Rhabdomyomas are divided into two major clinicopathologic categories: cardiac or extracardiac. The extracardiac group is further subdivided into adult, fetal, and genital types, with the genital type being the rarest [47–51]. Adult and fetal rhabdomyomas tend to involve the head and neck region [50, 52]. Genital rhabdomyomas involve the paratesticular region in males and the vulvovaginal region in females. Over 30 cases of genital rhabdomyoma have been reported in females, of which the vast majority arise from the vagina [47, 51]. A few reported cases involve the vulva [53], cervix [54, 55], urethra [56], and even ovary [57]. The average patient presents in the fourth decade [47, 58] with a polypoid vulvovaginal mass that produces a foreign body sensation [58] or dyspareunia [59]. Alternatively, the lesion is discovered incidentally [47, 55, 56, 60, 61]. Physical examination reveals a 1–3 cm, rubbery-to-firm polyp, rarely cystic [61], often pedunculated, with a smooth, intact surface, similar to a fibroepithelial polyp [47, 52, 55, 56, 58–60, 62].

Genital rhabdomyomas manifest benign behavior, with no reported metastases [47] and only a single reported recurrence following excision [63]. Simple excision is the treatment of choice [47, 59, 60, 62].

The pathogenesis of rhabdomyoma remains elusive. Some authors favor a hamartomatous rather than neoplastic origin [48, 62], but the distinction between the two is obscured by the finding that both entities can be clonal [64]. Given the definition of a hamartoma as a disorganized mass of cells indigenous to a particular site [64], this theory can only explain those developing near the vaginal orifice [48], which contains skeletal muscle as a component of the striated urogenital sphincter complex [65]. Moreover, hamartomas typically occur in young and old alike, whereas genital rhabdomyomas show a predilection for middle-aged women [47, 48, 60].

Histologic examination reveals unremarkable squamous epithelium overlying loose connective tissue stroma bearing loosely interweaving, polymorphous cells with abundant, brightly eosinophilic cytoplasm, ranging in shape from fusiform to polygonal to strap-like, with variably conspicuous cross-striations (Figs. 15.5 and 15.6a, b). Nuclei are centrally or peripherally located, are round to oval in shape, and display occasional prominent nucleoli [48, 49, 52, 56, 58]. Cells may contain multiple nuclei [52, 55]. Nuclear atypia and mitotic figures are universally absent [47, 48, 52, 56, 58, 60, 62].

Immunohistochemical studies confirm skeletal muscle differentiation, with expression of myogenin and alpha-sarcomeric actin. Pan-muscle markers desmin and muscle-specific actin are also expressed [56, 66]. Masson trichrome [67] and phosphotungstic acid-hematoxylin [48, 62, 67] stains were historically applied to highlight cross-striations. However, the characteristic cell morphology together with cross-striations visible by light microscopy usually obviates the need for such ancillary studies.

Little is known about aberrations in molecular pathways in genital rhabdomyoma. In contrast, fetal rhabdomyoma is associated with alterations in sonic hedgehog signaling, with or without concomitant basal cell nevus syndrome [51]. Emerging studies support a role for activated hedgehog signaling in the pathobiology of fetal rhabdomyoma [68]. Assessment of hedgehog signaling in genital rhabdomyomas would be of interest.

The two entities that most commonly enter the differential for rhabdomyoma are embryonal rhabdomyosarcoma and fibroepithelial polyp [47–49, 62]. The significant distinguishing features are summarized in Table 15.3. Consideration may also be given to rhabdomyomatous mesenchymal hamartoma, which is exceedingly rare in the vulvovaginal region [70]. This lesion consists of a disordered mixture of skeletal muscle fibers, mature adipose tissue, nerve bundles, and adnexal structures [71].

