-associated markers. Seven patients with bladder PEComa were surgically treated by partial cystectomy, 6 by transurethral resection, and 3 underwent both the treatments, one of whom had a total cystectomy.114 Five were alive and well, one died of widespread metastatic disease 12 months after diagnosis, and another had recurrence at 6 months from diagnosis. These latter 2 tumors showed positive immunostaining for TFE3 protein and TFE3 rearrangement by fluorescence in situ hybridization.118 In addition to these tumors, a separate report describes a single case in which some features differed from those reported to date in PEComas showing TFE-3 rearrangement and were more in common with those tumors where TFE-3 rearrangement was not present.73,123-126 This tumor contained a substantial component of spindle-shaped cells and showed a positive reaction for smooth muscle actin (Fig. 13) and MiTF (Fig. 14) by immunohistochemistry. This tumor was both the first primary bladder PEComa and the first PEComa with molecular confirmation of TFE3 gene rearrangement to behave aggressively. Over a relatively short time-frame, the patient developed metastases and died.

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149

As noted earlier, Folpe proposed a series of criteria to predict malignancy in AML (size greater than 5 cm, infiltrative growth pattern, mitotic count of more than 1 per 50 highpower fields, pleomorphism, and necrosis).11 It should be emphasized that these criteria are applicable to PEComas other than typical triphasic AML, which may achieve large size, contain foci of necrosis, and show significant pleomorphism, yet behave in a benign manner. Following this classification system, at least 6 of the cases reported until now108-110,112,118,120 (Table 3) should be classified as malignant lesions, but only 2 cases118,120 showed any aggressive behavior, although length of follow-up does remain an issue. Despite this, the behavior of urinary bladder PEComas does seem to be unpredictable, indicating that the investigation of more cases with long-term follow-up is needed. Perivascular epithelioid cell tumors of the bladder consisting primarily of an epithelioid cell type should be carefully distinguished from its various morphologic mimics, some of which may carry very different clinical implications and require aggressive therapy. In particular, this tumor must be differentiated from urothelial carcinoma, epithelioid smooth muscle tumors, invasive prostatic adenocarcinoma, metastatic renal cell carcinoma, paraganglioma, and epithelioid malignant melanoma. In this context, an immunohistochemical panel consisting of antibodies to cytokeratins, S100 protein, smooth muscle actin, desmin, HMB45/Melan-A, MiTF, chromogranin A, and synaptophysin should allow for the discrimination of PEComa from these various mimics.

Prostate, testis, and urethra Until now, just 3 PEComas, one each occurring in the prostate,127 testis,128 and urethra,129 have been reported. In 2003, Pan et al.127 described the only case of malignant PEComa involving the prostate and seminal vesicle reported to date. Histologically, the tumor cells were arranged in solid sheets, with clear-to-granular cytoplasm, distinct cell borders, and round nuclei with occasional nucleoli. A thin vascular stroma was present among the tumor nests. There was mild to moderate nuclear pleomorphism and a low mitotic activity. Coagulative necrosis was present. Immunohistochemically, the tumor was typically positive for HMB-45. Lane et al.128 reported a case of testicular AML diagnosed by microscopic findings without immunohistochemical analysis. Finally, De Dominicis et al.129 described the first case of PEComa, designated a clear cell “sugar” tumor of the urethra. This consisted of epithelioid cells with a “water-clear” cytoplasm containing glycogen and surrounded by thin-walled vascular channels arranged in a nested or alveolar architecture. Immunohistochemically, this tumor was positive for smooth muscle actin and HMB45 (Tables 2 and 3).

Cathepsin K and PEComas Cathepsin K is a lysosomal papain-like cysteine protease, which is selectively expressed in osteoclasts and is responsible for bone resorption and remodeling. Gene encoding for cathepsin K is located at chromosome 1q21. Germ line

150

Table 2 – Reported cases of genitourinary extrarenal PEComas in the literature from 2003 to 2014. Nuclear grade and cellularity

Mitosis

Necrosis

TSC

Treatment

Outcomes/ follow-up (months)

PEComa PEComa

F/33 F/19

4 3

W I

n.a. High

0 Few

No n.a.

