Classic AML is a benign mesenchymal tumor composed of thick-walled blood vessels, mature adipose tissue, and bundles of smooth muscle cells in variable proportions. It was previously described as a hamartomatous lesion; however, molecular studies revealed its clonality and neoplastic nature [2,8,40]. It presents almost exclusively in the kidney (99.7%) [2,8,41,42] and is therefore further classified as renal or extrarenal. Extrarenal AMLs (0.3%) have been reported in the liver (most common extrarenal AML) [43-51], spleen [52], retroperitoneum [53], nasal cavity [54], oral cavity [55,56], heart [57,58], colon [59], lung [60], vagina [61,62], ovary [63], fallopian tubes [64], mediastinum [65], spermatic cord [66], penis [67], bone [68], and skin [69].

Classic AML belongs to the perivascular epithelioid cell tumor (PEComa) family, which also includes lymphangioleiomyomatosis [40,70-73], clear cell “sugar” tumor [40,74-79], clear cell myomelanocytic tumor of the falciform ligament or ligamentum teres [80,81], abdominopelvic sarcoma of PECs [3-7], and cutaneous PEComa [82-85]. Classic AML is the most common PEComa [40].

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].

The majority of classic AMLs are sporadic (80%). In comparison, up to 20% of them are associated with TSC [87,88]—a rare, autosomal dominant, multisystemic syndrome characterized by cutaneous abnormalities such as facial angiofibromas, ash-leaf macules, and shagreen patches—and diverse tumors, including classic AML (80% of patients with TSC) [2,40], subependymal giant cell tumor, cardiac rhabdomyoma, and lymphangioleiomyomatosis (LAM) [8,89]. Biallelic mutations in TSC1 (~25%, hamartin in 9q34) and TSC2 (~75%, tuberin in 16p13.3) [8,40,90-92] via point mutations, deletions, missense mutations, or copy neutral loss of heterozygosity [88,93] cause mTOR hyperactivation and consequently stimulate cell growth. Sporadic AML has also been associated with TSC2 mutations [8,40,93]. TSC-associated classic AML tends to be bilateral and multifocal, while sporadic AML cases are isolated and unilateral [3,5,41].

Classic AML can also be associated with adult polycystic kidney disease, neurofibromatosis type 1 (NF1), and von Hippel-Lindau syndrome [32].

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].

Most classic renal AMLs are asymptomatic and incidentally detected through imaging, surgery, or autopsy [8]. However, more than 80% of those larger than 4 cm are associated with abdominal or flank pain, hematuria, nausea, vomiting, fever, mass palpation [2,8], and renal failure (on rare occasions) [87], or new-onset hypertension [8]. Half of the symptomatic cases develop spontaneous bleeding, which may result in massive retroperitoneal hemorrhage and hypovolemic shock [2,8,41,95,96]. Rupture and bleeding during pregnancy are well-recognized complications [97,98]. Hence, tumors larger than 4 cm warrant prompt surgical intervention.

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 [99-102].

Classic AML is a yellow-white, smoothly rounded tumor with well-circumscribed, nonencapsulated borders. Its appearance varies depending on the proportion of adipose, vascular, and muscular components present [2-8,41]. Tumor size is variable, with those of sporadic cases ranging 1-30 cm (median 9 cm), while those of TSC-associated cases are usually smaller and can be multiple [2,103].

Classic AML comprises the characteristic triad of thick-walled blood vessels devoid of lamina elastica, mature adipose tissue, and bundles of spindled or epithelioid smooth muscle cells [2-8,41,42,87]. Hemorrhage and necrosis are commonly detected [8].

There are several histologic variants, including microscopic AML (absent thick-walled blood vessels) [104,105], intraglomerular AML (epithelioid smooth muscle cells intermixed with a few adipocytes in capillary tufts) [106,107], AML with epithelial cyst (cysts, “cambium-like” stromal cells, solid smooth muscle predominant areas, prominent lymphovascular network, and rare adipose tissue) [108,109], lymphangiomatosis of the renal sinus (plaque-like mass in the renal pelvis) [110], sclerosing AML (cords and trabeculae of bland epithelioid cells in abundant sclerotic stroma) [111], and epithelioid AML (EAML) [40,87,104,112]; the latter has distinct implications that require further description.

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.

Classic AML is typically positive for melanocytic markers (95%) such as HMB-45 (expressed in a patchy pattern), Melan-A, Micropthalmia transcription factor, and Tyrosinase [2,8,40,114]. Smooth muscle cells are also immunoreactive to myogenic markers such as SMA, Calponin, and Desmin [8]. Other positive markers include cathepsin K [2,8,40] and, less frequently, CD117, CD68, S-100, estrogen receptor, and progesterone receptor (more common in the epithelioid variant) [2,8,40,115-117].

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].

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.

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.

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%).

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].

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.

Cutaneous AMLs are well-circumscribed, whitish-gray dermal tumors, measuring 0.4-5 (median 1.5) cm, generally smaller than their classic counterpart (median 9 cm).

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].

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.

Cutaneous AML is characteristically positive for smooth muscle markers such as SMA, Calponin, and Desmin. However, unlike classic AML, all cutaneous AMLs are negative for melanocytic markers such as HMB-45, Melan-A, MART-1, and SOX-10. Other frequently positive markers include S-100, Factor VIII, CD31, CD34, and FLI1.

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.

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.