Since its emergence in the literature in 1946 [72], rhabdomyosarcoma (RMS) has unveiled several faces, consisting of embryonal (including botryoid), alveolar, and pleomorphic types. Currently, the World Health Organization provisionally lists a separate spindle cell/sclerosing type, but, until recently, it was generally included with embryonal cases [51]. RMS is known as a childhood sarcoma, constituting the largest proportion of soft tissue sarcomas in the pediatric population [73]. Although relatively rare in adults, RMS can affect any age, with age predilections corresponding to subtype [74, 75]. Embryonal RMS is the most common type, most commonly seen in children under age 10, with up to one-half of cases involving the genitourinary tract [73–76]. Second to embryonal in frequency is the alveolar type, which affects a slightly older cohort than embryonal RMS and most often arises in the extremities [73–75, 77]. A small fraction of both embryonal and alveolar types occur in the setting of genetic syndromes involving germ line mutations, such as Beckwith-Wiedemann syndrome [78–80]. The rare pleomorphic type preferentially affects the extremities of older adults [81, 82].

Among cases arising within the gynecological tract, the typical patient is a child or adolescent with a vaginal, uterine, or cervical mass. However, a range of ages from infancy to elderly have been affected, with involvement of the ovaries, fallopian tubes, labia, clitoris, and perineum [83–89]. Patients may present with vaginal bleeding or abdominal pain when the mass arises internally [83, 84]. Masses involving the external genitalia may present as a painless or painful mass [88, 90, 91] that can overgrow and efface the vulvar anatomy [86] or, if in a child, may produce asymmetry mimicking childhood asymmetric labium majus enlargement (Fig. 15.7) [89].

Notoriously an aggressive neoplasm, RMS overall carries 5-year survival rates of 27 % and 61 % for adults and children, respectively [92]. Similar rates are seen in the genital tract [83, 85]. Embryonal RMS manifests more favorable behavior than the other types [82, 84, 93]. All age groups enjoy a better outcome with localized disease, including pediatric gynecological tumors [85]. Data on adult genital RMS are suggestive but do not reach statistical significance [83]. Current data support multimodal treatment for both children and adults, incorporating a combination of surgery, chemotherapy, and radiotherapy [75, 76, 83–85].

The progenitor cell remains unknown but is postulated to be a mesenchymal stem cell transformed by myogenic and oncogenic events [94]. Genetic aberrations in RMS, whether sporadic or in association with germ line mutation syndromes, underlie changes in cell growth and apoptosis, myogenic differentiation, cell motility, and tumor suppression [94–96].

Other than the botryoid variant of embryonal RMS, the typical RMS specimen consists of a pale-tan, fleshy mass [51]. Embryonal morphology accounts for most genital RMS in general, but alveolar morphology more commonly accounts for vulvar lesions [83, 85–87, 91, 97]. Only one reported case of embryonal RMS occurred in the vulva [89]. Tumors with mixed alveolar-embryonal histology can occur [95]. Both types demonstrate a proliferation of primitive mesenchymal cells with scant cytoplasm and round nuclei. In embryonal RMS, these primitive cells assume a stellate shape and are suspended in a matrix of loose, myxoid material alternating with zones of cellular condensation (Fig. 15.8a–c). A cellular condensation beneath an epithelium (cambium layer) defines the botryoid variant of embryonal RMS [93]. The primitive, stellate cells often exhibit varying degrees of myogenic differentiation, characterized by the acquisition of dense, eosinophilic cytoplasm, peripheral displacement of the nucleus, and cellular elongation, eventually evolving into polymorphous shapes described as strap-like, spidery, and tennis-racket-like (Fig. 15.9a–c). With terminal differentiation, the rhabdomyoblasts fuse into multinucleated cells and develop cross-striations, a feature present in a minority of cases [93, 96].

Compared with the embryonal type, the alveolar type shows less obvious myogenic differentiation, often restricted to a thin rim of eosinophilic cytoplasm around the nucleus [74, 93]. Also, whereas the primitive cells in embryonal RMS assume a stellate shape, the cells of alveolar RMS are monomorphous, small, round cells, hence the alternative designation, “monomorphous round cell” RMS [74]. Alveolar RMS consists of fibrovascular septa forming pseudoalveolar spaces that compartmentalize the neoplastic cells (Fig. 15.10a). A layer of tumor cells is aligned along the septa (Fig. 15.10b), with dishesive clusters in the centers of the pseudoalveolar spaces. Multinucleated giant cells with a wreath-like nuclear configuration can be seen (Fig. 15.10d) [74]. Occasionally, the neoplastic cells grow in sheets without clear septal architecture, in which case the term “solid variant” is applied (Fig. 15.10d). Some cases may show clear-cell change [74, 93] or anaplasia [98, 99].