No No

Partial cystectomy TURBT

ANED
72 n.a

2006

Pan et al.107 Kalyanasundaram et al.108 Parfitt et al.109

PEComa

M/48

3

I

High

0

Incospicuous

No

ANED
48

2007 2008

Weinreb et al.110 Pianezza et al.111

PEComa CCMMT

M/39 F/24

I, focally I, focally

Yes, focal No

No No

ANED
8 ANED
3

Sukov et al.112

PEComa

M/36

0

Yes, focal

No

Partial cystectomy

ANED
10

Sukov et al.112

PEComa

M/37

n.a.

W

0

No

No

TURBT

ANED
21

Sukov et al.112

PEComa

F/26

5

W

High focal Low to moderate Low to moderate Low to moderate Low

Isolated 1/50 HPF

2009

5 3.4
2.5
1.8 4.8
4
3.5

Partial cystectomyþ partial small bowel resection þ adjuvant INF-α immunotherapy Partial cystectomy Partial cystectomy

0

Yes

No

n.a

2011

Huang et al.113

PEComa

M/23

9.2

W

Low

0

n.a.

No

2011

Chan et al.114

PEComa

M/42

6
5
4

W

No

Kyrou et al.115 Shringarpure et al.116 Yin et al.117 Williamson et al.118

PEComa PEComa

F/44 M/39

2.7 3
3

n.a n.a

o1/50 HPF 0 n.a.

No

2012 2012

Low to moderate n.a. n.a.

No n.a.

No No

Embolisation þ partial cystectomy Tumourectomy þ partial cystectomy TURBT þ partial cystectomy n.a. TURBT

PEComa PEComa

F/16 F/55

3 5

W I

Low Variable

0 2/10 HPF

No Yes, patchy

No No

2013

Ghaida et al.119

PEComa

M/54

3
2.5
1.5

I, focally

1/30 HPF

No

No

2014

Russel et al.120

F/27

No

W

Low

o3/50 HPF o1/10 HPF

Yes, focal

Sarti et al.121

4.2
3.7
3.3 1.5

I

2014

PEComa (multifocal) PEComa

Low to moderate Low

TURBT TURBT þ resection of nodule involving the wall of the sigmoid colon þ palliative sarcoma-directed CHT TURBT þ partial cystectomy TURBT þ cystectomy

No

No

TURBT

Bladder 2003 2005

n.a ANED
30 ANED
3 ANEDx13 DIED of metastatic disease 12 months after diagnosis

ANED
11 Recurrence at 6 months n.a.

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F/31

n.a

A T H O L O G Y

2012 2013

I

P

Border

I A G N O S T I C

Size (cm)

D

Sex/ age

E M I N A R S I N

Diagnosis

S

Reference

Year

n.a.: not available; CCMMT: clear cell myomelanocytic tumour; ANED: alive, not evidence of disease; W: well delimited; I: infiltrative; TURBT: transurethral resection of bladder tumour; CHT: chemotherapy; HPF: high-power field.

ANED
3 Urethral excision Polypoid CCST De Dominicis et al.129

F/15

2.5
2 cm2

n.a.

n.a.

n.a.

No

n.a. Radical orchiectomy No n.a. AML

Testis 2004 Urethra 2009

Lane et al.128

M/56

1.6

n.a.

n.a.

n.a.

Radical prostatectomy þ CHT Prostate 2003

Pan et al.127

PEComa

M/46

8.5
6.5
5.5

W

Low to moderate

Low

Yes

No

Died of metastatic disease 4 years after diagnosis

S

E M I N A R S I N

D

I A G N O S T I C

P

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151

Fig. 11 – PEComa of the bladder wall. mutations in this gene cause sclerosing osteochondrodysplasia pycnodysostosis, a rare autosomal recessive skeletal dysplasia characterized by abnormal bone and tooth development. It has been recently demonstrated that microphthalmia transcription factor (MITF), which activates expression of genes associated with melanin production in cells of melanocytic lineage, also binds to 3 consensus elements in the cathepsin K promoter in osteoclasts, resulting in increased cathepsin K mRNA and protein expression. Based on these findings, Chilosi et al., in 2009,13 investigated pulmonary lymphangiomyomatosis, a member of the family of PEC lesions, for the expression of cathepsin K and demonstrated strong immunostaining in both spindle and epithelioid cells. Subsequently, immunohistochemical expression of cathepsin K was found in 84 renal PEComas lesions, including 5 composed predominantly of fat (lipoma-like AML); 15 almost exclusively composed of spindle-shaped smooth muscle cells

Fig. 12 – PEComa of the bladder. The tumor is composed by an admixture of epithelioid and spindled cells.

