Cutaneous Angiomyolipoma—A Distinct Entity That Should Be Separated From Classic Angiomyolipoma: Complete Review of Existing Cases and Defining Fundamental Features

Cutaneous angiomyolipoma is a rare mesenchymal tumor that is demographically, clinically, and immunohistochemically distinct from its renal and extrarenal counterparts. We present a case of cutaneous angiomyolipoma in the right retroauricular area of a 35-year-old male patient and provide a broad systematic review of the literature and the largest compilation of cutaneous angiomyolipomas reported to date. According to the findings presented in this review, we conclude that cutaneous angiomyolipoma should be completely separated from renal and extrarenal angiomyolipomas and therefore be considered a distinct entity in the classification of skin tumors.


Introduction
Cutaneous soft tissue tumors are a heterogeneous group of neoplasms arising from different dermal and subcutaneous tissue components. Benign tumors vastly outnumber sarcomas [1]. Cutaneous angiomyolipoma (hereinafter described as "cutaneous AML") is a benign tumor composed of varying proportions of thick-walled blood vessels, mature adipose tissue, and smooth muscle cells arranged in bundles, histologically identical to renal and extrarenal angiomyolipoma (hereinafter described as "classic AML"). Cutaneous AML is extremely rare and is not included in the latest 2018 World Health Organization (WHO) classification of skin tumors [1].
A total of 43 cases have been reported in English and Spanish literature to date; we present a new cutaneous AML in a 35-year-old male, which would represent the 44th case. We present the largest compilation of cutaneous AMLs, describe their clinical and morphological features, and contrast them with classic AMLs.
Our findings reveal that although they share similar histopathologic features, classic and cutaneous AML should be considered separate entities owing to their distinct demographic, clinical, and immunohistochemical features. Immunostains for melanocytic markers (such as monoclonal antibody  are crucial in differentiating these 2 entities, being positive in classic AML [2][3][4][5][6][7][8] and negative in cutaneous AML. These differences allow us to conclude distinct histogeneses and

Macroscopic Findings
The excisional skin biopsy showed a subcutaneous nodular mass covered by a rugged grayish-tan epidermal surface. At the cut surface, a well-circumscribed, subepidermal, whitish-yellow, heterogeneous soft mass was present, measuring 1.3 × 0.6 cm ( Figure 2).

Microscopic Features
Hematoxylin-eosin-stained sections revealed a well-circumscribed nodule, a surrounding fibrous pseudocapsule (Figure 3), small or medium blood vessels, adipose tissue, and bundled smooth muscle cells ( Figure 3). Cellular pleomorphism, atypia, mitotic figures, and necrosis were absent. The tumor was in the junction between the reticular dermis and the hypodermis. The epidermal surface showed no significant histological changes.
Immunohistochemical analysis using the Ventana BenchMark ULTRA platform with the UltraView detection system revealed positive staining for smooth muscle actin (SMA, clone 1A4) ( Figure 4) and negative staining for the following melanocytic markers: anti-melanosome (monoclonal antibody HMB-45), MART-1 (Melan-A, clone A103) and Tyrosinase (clone T311; Figure 4). Both positive and negative controls were adequate for all studies.
Based on the findings, the case was diagnosed as a completely excised cutaneous AML. The patient had no recurrence at 1 month follow-up. . Low-power view demonstrating subcutaneous location and sharply demarcated border of the tumor (hematoxylin-eosin staining, ×10 magnification). The tumor is composed of thick-walled blood vessels (black arrows), mature adipose tissue (arrowhead), and smooth muscle cells arranged in bundles (white arrow; hematoxylin-eosin staining, ×100 magnification).

Figure 4.
Smooth muscle bundles and vascular smooth muscle stained in red, and fibrous pseudocapsule stained in blue (Masson's trichrome stain, ×20 magnification). Immunostaining showing the muscular components of the tumor (smooth muscle actin, ×100 magnification). Completely negative immunostaining for melanocytic markers in the tumor, with a positive reaction in the epidermal melanocytes (Melanoma Cocktail: HMB-45, MART-1, and Tyrosinase; ×50 magnification).