The pleomorphic type constitutes a small fraction of RMS cases in the gynecological tract, mainly affecting the uterus [81–83, 100]. The neoplastic cells are spindled or polygonal, with large, pleomorphic nuclei [81]. Tumors with the spindle cell/sclerosing morphology display fascicles of fusiform cells intermixed with variable amounts of collagen [93, 101].

Since skeletal muscle cells have a unique phenotype, a small panel of immunostains can establish the diagnosis [96]. Numerous studies have demonstrated high sensitivity and specificity of nuclear markers myogenin and MyoD1, which identify cells committed to skeletal muscle differentiation in their early stages [102–105]. Pan-muscle markers desmin and muscle-specific actin offer considerably less specificity [102], although desmin helps to assign cells to a general phenotypic group [96]. At present, myogenin and MyoD1 are the best available markers for confirming a histologic impression of RMS [102]. By far, most tumors entering the differential, including small round cell tumors and spindle cell tumors, lack expression of these markers [102–106]. However, the frequent background cytoplasmic staining for MyoD1 limits interpretation of this marker [102–105]. Notably, entrapped nonneoplastic skeletal muscle may express either marker [102, 104, 105]. Some studies demonstrated differences in staining patterns between alveolar and embryonal types, with alveolar tending to stain more diffusely than embryonal [102–104]. Data are limited on the pleomorphic subtype, but expression of nonspecific muscle markers and at least one skeletal-muscle-specific marker is expected [81].

Initially described by Seidal and colleagues [107], recurrent translocation t(2;13) characterizes most alveolar RMS, with t(1;13) being found in a minority [108, 109]. These translocations generate chimeric genes encoding PAX3- and PAX7-FOXO1 fusion proteins, which enhance transcriptional activity and ultimately affect cell-cycle regulation, apoptosis, and myogenesis [95, 96]. On the other hand, embryonal RMS lacks recurrent translocations, instead bearing multiple gains and losses of chromosome material. Notably, the region most affected by allelic loss (11p15.5) corresponds to the locus associated with Beckwith-Wiedemann syndrome [95]. Interestingly, embryonal RMS demonstrates an RNA expression profile similar to that of translocation-negative alveolar RMS and has similar favorable clinical behavior relative to fusion-positive alveolar RMS [95, 110–112], supporting the use of fusion status to assess risk and to guide therapy.

Morphologic and immunophenotypic overlap exists between RMS and primitive ectomesenchymoma, a sarcoma with both myogenic and neural differentiation. This entity behaves similarly to RMS [113]. Alveolar RMS bears morphologic semblance to various small round cell tumors. Immunohistochemistry usually resolves the differential, but overlap can be seen with desmin and CD99 (see Table 15.9) [96]. Notably, neuroendocrine markers may be expressed in 30–40 % of alveolar RMS, emphasizing the importance of applying a panel of markers to include desmin and myogenin or MyoD1 in the diagnosis of small round cell tumors [116]. Embryonal RMS often engenders a deceptively benign impression at first pass owing to its loose, myxoid background and varying degrees of large, eosinophilic cells. It resembles rhabdomyoma or fibroepithelial polyp with atypical stromal cells (pseudosarcoma botryoides) [69]. Importantly, myogenic marker expression in the latter poses a diagnostic pitfall [66, 96]. RMS with spindle cell morphology can mimic smooth muscle tumors and be SMA positive [96, 101], thus increasing the utility of myogenin and MyoD1. Table 15.4 reviews the key features of rhabdomyosarcoma. See also Vignette 2 at the end of this chapter.