152

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P

Fig. 13 – PEComa of the bladder. Smooth muscle actin immunoexpression. (leiomyoma-like AML); 31 common AMLs composed of a mixture of fat, spindle, and epithelioid smooth muscle cells and abnormal thick-walled blood vessels; 15 microscopic AML; 5 intraglomerular lesions; 2 oncocytoma-like AML; 8 epithelioid AML; 2 AML with epithelial cysts; and 1 example of lymphangioleiomyomatosis of the renal sinus. These results demonstrate that cathepsin K is expressed in the entire spectrum of PEC lesions of the kidney and suggest that cathepsin K is potentially a more powerful marker than others commonly used for the identification of renal PEComas. Moreover, the strong, diffuse, and constant immunohistochemical detection of cathepsin K in epithelioid AML and negative reactions for cathepsin K in the common types of renal cell carcinoma suggest the utility of immunohistochemistry for cathepsin K in the differential diagnosis of epithelioid AML and renal cell carcinoma.14 Recently, Rao et al.15 investigated the expression of cathepsin K in extrarenal PEComas, showing that cathepsin K is expressed in a wide spectrum of these tumors from various

Fig. 14 – PEComa of the bladder. MiTF immunoexpression.

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32 (2015) 140–159

anatomical sites including the lung, vertex subcutaneous tissue, uterus, abdominal wall, and liver. The tumors showed a higher percentage of cells with stronger positive reactions for cathepsin K (mean ¼ 91%; range: 80–100%) than for HMB45, Melan-A, and SMA, which while specific, often only exhibit focal or patchy immunoreactivity. In addition, their results suggested that cathepsin K can be used as a relatively specific marker to distinguish PEComas from the majority of human cancers. MiTF, TFE3, TFEB, and TFEC are related members of the same transcription factor subfamily known as MiTF/TFE. All these proteins relate to the same specific target DNA sequences, homodimerize and heterodimerize in all combinations, and have overlapping transcriptional targets. Both TFE3 and TFEB are implicated in gene fusions, resulting from chromosome translocations in 2 recently described subtypes of renal cell carcinoma, which while comprising the majority of pediatric renal cell carcinomas, also occur in adults. The expression of cathepsin K has been investigated in microphthalmia transcription factor/transcription factor E (MiTF/TFE) family translocation renal cell carcinomas,16 13 of 17 (76%) being positive for cathepsin K. All 7 of the renal cell carcinomas bearing the t(6;11) translocation showed strong and diffuse cytoplasmic labeling for cathepsin-K, while among the cytogenetically confirmed Xp11 translocation renal cell carcinomas, 6 out of 10 were positive. None of the 305 other renal cell neoplasms representing the most common renal cell neoplasms subtypes showed positivity. These results suggest that overexpressed native TFEB consistently activates cathepsin K expression as MiTF does but that only some TFE3 fusion proteins do this. Xp11 translocation renal cell carcinomas are a group of neoplasms distinguished by chromosomal translocations with breakpoints involving the TFE3 transcription factor gene, which maps to the Xp11.2 locus. The result is a TFE3 transcription factor gene fusion with one of multiple reported genes including ASPL, PRCC, NonO (p54nrb), PSF, CLTC, and unknown genes on chromosomes 3 and 10. The 2 most common Xp11 translocation renal cell carcinomas are those bearing t(X;1)(p11.2;q21), which fuses the PRCC and TFE3 genes,130 and t(X;17)(p11.2;q25), which fuses the ASPL and TFE3 genes.95 The latter translocation has identical breakpoints and results in the same ASPL–TFE3 gene fusion, as is found in alveolar soft part sarcoma. Other reported but rare translocations are the inv(X)(p11.2;q12), which fuses the NonO (p54nrb) and TFE3 genes; t(X;1)(p11.2;p34), which fuses the PSF and TFE3 genes;131 and t(X;17)(p11.2;q23), which fuses the CLTC and TFE3 genes.132 Variant translocations with no known fusion partner include t(X;3)(p11.2;q23) translocation133 and t(X;10)(11.2;q23).134,135 Different translocations involving chromosome Xp11.2 could result in different expression levels and structures of the TFE3 fusion products, potentially explaining why not all TFE3-positive carcinomas express cathepsin K.3,13,16 Recently, a gene network directing the maturation of lysosomes that is regulated by MiTF, which is a possible heterodimerization partner and close homolog of TFEB, has been identified.136,137 These findings shed light on the common expression of cathepsin K and melanogenetic markers

