Piloleiomyomas are circumscribed non-encapsulated tumors, centered on the dermis.^{14. and 15.} An overlying zone of uninvolved subepidermal tissue (so-called ‘grenz zone’) is usually present, and there may be some flattening of the epidermis. Epidermal hyperplasia was present in over 50% of cases in one series. ² The tumor is composed of bundles of smooth muscle arranged in an interlacing and sometimes a whorled pattern (Fig. 36.1). The cells have abundant eosinophilic cytoplasm and elongated nuclei with blunt ends. Nuclear palisading and the formation of Verocay bodies was reported in one case. ³⁷ Granular cell change is a rare variant. ³⁸ There are usually no mitoses in the pilar variant. Tumors of long standing may have fibrous tissue in the stroma, and occasionally this shows focal hyalinization. ³¹ Osseous metaplasia is rare. ³⁹ Focal stromal myxoid change and small lymphoid collections have been noted. Hair follicles are sometimes found surviving within the tumor. ¹⁴ The smooth muscle nature of the cells can be confirmed with the Masson trichrome stain or the use of immunoperoxidase markers for smooth muscle such as vimentin, smooth muscle actin (SMA), desmin, and caldesmon. ³⁹ SMA is more specific for smooth muscle than panactin HHF35. ⁴⁰ Lesions on the nipple are estrogen and progesterone receptor positive; both receptors are also found in normal subareolar muscle. ⁴¹ A Bodian stain has shown increased numbers of nerve fibers interlacing with the muscle fibers, and also in the surrounding tissue. ¹⁵

Scrotal leiomyomas often have ill-defined or focally infiltrative margins, differing from the circumscribed tumors of pilar origin. Scrotal lesions are often more cellular with occasional mitoses. Symplastic features have been reported in all types.^{31.42.43. and 44.} Clear cell and granular cell variants are rare. ⁴⁵ Lymphoid aggregates are sometimes present. Dartoic muscle is seen adjacent to the tumor. Male genital leiomyomas may express androgen receptors. ⁴⁶

Vulval leiomyomas are usually of spindle-cell type, although rare epithelioid and myxoid variants occur.^{31. and 47.} Sparse mitoses may be present. Stromal hyalinization is found in nearly one-half of the cases. Small fascicles of spindle cells may be trapped in these hyaline areas producing a plexiform appearance. ³¹ The majority of cases express estrogen and progesterone receptors, ⁴⁷ a feature not found in pilar lesions. ⁴⁸

Smooth muscle hamartoma differs from leiomyoma by having discrete bundles of smooth muscle fibers set in dermal collagen (see below). The multiple papular variant of pilar leiomyoma not infrequently exhibits small bundles of collagen between the smooth muscle bundles, but usually the collagen is not as plentiful as it is in smooth muscle hamartoma. ⁴⁹

All cutaneous leiomyomas in this syndrome are of pilar origin. They are localized to the upper two-thirds of the reticular dermis. Some are well circumscribed and nodular, but most are diffuse in arrangement.

The tumor is usually well circumscribed with a fibrous capsule of variable thickness and completeness (Fig. 36.2). The main component is smooth muscle, which is present as interlacing bundles between the numerous vascular channels.^{63.68. and 72.} Most of the vessels have several layers of smooth muscle in the walls which often merges peripherally with the intervascular fascicles (Fig. 36.3). Sometimes there are large sinusoidal vessels with little smooth muscle in their walls. Small slit-like channels are sometimes present. Most vessels have only scant and scattered elastic fibers in their walls.

