Kidney tumor
Benign/borderline adult tumors
Epithelioid angiomyolipoma
Author: Judy Sarungbam, M.D.
Editor-in-Chief: Debra L. Zynger, M.D.
Last author update: 30 December 2019
Last staff update: 3 October 2023 (update in progress)
Copyright: 2003-2023, PathologyOutlines.com, Inc.
PubMed Search: Renal epithelioid angiomyolipoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Frozen section description | Frozen section images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Molecular / cytogenetics images | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Cite this page: Sarungbam J. Epithelioid angiomyolipoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/kidneytumorepitheliodaml.html. Accessed October 4th, 2023.
Definition / general
- Epithelioid angiomyolipoma is a variant of angiomyolipoma with predominant (at least 80% according to some authors) epithelioid histology
- It belongs to the microphthalmia associated transcription factor (MiTF) family of tumors
- Epithelioid morphology is defined as round to polygonal cells with abundant pink to amphophilic to focally clear cytoplasm, enlarged vesicular nuclei, often with prominent nucleoli and nuclear inclusions
Essential features
- Rare variant of angiomyolipoma with predominant epithelioid (> 80%) histology
- Positive for melanoma markers (cathepsin K, HMB45, Melan A, MiTF) and negative for PAX8, cytokeratins, S100 and SOX10
- Unlike classic angiomyolipoma, they are considered potentially malignant and can metastasize or recur
Terminology
- Epithelioid perivascular epithelioid cell (PEC) tumor (epithelioid PEComa)
- Pure PEComa
- Traditionally, epithelioid angiomyolipoma term is used for tumors in the kidney; at other sites the term epithelioid PEComa is used
ICD coding
Epidemiology
- Mean age of presentation = 50 (30 - 80) years
- M:F = 9:11
- Rare tumor; constitutes 4.6 - 4.8% of all resected angiomyolipoma (Mod Pathol 2013;26:1355, Zhonghua Bing Li Xue Za Zhi 2017;46:378)
Sites
- Kidney
- Can also occur in liver, adrenal gland, retroperitoneal soft tissue, urinary bladder, nasal cavity / skin, etc.
Etiology
- Like classic angiomyolipoma, may or may not be associated with tuberous sclerosis complex (TSC), an autosomal dominant inherited disorder due to inactivating losses of TSC1 (9q34) or TSC2 (16p13.3) (Am J Surg Pathol 1998;22:180, Am J Surg Pathol 1998;22:663)
- Wild type gene products of TSC1/TSC2 inhibit mammalian target of rapamycin (mTOR) complex 1 (mTORC1); lack of the product activates mTORC1 and likely causes tumorigenesis (Mol Cell Biol 2008;28:4104)
- They may also be associated with TSC2/PKD1 contiguous gene syndrome (Am J Surg Pathol 2002;26:198)
Clinical features
- Usually asymptomatic and discovered as incidental findings on imaging
- When symptomatic, presents with abdominal pain, hematuria or palpable mass
Diagnosis
- Imaging: CT scan, MRI may detect adipose tissue
- Biopsy or resection: diagnosis is by histologic examination of tissue
Radiology description
- Can be indistinguishable from renal cell carcinoma and angiomyolipoma with minimal fat; diagnosis can be considered when a mass is found that has small, macroscopic foci of fat without calcification or when acute hemorrhage of a renal mass occurs (AJR Am J Roentgenol 2013;200:W178)
- Tendency to be hyperattenuating on unenhanced CT images, with low intensities on T2-weighted images; they can be heterogeneously or homogeneously solid or a multilocular cystic lesion with massive hemorrhage (Int J Urol 2013;20:1105)
Radiology images
Images hosted on other servers:
Large renal mass
Heterogeneous mass
Prognostic factors
- Potentially malignant, they can recur and metastasize (Mod Pathol 2013;26:1355, Am J Surg Pathol 2011;35:161, Kaohsiung J Med Sci 2019;35:33)
- Studies have shown metastatic rate ranging from < 5% to > 45%
- Few studies have proposed prognostic criteria
- Nese et al. (Am J Surg Pathol 2011;35:161)
- Presence of tuberous sclerosis complex, tumor necrosis, extrarenal extension or renal vein invasion, carcinoma-like histology and tumor size greater than 7.7 cm
- 80% of their cases with three or more of these features showed aggressive behavior
- Brimo et al (Am J Surg Pathol 2010;34:715)
- ≥ 70% atypical epithelioid cells, ≥ 2 mitotic figures per 10 HPF, atypical mitotic figures and necrosis
- Presence of 3 or more of these features was highly predictive of malignant behavior
- This model accurately categorized 78% of clinically malignant and 100% of the clinically benign tumors with atypia
- However, the above features did not correlate in other studies on consecutively resected cases (Mod Pathol 2013;26:1355, Zhonghua Bing Li Xue Za Zhi 2017;46:378)
- Nese et al. (Am J Surg Pathol 2011;35:161)
Case reports
- 34 year old Caucasian man with unexplained weight loss (BMC Cancer 2018;18:561)
- 38 year old man presented with gross hematuria (J Immunother Cancer 2018;6:97)
- 53 year old woman presented with history of painless, gross hematuria with presence of lumbago and fatigue over the past 6 months (Clin Nephrol Case Stud 2018;6:11)
- Man in his 50s with history of multiple bilateral renal masses and multiple pulmonary nodules (Case of the Month #506)
Treatment
- Surgical resection
- Targeted therapy with mTORC1 inhibitors, e.g. everolimus, sirolimus have been used in some tumors (J Clin Oncol 2010;28:e65, Cancer Biol Ther 2019 Oct 10 [Epub ahead of print], Clin Genitourin Cancer 2013;11:e1)
- Durable near complete response to the anti-PD-1 immune checkpoint inhibitor, nivolumab, have been reported (J Immunother Cancer 2018;6:97).