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153

Table 3 – Criteria for malignancy. Study

Classification

Criteria

Folpe et al.11

Benign

No worrisome features (o5 cm, non infiltrative, non high nuclear grade and cellularity, mitotic rate r1/50 HPF, no necrosis, no vascular invasion) (1) Nuclear pleomorphism/multinucleated giant cells only or (2) Size 45 cm only Two or more worrisome features (45 cm, infiltrative, high nuclear grade and cellularity, mitotic rate Z1/50 HPF, necrosis, and vascular invasion)

Uncertain malignant potential Malignant

Brimo et al.66

Nese et al.72

Benign EAML with atypia (r2 adverse features) Malignant EAML with atypia (Z3 adverse features) Low-risk group (0–1 adverse parameters) Intermediate-risk group (2–3 adverse parameters) High-risk group (4–5 adverse parameters)

(1) (2) (3) (4) (1) (2) (3) (4) (5)

Z70% atypical epithelioid cells Z2 Mitotic figures per 10 HPF Atypical mitotic figures Necrosis TSC and/or concurrent angiomyolipoma Tumor size (47 cm) Morphologic pattern A Extrarenal extension and/or involvement of renal vein Necrosis

EAML: epithelioid angiomyolipoma; HPF: high-power field; TSC: Tuberous Sclerosis Complex.

such as HMB45 and Melan-A in both renal PEC proliferations and the MiTF/TFE family of renal translocation carcinomas, in particular tumors with the t(6;11) translocation. Although these findings are intriguing and highlight the possibility of some sort of relationship among these lesions,123 the common expression of melanogenetic markers and numerous overlapping morphological features underline the diagnostic difficulty in distinguishing epithelioid AML from t(6;11) translocation renal cell carcinomas.14,66,123 Seven out of 8 genitourinary PEComas reported as positive for TFE3 by immunohistochemistry73,118,123 occurred in the kidney.73,123 FISH analysis of TFE3 gene fusion demonstrated the presence of translocation in 3 cases having these PEComas, but only one case was a renal epithelioid AML. Malinowska et al.125 have recently evaluated TFE3rearranged PEComas for TSC2 LOH and for tuberin expression by immunohistochemistry. The study cohort consisted of 4 PEComas previously shown to harbor TFE3 gene fusions123 and 4 conventional PEComas that lacked TFE3 alterations. All 4 of the conventional non-TFE3 PEComas demonstrated loss of tuberin protein labeling by immunohistochemistry. In contrast, all 4 of the PEComas previously shown to harbor TFE3 gene fusions demonstrated intact, robust tuberin protein labeling. In addition, 2 of the 4 conventional PEComas showed LOH or allelic loss for one or more TSC2 microsatellite markers, as others have seen previously.138-140 In contrast, none of the 4 PEComas previously shown to harbor TFE3 gene fusions demonstrated TSC2 LOH. These observations suggested a different pathogenetic mechanism in TFE3rearranged PEComas that does not involve the TSC2 gene through mutation or allelic loss, or other mechanisms of loss of expression. Thus, the authors suggested that TFE3rearranged PEComas represent an entity that morphologically overlaps with conventional PEComas but is biologically distinctive. This concept has clinical translational importance in that mTORC1 inhibitors, such as rapamycin and everolimus, have been shown to be effective in some cases of PEComas,24 and if there is no TSC2 gene involvement in TFE3-rearranged