Traumatic neuroma is a nonneoplastic proliferation of neural tissue occurring in response to transection of a nerve following surgery or other trauma [117], most commonly occurring on the lower extremities after amputation (hence, the alternative designation “amputation neuroma”), followed by the head and neck, especially after tooth extraction [118]. Only a handful of cases have been reported in the vulva, seen in association with episiotomy scar [119, 120], traumatic fall [121], and female genital mutilation [122, 123]. Given the estimated 125 million girls and women across the world who have undergone female genital mutilation [124] together with the relatively high frequency of neuromas developing after limb amputation at 12–26 % [118, 125], vulvar neuromas are perhaps underreported [122] or underdiagnosed [123]. Patients may not present for many years following the initial injury [119]. Clinical examination discloses a tender clitoral nodule (Fig. 15.11) [122, 123], an irregular scar-like thickening of the labia minora [119], or vaguely defined labial pain without a palpable abnormality [121]. Patients report a spectrum of symptoms, including dyspareunia [119, 122, 123] or even pain with simply sitting or wearing tightly fitting clothing [123]. In one case, the patient required analgesics to permit coitus [121]. Surgical excision successfully resolves the symptoms [119–123].

Normally, after a nerve is injured or severed, the distal segment degenerates while the proximal segment sends regenerating axons distally. The regenerating axons extend toward and into the endoneurial tubes of the degenerating distal segment under the guidance of bands of Büngner, which are columns of proliferating Schwann cells [126]. The outcome of the regenerative attempt hinges on several factors, such as the length of the path from the axons to their final destination as well as the presence of any obstruction within this path (e.g., fibrosis) [127]. If the regeneration path is obstructed by scar tissue, as in traumatic neuroma, then the axons may turn backward onto themselves, leading to a tumultuous knot of nerve fibers [128, 129]. Within this altered environment, the tangled, intact axons become hypersensitive and spontaneously active, generating abnormal pain signals out of proportion to the stimulus [130, 131], producing the constellation of pain symptoms described above.

The histology reflects the failed attempt at regeneration, demonstrating variably sized, haphazardly arranged nerve fascicles embedded within a collagenous matrix, often in association with a connecting nerve (Fig. 15.12a, b) [128, 132]. The fibrotic matrix may demonstrate myxoid change, corresponding to acidic mucopolysaccharides [128]. The nerve fascicles themselves are normal [132], each ensheathed by perineurial cells, rendering an appearance of multiple separate nerves [128, 133].

The perineurial cells encasing the nerve fascicles demonstrate epithelial membrane antigen and GLUT-1 expression (Fig. 15.13) [134, 135]. D2-40 (podoplanin) and claudin-1 immunostaining also highlights the perineurium [136, 137]. Numerous axons within each fascicle can be highlighted either by silver stains (Bielschowsky or Bodian techniques) [128, 132] or by immunohistochemistry for neurofilament [133]. S100-positive Schwann cells and CD34-positive dendritic stromal cells are also present within the fascicles, as in normal nerves [135].

Occasionally, solitary circumscribed neuroma or neurofibroma enters the differential. The salient discriminatory features are shown in Table 15.5.

Ever since the 1987 recommendation by the Writing Group of the Histiocyte Society [138], Langerhans cell histiocytosis (LCH) has been the unifying term for a group of clinically heterogeneous diseases that were once considered as separate entities under the names Hand-Schüller-Christian disease, Letterer-Siwe disease, eosinophilic granuloma, histiocytosis X, Hashimoto-Pritzker syndrome, self-healing histiocytosis, and pure cutaneous histiocytosis. The prototypical LCH patient is a male child or young adult with bony involvement, either localized or multifocal. However, all ages, both genders, and nearly all organ systems have been affected, including the skin, lung, lymph nodes, liver, spleen, mucosal sites, and endocrine glands [139, 140]. Cutaneous manifestations are relatively common [141], but involvement of the female genital tract is unusual [139], with most cases representing part of a multifocal process [142, 143]. Localized disease affects the vulva more often than the vagina, cervix, endometrium, or ovary [142]. Approximately 30 cases of isolated vulvar LCH have been described, affecting a range of ages from infancy to elderly (average 50 years) [142–144]. Nearly half of vulvar lesions present as ulcers (Fig. 15.14), followed by erythematous plaques, irregular nodules, papules, and macules [144], frequently accompanied by pruritus or pain [143, 144]. The clinical picture can simulate venereal disease, eczema, or Paget disease [142, 144–146].