Gross description
- Usually large, predominantly solid pink-tan mass
- Most contain areas of hemorrhage
- Necrosis may be present
- Well circumscribed to having infiltrative borders
- Extrarenal extension and involvement of renal veins may occur
Gross images
Contributed by Judy Sarungbam, M.D.
Circumscribed pink-tan mass
Frozen section description
- Usually sheets of polygonal to plump spindle cells with abundant pink granular cytoplasm
- Significant nuclear pleomorphism with nuclear inclusions and nucleoli
- Areas with admixed adipocytes and abnormal vessels help in the diagnosis
Frozen section images
Contributed by Judy Sarungbam, M.D.
Abundant pink granular cytoplasm
Microscopic (histologic) description
- At least 80% epithelioid histology (Mod Pathol 2013;26:1355)
- At least 2 different histologic patterns described (Am J Surg Pathol 2011;35:161):
- Carcinoma-like growth pattern (Am J Surg Pathol 2011;35:161):
- Large, polygonal cells with dense, deeply eosinophilic cytoplasm and diffusely atypical nuclei with prominent nucleoli arranged in cohesive nests, broad alveoli and compartmentalized sheets separated by thin vascular rich septae
- Often show intranuclear inclusion, nuclear degeneration and multinucleation
- Some show mitosis of > 2/HPF; majority show no mitosis; no atypical mitosis seen
- Variable amount of hemorrhage and necrosis present
- Combination of prominent nucleoli with intranuclear inclusions, in large discohesive cells with eosinophilic cytoplasm, imparts a ganglion cell-like appearance to the tumor cells
- Epithelioid and plump spindled cells in diffuse growth (Am J Surg Pathol 2011;35:161):
- Tumors with epithelioid and plump spindled cells arranged in densely packed diffuse sheets without compartmentalization by vascular septae
- Overall, a greater homogeneity of growth pattern compared with carcinoma-like growth pattern
- Cells are relatively uniform epithelioid with clear to granular, feathery eosinophilic cytoplasm and may lack atypia throughout
- Chromatin is vesicular and with prominent nucleoli; intranuclear inclusions may be uncommonly seen
- Multinucleate giant cells can be present singly or in groups; these cells show no mitotic activity
- Often lack areas of hemorrhage
- Carcinoma-like growth pattern (Am J Surg Pathol 2011;35:161):
Microscopic (histologic) images
Contributed by Judy Sarungbam, M.D.
Sheets of epithelioid cells
Atypical nuclei
Mitosis
Necrosis
Cathepsin K
MelanA / A103
HMB45
Contributed by Christopher Metter, M.D., Rajal Shah, M.D. and the Genitourinary Pathology Society (Case #506)
Melanoma cocktail
Cathepsin K
Cytology description
- Round to polygonal to plump spindle cells with indistinct cell borders with fibrillary or finely vacuolated abundant cytoplasm (Diagn Cytopathol 2000;23:192, Cancer Cytopathol 2017;125:257)
- Variable degrees of nuclear atypia, including nuclear enlargement, pleomorphism, prominent nucleoli and occasional mitosis and necrosis
- Bare nuclei, occasional intranuclear inclusions and multinucleated giant cells in some cases
- Immunostaining is important to improve diagnostic accuracy
Positive stains
Electron microscopy description
- Presence of glycogen, mitochondria and prominent electron dense, membrane bound granules (60 nm - 250 nm)
- Absence of melanosomes or premelanosomes (Am J Surg Pathol 1998;22:663)
Molecular / cytogenetics description
- Loss of heterozygosity (LOH) of chromosome 16p (TSC2) has been reported in occasional sporadic cases (Am J Surg Pathol 1998;22:663)
- Though extremely uncommon, occasional cases with TFE3 gene rearranged have been described (Am J Surg Pathol 2010;34:1395)
- Most of the renal epithelioid angiomyolipomas expressing TFE3 by immunohistochemistry do not show TFE3 gene rearrangement by FISH
- TFE3 gene amplification without TFE3 gene fusion has also been described (Clin Nephrol Case Stud 2018;6:11)
Molecular / cytogenetics images
Images hosted on other servers:
TSC2 mutation
Sample pathology report
- Kidney, left, radical nephrectomy:
- Epithelioid angiomyolipoma, 6.5 cm, involving renal parenchyma and extending into sinus fat (see comment)
- Surgical margins, negative for tumor
- Comment: Focal necrosis (5%) is present. Immunohistochemical stains show the tumor to be positive for cathepsin K, Melan-A and HMB-45, supporting the diagnosis.