PEComas, then these patients may not respond to mTORC1 inhibitors.125

TSC genes, mTOR pathway, and PEComa TSC1 and TSC2 are tumor suppressor genes. The TSC 1 gene is located on chromosome 9q34 and consists of 21 exons encoding hamartin, a 1164-amino acid protein. The TSC 2 gene on chromosome 16p13 contains 41 exons encoding a 1807-amino acid protein known as tuberin.141 Hamartin and tuberin form a protein complex, which reduces the level of Rheb-GTP through activation of GTP-ase, resulting in an inhibitory effect on mammalian target of rapamycin (mTOR), which plays an important role in the regulation of cell growth and proliferation. Growth factors as well as phosphoinositide 3-kinase (PI3K) and phosphoinositide-dependent kinase1 (PDK1)-dependent stimulation lead to the phosphorylation and activation of protein kinase B (Akt). Activated Akt, in addition to extracellular signal-regulated kinase (ERK), phosphorylates TSC2, resulting in inhibition of its activity as a GTP-ase. Akt is known as an activator of mTOR and is involved in the pathogenesis of many cancer types. Mutation in one of the TSC genes causes the protein complex (TSC1/TSC2) to be inactivated, which promotes mTOR activation, leading to the phosphorylation and activation of ribosomal protein S6 kinase beta-1 (S6K1) and the S6 ribosomal subunit. This results in the activation of translational mechanisms, increased cell growth, and proliferation.142 Active mTOR kinase phosphorylates eukaryotic translation initiation factor 4E binding protein1 (4E-BP1), which inhibits its interaction with eukaryotic initiation factor-like protein (elF4E), resulting in the activation of translation and increased cell cycling.143 mTOR kinase is a component of 2 functional complexes: TORC1 and TORC2. In mTOR complex 1 (mTORC1), mTOR associates with 2 highly conserved proteins—Raptor and

154

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mLST8. Akt signaling stimulates mTOR within this complex to directly phosphorylate the ribosomal S6 kinases—S6K1 and S6K2—and the eIF4E-binding proteins—4EBP1 and 4EBP2. mTORC1-mediated phosphorylation of S6K1/2 and 4EBP1/2 stimulates mRNA translation and, ultimately, cell growth and proliferation and inhibits autophagy.144-146 The second mTOR-containing complex—mTORC2—consists of mTOR, Rictor, mSIN1, and mLST8. mTORC2's functions can be distinguished from mTORC1's functions through use of the mTOR inhibitor rapamycin. Rapamycin inhibits mTORC1, whereas its effects on mTORC2 are more variable and generally require prolonged treatment.147 By far, the best-characterized function of mTORC2 is in the phosphorylation of Akt on Ser-473,148 but it is also involved in the phosphorylation of a similar motif of PKCα.149,150 These kinases, along with S6K, belong to the AGC kinase family. Therefore, within these 2 complexes, mTOR phosphorylates the hydrophobic motif on several members of this kinase family. The phosphorylation of a second conserved motif on Akt and PKCα, referred to as the turn motif (Thr-450 on Akt1), is also dependent on mTORC2.151,152 Therefore, mTOR lies both upstream (mTORC2) and downstream (mTORC1) of Akt.153 TSC1/TSC2 complex, while inhibiting mTORC1 signaling, promotes mTORC2 activity.154 Hence, loss of the TSC tumor suppressors results in elevated mTORC1 signaling and attenuated mTORC2 signaling. These findings suggest that the TSC1/TSC2 complex plays opposing roles in tumor progression, both blocking and promoting specific oncogenic pathways through its effects on mTORC1 inhibition and mTORC2 activation, respectively.155 Some studies156-158 have identified Transcription Factor EB (TFEB) as a master regulator of lysosomal biogenesis, which co-localizes with mTORC1 on the lysosomal membrane and through this interaction, it senses the lysosomal content. When nutrients are present, phosphorylation by mTORC1 via the amino acid/Rag GTP-ase pathway maintains TFEB in the cytoplasm and prevents it from translocating to the nucleus. Conversely, pharmacological inhibition of mTORC1, as well as starvation and lysosomal disruption, activates TFEB by promoting its nuclear translocation. In addition, the transcriptional response of lysosomal and autophagic genes to either lysosomal dysfunction or pharmacological inhibition of mTORC1 is suppressed in TFEB/cells. These data point to the lysosome as the site where mTORC1-dependent phosphorylation of TFEB occurs. The finding that MiTF (with the exception of the melanocyte-specific M-isoform) and TFE3 also exhibit lysosome localization and nuclear accumulation in response to perturbation of lysosome function suggests that the mTORC1 and the regulatory mechanism that has been defined for TFEB also apply to these closely related transcription factors, suggesting a conservation of this regulatory mechanism within this family of transcription factors. While MiTF and TFE3 have not previously been linked to regulation of lysosome gene expression, they have been shown to be important for osteoclast development and function159 at least in part through the regulation of gene encoding proteins that are critical components of the