Background
Soft tissue cutaneous tumors are a heterogeneous group of neoplasms originating from distinct dermal and subcutaneous tissue components. The most common benign mesenchymal tumors are lipomas, dermatofibromas (fibrous histiocytomas), vascular or smooth muscle lesions, and nerve sheath tumors. These tumors are usually superficial and small, measuring less than 5 cm, and present clinically as painless plaques or nodules with variable growth rates. Benign tumors are generally successfully treated with complete excision and rarely recur locally [1].
Cutaneous AML was first described by Argenyi et al [9] in 1986. Since then, according to a comprehensive review of English and Spanish literature (PubMed, SciELO, and Google Scholar) by searching the databases using the terms cutaneous angiomyolipoma and cutaneous angiolipoleiomyoma without date restrictions, 43 patients with cutaneous AML have been reported to date (Table 1)  . To our knowledge, our case is the 44th case of cutaneous AML described.
Data analysis from all reported cases of cutaneous AML reveals significant differences with classic AML and should therefore be classified as separate clinicopathological entities. To support this statement, we first describe classic AML, establish clinical and diagnostic criteria for cutaneous AMLs based on all cases reported to date, and finally contrast its characteristics with those of classic AML.
Although all these tumors have distinct histologic features, they all originate from perivascular epithelioid cells, which have the peculiarity of coexpressing both melanocytic and myogenic markers. Therefore, these tumors probably originate from a cell with myomelanocytic differentiation, although no normal counterpart for this cell has been described [40,86].

Epidemiology
Classic AML accounts for less than 1% of renal tumors; however, it is the most common renal mesenchymal tumor [8,87]. Sporadic classic AML has a female predilection (4:1) and occurs in patients between the age of 40-60 years, whereas TSC-associated classic AML has no gender predominance and occurs in patients between the age of 30-40 years [2,8,40,94].

Radiologic Findings
Classic renal AML is easily diagnosed with uncontrasted computed tomography (CT) or magnetic resonance imaging (MRI) because of its abundant fat tissue. In 2016, Song et al [99] established a radiologic classification of renal AML as being "fat-rich," "fat-poor," or "fat-invisible"; the latter can have overlapping radiologic features with renal cell carcinoma and may often require percutaneous biopsy for adequate diagnosis [99][100][101][102].
EAMLs (5%-7% of classic AML) require more than 80% of epithelioid morphology [8,40,104], consequently reducing the proportion of blood vessels and adipose tissue. It has varying degrees of nuclear atypia and may contain multinucleated giant cells. This rare subtype is potentially malignant and may exhibit aggressive behavior such as recurrence, invasion into the inferior vena cava, and metastasis (to the lungs, bone, and liver) [8]. Brimo et al [113] established a model to predict malignant and aggressive clinical behavior in EAMLs when finding 3 or more of the following: ≥70% of atypical epithelioid cells, ≥2 mitotic figures per 10 high-power fields, atypical mitotic figures, and necrosis. Hence, EAMLs must be monitored closely.

Treatment
Surgical management is recommended in AMLs with a tumor size greater than 1 cm, symptomatic patients, or those with a high risk of tumor bleeding or rupture. Some tumors have been treated with embolization. In some cases, medical therapy with mTORC1 inhibitors, such as sirolimus, has shown a positive clinical response and prevented renal failure [40,101,118,119].
Asymptomatic patients with AMLs smaller than 1 cm and those with significant comorbidities with AMLs smaller than 3 cm should be followed up periodically with CT or MRI [101].

Prognosis
Recurrence in classic AML is rare; however, approximately 25% of cases of EAML with atypia can recur, metastasize, and cause cancer-related death [8,114]. In a series of 41 cases of pure (monotypic) epithelioid cell PEComa neoplasms, Nese et al [120] observed recurrence in 17%, metastasis in 49%, and cancer-related death in 33% of cases.

Overview
Cutaneous AML is demographically, clinically, and immunohistochemically distinct from its classic counterpart (Tables 1 and 2). Cutaneous AML, previously termed cutaneous angiolipoleiomyoma [11,24,34], is a rare, benign tumor with varying proportions of thick-walled blood vessels, adipose tissue, and smooth muscle cell bundles.

Epidemiology
Unlike its classic counterpart, cutaneous AML occurs predominantly in males (70%). The age range is wide (2-77 years), with a peak incidence between the age of 30-50 (median 48) years.
This tumor occurs predominantly in the head (76%) but has also presented in the limbs (22%) and abdomen (2%). Of the head tumors, the ear was the most frequent location in 62% of cases, followed by the nose in 19%, and, less frequently, in the forehead, chin, and eyelid (19%).