Axiotis et al. [145] proposed four nosological groups for LCH of the genital tract based on clusters of clinical findings, but they found no prognostic differences among these groups. Despite its limited utility [142], this grouping paradigm has appeared in multiple subsequent reports [146–151]. LCH usually follows an indolent course, with few disease-related deaths [139, 140, 152]. In a recent review of 27 cases of purely vulvar LCH, 18 cases achieved complete remission following initial treatment, but over half recurred [144]. In general, the combination of osseous and extraosseous involvement often heralds progressive disease [140]. Vulvar treatments are chosen largely on an ad hoc basis and range from topical corticosteroids to radical vulvectomy, with or without chemotherapy and radiation. Thalidomide and its analogs have demonstrated success [142–144].

The discovery of recurring BRAF mutations in over half of LCH cases, together with evidence of LCH cell clonality, supports a neoplastic basis for LCH [153]. The origin of pathologic cells (LCH cells) remains undetermined. LCH cells demonstrate phenotypic and behavioral characteristics of both resting and activated normal Langerhans cells (LCs), which originally led to the assumption that the normal LC is the precursor for LCH [153]. However, a 2010 study by Allen et al. [154] challenged this assumption by revealing disparate mRNA expression profiles between the two cell types, with LCH cells demonstrating overexpression of several genes encoding myeloid dendritic cell markers. Thus, LCH cells may derive from myeloid dendritic cell precursors. At present, there is insufficient evidence to draw firm conclusions.

The overall inflammatory picture of LCH by light microscopy has led to suggestions of infectious, environmental, or immune causes [153]. The literature does not support an infectious cause [155, 156]. Immune dysregulation has been postulated based on evidence of reduced numbers of circulating suppressor T-cells in LCH patients [157], but given the role of LCs in affecting T-cell function, the LCH cells may instead drive the immune dysfunction [153]. Environmental cytokines may have a role in LCH pathobiology, particularly IL-17A, as indicated by studies showing high levels of this cytokine in the plasma of LCH patients and the ability of this cytokine to induce dendritic cell fusion in vitro, possibly explaining the appearance of multinucleated giant cells in LCH. The source of production of IL-17A is unclear [153].

Aggregates and clusters of histiocytoid¹ (LCH) cells occupy the dermal or subepithelial connective tissues, often with epithelial infiltration [158, 159]. Unlike normal LCs, which exhibit dendritic morphology, LCH cells have a round shape. They demonstrate abundant, pale, eosinophilic cytoplasm with indistinct cell borders and a characteristic reniform or convoluted nucleus (Fig. 15.15a, b) [139, 160]. These cells are the sine qua non of LCH. Varying proportions of mature eosinophils are interspersed throughout, often accompanied by lymphocytes, macrophages, and multinucleated giant cells [139]. Mitotic figures, if present, usually pertain to the non-LCH cells. Fibrosis may develop in older lesions [139].

Notwithstanding the characteristic histologic picture, definitive diagnosis requires ancillary techniques [160, 161]. The LCH cells consistently express S-100 protein and CD1a (Fig. 15.16a) [139, 162–164]. Diagnosis previously relied on demonstration of tennis-racket-shaped Birbeck granules by electron microscopy, but immunohistochemistry for langerin (CD207), which localizes within Birbeck granules, has largely replaced this practice (Fig. 15.16b) [161, 165–167]. CD68 expression is usually less intense than that seen in macrophages (Fig. 15.16c) [158].

As mentioned above, over half of LCH cases harbor BRAF mutations. In the remaining cases, the BRAF signaling cascade is activated by unknown mechanisms [153]. Recurring cytogenetic abnormalities have not been consistently found in LCH [168].