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specialized lysosome-related organelles whose regulated exocytosis allows these cells to degrade bone.160,161 AMLs occurring in TSC are well known to show evidence of bi-allelic inactivation of the TSC1 or TSC2 gene, corresponding to the germ line mutation present in such individuals.162 Limited studies have been performed to analyze the genetic basis of AML development in non-TSC individuals. LOH of the TSC2 region has been reported,36,163 and AMLs associated with pulmonary lymphangioleiomyomatosis have been shown to contain TSC2 mutations in a small number of cases.164 However, other AMLs do not appear to have this finding consistently.165 Pan et al. identified LOH for the TSC2 region in 11 of 12 PEComas and 6 of 14 “classic” AMLs.140 Many reports have documented the consistent activation of the mTOR pathway in these tumors,139,140,166 and reduction or absence of TSC2 expression was shown in 4 cases examined by immunoblotting.139 Lesma et al.167 studied renal AML cells, obtained during total nephrectomy from a 36-year-old man with a history of TSC, and provided the first evidence that the methylation of the TSC2 promoter as a second hit may cause the blockade of tuberin expression and full deployment of TSC2 cellular phenotype. Qin et al.37 performed cDNA sequencing for the entire coding region of TSC1, TSC2, and RHEB on 9 AMLs, of which 2 were epithelioid AMLs, using RNA preparations and RT-PCR. They found small mutations in TSC2 in 7 of 8 AML that were sequenced, and the single case that did not harbor a mutation was the VHL patient. No mutations were identified in either TSC1 or RHEB, consistent with previous reports.165 Dickson et al.168 provided a compilation of all previously published reports of extrarenal nonpulmonary PEComa patients treated with mTOR inhibitors, including 5 new cases.24,169-171 They identified point mutations and/or LOH in TSC2 in 4 of their 5 cases, and combined with previous analyses of TSC1/TSC2, 6 of 7 (85%) PEComas showed these hallmarks of TSC1/TSC2 involvement. Their results strongly supported the model that loss of the tumor suppressor gene TSC2, or more rarely TSC1, is a common event in sporadic PEComa.

PEComas and therapy Failure in the regulation of the mTOR pathway has been shown to be critical to the pathogenesis of AML, pulmonary lymphangioleiomyomatosis, and in general in benign and malignant PEComas occurring in and outside the genitourinary tract. In 2008, Bissler et al.22 reported on the treatment of 25 patients with AML and lymphangioleiomyomatosis with sirolimus for 12 months followed up by 12 months of observation. After 12 months of therapy, the AML volume decreased to 53% but returned to 86% of baseline after the year of observation, which indicated the need for continued inhibition to maintain tumor shrinkage. Less-impressive improvements in respiratory function were observed in patients with lymphangioleiomyomatosis, which also reversed on observation alone.

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In 2010, Peces et al. demonstrated that low-dose rapamycin reduces kidney volume AMLs and prevents the loss of renal function in a patient with TSC.172 In 2010, Wagner et al.24 reported 3 cases of malignant PEComas, one of which occurred in the kidney, demonstrating clinical activity of mTOR inhibition with sirolimus in all 3 tumors. In the same year, Wolff et al. showed the activity of both sirolimus and temsirolimus on 2 malignant renal epithelioid AMLs arising in a patient with and without TSC, respectively.173 Recently, a minor response to temsirolimus compared with the adult population has been described by Alaggio et al. in a malignant perivascular epithelioid cell tumor in a 2-yearold girl.174 Finally, in 2013, Dickson et al.168 provided a review of all extrarenal nonpulmonary PEComa patients treated with mTOR inhibitors, which were previously reported, adding 5 new cases. This showed a partial or complete response in 6 out of 11 PEComas, with 5 of 6 having a complete response.

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