Clinical Features
Most patients are asymptomatic, presenting only with a visible or palpable nodular lesion with slow growth, ranging from 2 months to 40 years (median 5 years). Some patients experience tumor size fluctuation over time or that associated with environmental temperature changes (clinical manifestation of the vascular component of the tumor) [22,28], pain (probably associated with increased sensitivity due to location or trauma) [21], and obstructive symptoms related to specific sites (such as nasal cavity) and large tumor size [39].
In the majority of cases, cutaneous AMLs are clinically misdiagnosed. The most common clinical diagnoses are cystic lesions (35%, mainly epidermoid cysts), lipomas (28%), and benign vascular tumors (17% ; Table 1), the latter two being consistent with the tumors' components.
No cases of cutaneous AML have been associated with TSC to date. Only one case of AML in the skin in a patient with TSC has been reported [69]; however, this tumor had all the features of classic AML (including expression of melanocytic markers), which suggest classic AML with skin extension rather than a true cutaneous AML. A sole case of true cutaneous AML was reported in a patient with NF1 [35].

Radiologic Findings
Owing to its superficial location and easily accessible surgical approach, imaging studies are usually unnecessary for diagnosis. In the few cases reported, CT and MRI confirmed adipose and vascular components [33], similar to classic AMLs' radiologic findings.

Microscopic Features
Histologically, most cases are well-circumscribed, with an admixture of small to medium, thick-walled, muscular blood vessels (some dilated and containing thrombi), mature adipose tissue, and smooth muscle bundles in variable proportions, identical to classic AML.
Half of the cutaneous AMLs are surrounded by a fibrous pseudocapsule, probably as a stromal response to tumor growth. Some cases present epidermal changes such as atrophy or hyperplasia. Faint chronic inflammatory infiltrate was also present in some cases [16,22].
Unlike classic AML, there is no epithelioid variant in cutaneous AMLs; consequently, they do not display cellular atypia, necrosis, or mitosis. Only one case had pleomorphic and bizarre nuclear changes in the smooth muscle component [13]; however, the absence of epithelioid cells, mitotic activity, necrosis, and the prolonged clinical duration (15 years) support the degenerative nature of these findings, similar to those observed in ancient schwannomas [13,121].

Special Stains
When requested, Masson's trichrome staining revealed smooth muscle cells in red and collagen fibers (present in the stroma and fibrous pseudocapsule) in blue. Elastic fiber staining shows an absent or defective lamina elastica in some vessels.

Treatment and Prognosis
Complete surgical excision is the diagnostic and therapeutic procedure indicated for cutaneous AML; these tumors are usually easily "shelled out" [11,12,23]. Cutaneous AMLs are always benign, do not progress, and only recur if excision is incomplete [17], highlighting the importance of complete removal with negative margins.

Differential Diagnosis
In the skin, some tumors are composed of one or more of the AML components. Angiolipoma is composed of mature fat cells and clusters of thin-walled capillaries and lacks smooth muscle bundles. Although angioleiomyoma is also characterized by thick-walled blood vessels (as in AML), its smooth muscle cells are arranged concentrically around blood vessels, and it lacks adipose tissue. Arteriovenous malformation is composed of large-caliber arteries, arterioles, capillaries, venules, and thick-walled veins; however, it lacks smooth muscle bundles and adipose tissue [1].
The most important differential diagnosis is classic AML in the skin [69] since they are histologically identical. The expression of melanocytic markers and distinct demographic/clinical features (previously described) are crucial for proper differentiation between these two entities.

Conclusions
Owing to the rarity of cutaneous AML, it is currently not included in the 2018 WHO classification of skin tumors [1]. Moreover, the current information still associates these tumors as cutaneous presentations of the classic AMLs with some differences.
Our review strongly suggests that cutaneous and classic AMLs must be considered separate entities. In summary, the main differences reside in the following aspects: • Clinical: predominantly in males, more frequent in or around the ear, and presenting exclusively as a solitary lesion.
• Etiopathogenesis: without any reported association with TSC.
• Prognosis: benign behavior with lack of recurrence following complete surgical excision.
The immunohistochemical findings discard PECs or any other cell with melanocytic differentiation as a possible origin for cutaneous AML; hence, unlike classic AML, this tumor does not belong to the PEComa family. It is reasonable to consider cutaneous AML as a true and pure "angio-myo-lipoma." Future updates of the WHO classification of skin tumors should consider including cutaneous AML as a separate entity. Finally, physicians should be aware of the possibility of a cutaneous AML when presented with a nodular mass in the ear, as appropriate treatment can provide patients with complete clinical resolution.

Conflicts of Interest
None declared.