The stroma contains varying amounts of fibrous tissue, and in about a third of cases there is a sparse lymphocytic infiltrate. Myxoid change is quite common in the stroma, particularly in the larger tumors. ⁶⁷ The presence of fat in a few cases has led to suggestions of a hamartomatous origin; ⁶⁸ a designation of ‘angiomyolipoma’ can be used for these cases which also contain fat (Fig. 36.4).^{74.75.76.77.78. and 79.} The HMB-45 is negative in cutaneous tumors, in contrast to the finding in renal lesions.^{80. and 81.} For these reasons, cutaneous angiomyolipomas should be regarded as an angioleiomyoma with fat.^{82. and 83.}The term ‘myolipoma’ is used for the rare tumors containing smooth muscle and adipose tissue, but no vascular component. ⁸⁴ Uncommon changes include thrombosis of vascular channels, focal calcification, ⁸⁵ stromal hemosiderin, and hyalinization of vessel walls. Nuclear palisading, producing Verocay-like bodies, is a rare occurrence. ⁸⁶ Nerve fibers are only seen occasionally. ¹ An angioleiomyoma arising in a histiocytoma has been reported. ⁸⁷

In a review of 562 cases, three histological variants were described: a solid type, in which smooth muscle bundles surround numerous small slit-like channels; a cavernous type, with dilated vascular channels, the walls of which are difficult to distinguish from the intervascular smooth muscle; and a venous type, with thick-walled vessels which are easily distinguished from the intervascular smooth muscle. ⁶⁸ Using this classification, a more recent study has found that of 122 cases, 74 were of solid type, 11 were cavernous and 37 venous in type. ⁷⁰ In this study, the authors commented on the close histological resemblance of cases with a concentric perivascular arrangement to myopericytoma, a finding noted earlier by Mentzel et al. ⁸⁸ Another variant is the epithelioid type, which is composed of cells with round to oval nuclei and a moderate amount of finely granular eosinophilic cytoplasm with occasional vacuoles. ⁸⁹ An epithelioid variant with clear cell change has also been reported. ⁹⁰ The pleomorphic type has marked nuclear pleomorphism but only rare or absent mitoses. There is some resemblance to the symplastic change seen in uterine leiomyomas.^{91.92. and 93.}

In the series of 122 cases (mentioned above), all cases were diffusely positive for actins (α-smooth muscle actin and HHF35) and calponin and diffusely or focally positive for h-caldesmon. ⁷⁰ Desmin was diffusely positive in three-quarters of solid-type angioleiomyomas, a half of the venous type, but only 18% of the cavernous type. ⁷⁰ In contrast most of the myopericytomas were negative for desmin, but they stained for the actins and calponin, and, with one exception, also h-caldesmon. ⁷⁰

There are well-defined smooth muscle bundles in the dermis, oriented in various directions. Some are attached to, or surround, hair follicles.100. ^{and 108.} Often there is a thin retraction space around the bundles, separating them from the adjacent dermal collagen (Fig. 36.5). The smooth muscle bundles are clearly seen with the Masson trichrome stain. Bundles of nerve fibers may also be present. ⁹⁹ These findings can be confirmed with appropriate immunohistochemical stains. The smooth muscle expresses desmin and smooth muscle actin.^{102.105. and 107.} Interestingly, large numbers of CD34-positive cells may be present in the stroma surrounding the smooth muscle bundles. ¹³¹ They were not present in the acquired scrotal cases secondary to lymphedema. ¹⁰⁷ There is often slight elongation of the rete ridges of the overlying epidermis, and mild basal hypermelanosis. ¹²⁸

The smooth muscle hamartoma reported in a patient with the MLS syndrome (microphthalmia with linear skin defects) appeared to consist of hypertrophied arrectores pilorum muscle with some thinning of the epidermis and upper dermis. ¹³²

Dermal leiomyosarcomas are irregular in outline, with tumor cells blending into the collagenous stroma at the periphery. ¹⁶⁶ By definition, the major portion of the tumor is in the dermis, although subcutaneous extension occurs in two-thirds. ¹³³ A superficial grenz zone is present in many. Ulceration and pseudoepitheliomatous hyperplasia are rare. There is usually some flattening of the rete ridges of the overlying epidermis.