Clinically, vulvar LCH may simulate venereal disease, such as herpes simplex or syphilitic chancres [145], but infectious agents are not found [155, 159]. Microscopically, florid LC hyperplasia can mimic LCH as a secondary phenomenon in lymphomatoid papulosis [169] and scabies infestation [170]. In these cases, the dendritic processes of the LC cells (highlighted by immunohistochemistry) contrast with the round morphology of LCH cells. The LCH cells might be overlooked in the storm of inflammatory elements [145] or may be misinterpreted as a granulomatous process, but careful evaluation reveals their predominance. Once identified, the differential diagnosis narrows to various histiocytic proliferations, such as Erdheim-Chester disease, juvenile xanthogranuloma, and Rosai-Dorfman disease. The salient distinguishing features are provided in Table 15.6. See also Vignette 1 at the end of this chapter.

Originally defined as a sarcoma of young adult males with a predilection for the aponeuroses of extremities, epithelioid sarcoma is now recognized in two forms: (1) the distal (or “classic”) type and (2) the proximal type [175–177]. These two types together constitute less than 1 % of all soft tissue sarcomas [178]. The distal type reflects the original description of the tumor, presenting most commonly between ages 10 and 39 (mean 28) as a mass in the dermis, subcutis, or deep soft tissues of the distal extremities, particularly the hands and forearms [179]. A fair number (12 % [179]) present with nonhealing ulcers with raised margins [177], mimicking various inflammatory dermatoses [180]. Relatively recently, the proximal type was delineated as a unique subtype presenting at a somewhat older age (mean 35–40 years) as a deep-seated mass preferentially involving proximal axial body sites such as the trunk, limb girdles, pelvis, and external genitalia [175, 176]. Over 20 vulvar cases have been reported, presenting at an average age of 31 [181], most commonly presenting as a painless, firm mass in the labia majora simulating a benign cyst [182–184]. The mons pubis [184, 185] and labia minora may be involved [186]. Rarely, ulceration accompanies the vulvar mass [187].

Epithelioid sarcoma usually proceeds along a relentless course of successive recurrences with eventual metastases, mainly to the lungs and lymph nodes [176, 177, 181, 188]. This is one of the few soft tissue sarcomas that regularly metastasizes to lymph nodes, reported in up to 60 % of cases [176], in contrast to only ~3 % for other soft tissue sarcomas [178]. Less commonly, epithelioid sarcoma metastasizes to the scalp [177], including from a vulvar primary [189]. A review of 20 vulvar cases by Argenta et al. [181] indicated that 50 % of patients succumbed to the disease within 8 years. Although adverse prognostic factors have not been specifically established for the vulva, those that have been demonstrated for epithelioid sarcoma in general include proximal type, FNCLCC grade 3, tumor size > 5 cm, and mitotic count ≥ 20 per 10 high-power fields [51]. Commensurate with treatment regimens elsewhere, wide surgical excision remains the cornerstone of therapy for vulvar epithelioid sarcoma, with possible radiation therapy for cases with close margins. Lymph node dissection and chemotherapy remain controversial [181, 190].

The origin of epithelioid sarcoma has been debated since its first description [179, 191], with consideration given to fibroblastic, (fibro)histiocytic, myofibroblastic, synovial, endothelial, and perineurial lineages [177]. Guillous et al. [175] briefly entertained the notion that epithelioid sarcoma could be a primary carcinoma of soft tissues, perhaps representing the spectrum of epithelial-mesenchymal transdifferentiation. At present, epithelioid sarcoma is considered a tumor of mesenchymal cells exhibiting multidirectional differentiation, primarily epithelial [177], the pathogenesis of which has been linked to the loss of tumor suppressor SMARCB1 (also called INI-1), a protein involved in genomic stability and regulation of cell-cycle progression [192, 193].