Differential diagnosis
- Clear cell renal cell carcinoma:
- Nests of cells with abundant mostly clear cytoplasm surrounded by delicate intricately branching vasculature
- Positive for PAX8, CAIX (complete membranous) and CD10
- Negative for HMB45, Melan A and cathepsin K
- Chromophobe renal cell carcinoma:
- Oncocytoma:
- Usually small solid nests of tumor cells but can also show micro and macrocystic architecture
- Abundant granular eosinophilic cytoplasm with uniformly round nuclei with smooth nuclear border
- Can show some degenerative type nuclear atypia
- Positive for PAX8, CD117
- Negative for CK7, HMB45, Melan A and cathepsin K
- MiTF translocation associated renal cell carcinoma:
- Renal cell carcinoma, unclassified type with oncocytic features:
- Positive for PAX8 and usually cytokeratins, while negative for cathepsin K, HMB45 and Melan A
- Malignant melanoma:
- Adipocytes and abnormal vessels are not seen in melanoma
- Positive for S100, SOX10, Melan A, HMB45 and PRAME
- Negative for cathepsin K, SMA and cytokeratins
- Epithelioid angiosarcoma:
- Positive for CD31, CD34, ERG or FLI1; may stain for cytokeratins
- Negative for cathepsin K, Melan A and HMB45
- Dedifferentiated liposarcoma:
Additional references
Board review style question #1
- Which of the following is true in epithelioid angiomyolipoma?
- Positivity for TFE3 immunohistochemical stain usually correlates with TFE3 gene rearrangement
- Positive for cathepsin K, HMB45, Melan A and MiTF
- Positive for PAX8
- Positive for S100, SOX10, HMB45 and Melan A
Board review style answer #1
B. Positive for cathepsin K, HMB45, Melan A and MiTF. Angiomyolipomas are positive for melanoma markers including cathepsin K, HMB45, Melan A and MiTF, however they are negative for S100 and SOX10. TFE3 gene rearrangement is extremely uncommon in epithelioid angiomyolipoma. Positivity of TFE3 immunohistochemical stain does not correlate with TFE3 gene rearrangement. Malignant melanoma is positive for S100, SOX10, HMB45 and Melan A. Angiomyolipomas are negative for PAX8 and cytokeratins.
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Reference: Epithelioid angiomyolipoma
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Reference: Epithelioid angiomyolipoma
Board review style question #2
- A CT scan of a 58 year old woman complaining of flank pain showed a 7.5 cm kidney tumor encroaching upon the renal sinus. Radical nephrectomy showed a tumor with the morphology depicted in the picture above. There are also focal areas of necrosis (< 5%). The tumor is positive for cathepsin K, HMB45 (focal) and Melan A and negative for PAX8 and EMA. Which of the following genetic syndromes can be associated with this entity?
- Birt-Hogg-Dubé syndrome
- Tuberous sclerosis complex
- Succinate dehydrogenase deficiency
- Von Hippel-Lindau syndrome
Board review style answer #2
B. Tuberous sclerosis complex. Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder resulting from inactivating losses of TSC1 (9q34) or TSC2 (16p13.3) genes. This is characterized by mental retardation, seizures and the development of neoplasms such as angiomyolipoma, subependymal giant cell tumors, cutaneous angiofibromas, cardiac rhabdomyomas, lymphangioleiomyomatosis and pulmonary multifocal micronodular hyperplasia.
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Reference: Epithelioid angiomyolipoma
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Reference: Epithelioid angiomyolipoma
Board review style question #3
- Which is a true feature of epithelioid angiomyolipoma?
- They are a common (> 10%) variant of angiomyolipoma
- Diagnosis requires at least 20% epithelioid cells
- Tumors are almost always associated with tuberous sclerosis
- Tumors may have malignant behavior
Board review style answer #3