Leiomyosarcomas are composed of interlacing fascicles of elongated spindle-shaped cells with eosinophilic cytoplasm and eccentric, blunt-ended (cigar-shaped) nuclei (Fig. 36.6). Rare variants with intracytoplasmic eosinophilic granules (granular cell leiomyosarcoma)^{38.167. and 168.} or with epithelioid cells (epithelioid leiomyosarcoma)^{169. and 170.} have been reported. Sometimes there is a suggestion of nuclear palisading. There is variable nuclear pleomorphism, with at least one mitosis per 10 high-power fields in cellular areas. Pockets of greater mitotic activity (mitotic ‘hot spots’) ¹⁷¹ are found. Tumor giant cells are usually present in the less well-differentiated variants. Perinuclear halos are rare. Small lymphoid aggregates are sometimes present within the tumor, ¹³³ but a dense infiltrate (inflammatory leiomyosarcoma) is quite rare. ¹⁵² Stromal sclerosis (desmoplastic leiomyosarcoma) is a rare phenomenon.^{151.172.173. and 174.} The resemblance of this tumor to other desmoplastic tumors of the skin is striking and immunohistochemistry is necessary for its diagnosis. ¹⁷³ Arrector pili muscles are often prominent or hyperplastic, and in some cases transitions from normal to hyperplastic, to benign neoplastic, and to a frankly sarcomatous pattern occur.^{133. and 134.}

In one large series, two predominant growth patterns were observed: nodular and diffuse (infiltrative). ¹³⁵ Nodular tumors were usually quite cellular with nuclear atypia and many mitoses. Sometimes there were small foci of necrosis. Diffuse tumors were less cellular with well-differentiated smooth muscle cells and inconspicuous mitoses. ¹³⁵

Subcutaneous leiomyosarcomas often extend into the lower dermis (Fig. 36.7). They frequently have a prominent vascular pattern; ¹³⁴ vascular invasion is an adverse prognostic feature. ¹⁶² Small areas of necrosis are sometimes present. Deep variants with either a heavy inflammatory cell component¹⁷⁵ or osteoclast-like giant cells¹⁷⁶ have been reported. A myxoid and a pleomorphic variant have been reported in the deeper soft tissues.^{177.178.179. and 180.}

Secondary leiomyosarcomas are often multiple, spheroidal in outline, and sometimes present in vascular lumina.^{133. and 181.}

Leiomyosarcomas of all three types will have myofilaments, demonstrated by the Masson trichrome stain. Reticulin stains show a fine reticulin network interspersed between adjacent fibers. A small amount of glycogen is usually present. ¹⁸² Immunoperoxidase preparations show the presence of vimentin, smooth muscle actin, and h-caldesmon.^{174. and 183.} Desmin is present in about 70% of cases but is less common in the higher-grade tumors.^{135. and 163.} Pan-muscle actin (HHF35) is usually present. Cytokeratin, CD117, S100 protein, and factor XIIIa have been demonstrated in a small number of cases.^{135.184.185. and 186.} In the case of the cytokeratin marker MNF116, Iwata and Fletcher found positivity in 5 of 20 cutaneous cases; EMA was expressed in nine of these cases. ¹⁸⁷β-catenin is not expressed.

Reliable criteria for malignancy remain to be established. ¹⁷¹ Usually accepted features include high cellularity, significant nuclear atypia, tumor giant cells, and at least one mitosis per 10 high-power fields. Tumor size of 5 cm or more is an adverse feature in subcutaneous tumors. ¹⁸⁸ The cell-matrix adhesion protein migfilin is increased in the cytoplasm of tumor cells in the progression of leiomyosarcomas from low to high grade. ¹⁸⁹ It is not found in normal smooth muscle cells.