The usual gross appearance is of a firm, irregular, white-tan, unencapsulated mass, often with hemorrhage and necrosis (Fig. 15.17) [175, 176, 179], arising in the deep soft tissues, subcutis, or dermis [175]. Microscopically, the distal and proximal types exhibit different morphology and, although the vulva is more likely to manifest the proximal type, overlap can occur [177, 194]; occasionally, a single lesion displays hybrid features [195]. The most common and recognizable pattern of the distal type consists of a “pseudogranulomatous” proliferation of polygonal cells growing in waves around central necrosis, reminiscent of necrobiotic granuloma (Fig. 15.18a) [179]. The polygonal cells are relatively uniform, with minimal pleomorphism and voluminous eosinophilic cytoplasm, often with a loss of cohesion. These polygonal cells transition subtly into spindle cells (Fig. 15.18b, c) [177, 179]. In comparison, the proximal type grows in sheets of large, polygonal cells with voluminous cytoplasm, bearing enlarged, often pleomorphic, vesicular nuclei with frequently prominent nucleoli, consistently imparting a carcinoma-like appearance, with a minor spindle cell component (Fig. 15.19a–c) [175, 176]. Rhabdoid cells are frequently observed (Fig. 15.19c), characterized by epithelioid cells with intracytoplasmic, hyaline-like inclusions compressing and eccentrically displacing the nucleus [175]. Rarely, the distal type demonstrates these rhabdoid cells [176]. The pseudogranulomatous or necrotizing granuloma-like pattern is not as prominent in the proximal type as in the distal type [175, 177]. Both types may demonstrate pseudoangiomatoid spaces, osteoclast-like giant cells, calcification with or without osseous metaplasia, myxoid change, and vascular and perineural invasion [175–177, 179, 194]. Mitotic count varies in both types [188, 196], with > 20 per 10 high-power fields portending a worse prognosis (see above).

Congruent with its definition as a mesenchymal tumor with primarily epithelial differentiation, the vast majority of epithelioid sarcomas coexpress vimentin and cytokeratins or EMA, usually diffusely (Figs. 15.20 and 15.21a) [175, 176, 178, 188, 197]. Over half demonstrate CD34 expression. Expression of S100, desmin, SMA, and HMB45, when seen, is usually focal [175, 176, 178, 188, 197]. A key negative marker is INI-1 (also known as hSNF5 and SMARCB1), with nearly 90 % of epithelioid sarcomas showing complete absence of its expression, whereas normal cells express this protein (Fig. 15.21b) [178, 195, 197].

The discovery of INI-1 protein loss by immunohistochemistry was fueled by cytogenetic studies describing chromosomal aberrations of 22q, which harbors the tumor suppressor gene SMARCB1/INI-1 [198, 199]. Alterations of 22q, however, are also characteristic of malignant rhabdoid tumor/extrarenal rhabdoid tumor (MRT/ERT), although the mechanisms of 22q inactivation differ. In MRT/ERT, 98 % of cases demonstrate genomic changes of both SMARCB1/INI-1 alleles [200], whereas biallelic genomic changes in epithelioid sarcoma have been far less consistently demonstrated [196, 201, 202]. In fact, a study by Papp et al. [201] found that 25 of 31 epithelioid sarcoma cases had at least one intact SMARC allele. The results of the study led the authors to favor an epigenetic mechanism of gene silencing by microRNAs to explain the second inactivating event.

As indicated by the title of the first paper on epithelioid sarcoma [191], the tumor can mimic a granuloma or carcinoma. The former can be excluded by diffuse reactivity for epithelial markers [177]. The latter is almost always CD34 negative [177], and unlike epithelioid sarcoma, carcinomas retain INI-1 expression [195]. Melanoma can usually be distinguished from epithelioid sarcoma by immunohistochemistry, with a notable pitfall in cases of rhabdoid melanoma, which may express cytokeratins and often lacks S100 and HMB45 expression [177, 203]. In such cases, INI-1 expression is key. Of note, INI-1 loss has been noted in up to 50 % of epithelioid malignant peripheral nerve sheath tumors [195]. Table 15.7 reviews the salient discriminating features.