The polypoid tumors contain multiple bundles of normal-appearing striated muscle surrounded by fibrofatty tissue containing a few telangiectatic vessels.^{193. and 196.} Smooth muscle as well as striated muscle was present in the lesion from the perianal region reported as a cutaneous mesenchymal hamartoma with mixed myogenous differentiation. ²⁰⁴ Numerous vellus hair follicles or folliculosebaceous structures are usually present. ²⁰⁵ Lentiginous melanocytic hyperplasia was present in one case. ²⁰⁶ It was not known if this was a component of the hamartoma or an inductive phenomenon. ²⁰⁶ The worm-like, flesh-colored, cutaneous polyps that occur in the disorganization syndrome (OMIM 223200) lack striated muscle, a feature of multiple rhabdomyomatous mesenchymal hamartomas. ²⁰¹

The subcutaneous tumor with desmin-positive spindle cells, reported as pleomorphic hamartoma of the subcutis, is of uncertain histogenesis. ²⁰⁷

Adult rhabdomyomas are composed of sheets of large polygonal cells with granular, eosinophilic cytoplasm. The cells are partly vacuolated due to their glycogen content. ‘Spider-web’ cells, with residual strands of cytoplasm between the vacuoles, and cells with cross-striations may both be present. ²⁰⁹ The tumor cells stain strongly for desmin and myoglobin; some may stain weakly for S100 protein. ²¹⁰

Fetal rhabdomyomas are composed of immature striated muscle. Fascicular bundles of immature cells with oval to spindle-shaped nuclei are present. ²⁰⁸ Scattered among these bundles are elongated cells with rhabdomyoblastic differentiation.

There are three major histological subtypes of rhabdomyosarcoma: embryonal (including the botryoid variant), alveolar, ²²¹ and pleomorphic.^{222. and 223.} The spindle-cell rhabdomyosarcoma is a rare variant of the embryonal type. ²¹⁶ Rhabdomyosarcomas may be composed of small round cells, spindle or polygonal cells, or large pleomorphic cells. Cross-striations are sometimes seen using the phosphotungstic-acid–hematoxylin stain.

Immunoperoxidase techniques using monoclonal antibodies to vimentin, desmin, myogenin, myoglobin, MyoD1, Myf-4, and muscle-specific actin may be used to confirm the diagnosis.^{213.216. and 218.} Myogenin and MyoD1 are very specific for striated muscle, but they may be negative in some pleomorphic rhabdomyosarcomas. ⁴⁰ In one cutaneous embryonal rhabdomyosarcoma, the spindle cells stained for S100 protein. ²¹⁵ Some tumors, particularly the alveolar variant, express ALK protein. ²²⁴

The cells invariably express vimentin and cytokeratins AE1/AE3 and/or CAM5.2. They often show strong focal to diffuse membranous staining for epithelial membrane antigen.^{234. and 239.} Focal positivity for muscle-specific actin and desmin may occur. ²³⁴ Malignant rhabdoid tumor has some morphological and immunohistochemical features in common with epithelioid sarcoma (see p. 840), although the cells in epithelioid sarcoma do not contain rhabdoid filamentous masses.^{226. and 227.} Rhabdoid differentiation has been reported in some malignant nerve sheath tumors. ²⁴⁰

Chondroma is a well-circumscribed expansile tumor composed of single and grouped chondrocytes embedded in a cartilaginous matrix. It usually produces effacement of the epidermal rete ridge pattern. ²⁴⁵ The cells exhibit reactivity for S100 protein.

The lesion consists of a base of mature trabecular bone with a proliferating cap of mature cartilage. ²⁵⁰ Osteogenesis occurs by endochondral ossification.

As in chordomas, there are strands and cords of vacuolated (physalipherous) cells set in a myxoid stroma (Fig. 36.8). ²⁵⁴ The cells stain for S100 protein, vimentin and epithelial membrane antigen.^{255. and 256.} Parachordomas are strongly positive for cytokeratin 8/18, but not for CK1/10, 7, and 20. ²⁵⁶ Extraskeletal myxoid chondrosarcoma is negative for all cytokeratins.^{256. and 258.}

The tumor may be found in the dermis and/or the subcutis. ²⁶⁷ Ulceration often occurs. Highly cellular areas composed of spindle cells with scant eosinophilic cytoplasm and elongated hyperchromatic nuclei are usually present, in addition to foci of chondroid and osteoid differentiation. ²⁶⁵ The tumor cells are positive for vimentin but negative for S100 protein and cytokeratins.