Tumors of Smooth Muscle, of Skeletal Muscle, and of Unknown Origin and Tumor-Like Conditions of the Vulva


Criteria

• Size > 5 cm

• ≥ 5 mitotic figures per 10 high-power fields

• Infiltrative edges

• Moderate or severe cytologic atypia

• Coagulative necrosisa

Number of criteria met

Diagnosis

0–1b

Leiomyoma

2

Atypical Leiomyoma

> 3

Leiomyosarcoma


aAlthough the initial studies did not include coagulative necrosis as a worrisome feature, subsequent works recommended its inclusion (see text)

bRecurrence potential still exists in this category, leading some to suggest a diagnosis of atypical leiomyoma if any criterion is met (regardless of size) [4, 10]





Etiology/Pathogenesis


Vulvar smooth muscle tumors may arise from the tunica dartos labialis within the dermis of the labia majora, the muscular walls of vessels within the crura forming the clitoris, and the erectile tissues within the labia minora [31]. As the pathobiology underlying uterine and soft tissue smooth muscle tumors continues to unravel [6, 30, 32, 33], similar progress in the vulva lags behind. Nonetheless, knowledge of hormone receptor expression in uterine tumors drove analogous vulvar studies [8], which found that most vulvar smooth muscle tumors express estrogen receptor (ER) and progesterone receptor (PR) [8]. These findings, together with ties to pregnancy and hormone therapy [9, 21, 34], support a pathogenic role for hormones and indicate potential for treatment with hormone manipulation [5], which has demonstrated success in uterine tumors [6]. Notably, cutaneous smooth muscle tumors lack ER/PR expression [35], supporting their nosological separation from genital tumors. A potential limiting factor in separating genital and cutaneous tumors is that part of the vulva (the mons pubis and labia majora) is covered by skin. The authors of the studies on vulvar tumors [79] do not clarify how cutaneous tumors were excluded from their material.


Histopathology


Macroscopic inspection reveals a gray or tan, rubbery, usually circumscribed tumor averaging 5 cm [8]. Microscopic examination discloses interlacing fascicles of fusiform cells with eosinophilic cytoplasm and cigar-shaped (sometimes corkscrew) nuclei that may have adjacent cytoplasmic vacuoles (Fig. 15.1a, b). The spindled morphology predominates among vulvar tumors, but the cells occasionally assume an epithelioid appearance, with abundant eosinophilic to clear cytoplasm and round cell borders (Fig. 15.2a). Usually, these epithelioid cells intermingle with the typical spindled cells. Vulvar tumors often demonstrate a myxohyaline extracellular matrix that percolates among the fascicles of cells, imparting a plexiform or lacy appearance (Fig. 15.2b). This feature is noted in a higher proportion of vulvar than uterine tumors. Mucin pools may be observed [4, 5, 7, 8, 10]. The histopathologic features of malignancy are reviewed in Table 15.1 (see also Figs. 15.3a–c and 15.4).

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Fig. 15.1
Leiomyoma, spindle cell pattern. (a) Fascicles often intersect perpendicularly. (b) The spindle cells demonstrate eosinophilic cytoplasm. This field shows both cigar-shaped and corkscrew nuclei


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Fig. 15.2
Histomorphologic patterns in smooth muscle tumors. (a) Epithelioid morphology with well-defined cell borders and abundant, pale to clear cytoplasm. (b) Myxohyaline extracellular matrix imparts a lacy configuration (Images by authors, from case of Dr. Thomas Krausz)


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Fig. 15.3
Features of malignancy in smooth muscle tumors. (a) Coagulative necrosis, as seen on the right side of the field, should be viewed with concern. (b) Cytologic atypia is seen as pleomorphic, hyperchromatic nuclei with occasional bizarre forms. (c) Numerous mitotic figures are apparent


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Fig. 15.4
Leiomyosarcoma. This unusual case demonstrates the convergence of three morphologic patterns: spindled (top), epithelioid (left and center), and pleomorphic transformation (bottom right) (Images by authors, from case of Dr. Thomas Krausz)


Immunohistochemical Features


Pan-muscle markers (desmin and muscle-specific actin) highlight both smooth and striated muscle. For unknown reasons, desmin expression can be absent from smooth muscle tumors arising from vessel walls, making smooth muscle actin (SMA) a better screening marker for smooth muscle tumors [36]. SMA and calponin expression is seen in smooth muscle and myofibroblasts. H-caldesmon and smooth muscle myosin heavy chain demonstrate specific (but variably sensitive) expression with respect to smooth muscle [37, 38]. Generally, expression of the above markers declines with dedifferentiation and pleomorphic transformation [39]. As noted above, most vulvar smooth muscle tumors express ER and PR [8].


Genetics and Molecular Findings


Numerous aberrations in genetic material and molecular signaling pathways have emerged from studies on smooth muscle tumors in the uterus and soft tissues [6, 30, 32, 33], indicating heterogeneous and complex underpinnings. In the vulva, a single cytogenetic study of a leiomyoma revealed clonal rearrangement of 8q11, a finding detected in uterine leiomyomas [22], but further studies are indicated.


Differential Diagnosis


In the vulva, cellular angiofibroma may enter the differential owing to its intersecting, spindle-shaped cells in a fibrous stroma. In this tumor, mitotic figures can be numerous without clinical consequence, whereas in smooth muscle tumors, they constitute a criterion for malignancy [1, 35]. Myxoid components of smooth muscle tumors have been confused with the characteristically paucicellular aggressive angiomyxoma [18]. Distinction between the two may require ancillary studies in cases with sampling issues. Table 15.2 aims to resolve this differential. Overtly malignant smooth muscle neoplasms evoke another set of possible diagnoses, including other spindle cell sarcomas, spindle cell carcinoma, and spindle cell melanoma. When low-power patterns and nuclear features fail to provide the answer, immunohistochemistry is required. A recommended panel includes epithelial markers (broad-spectrum cytokeratins and epithelial membrane antigen), S100, SMA, and desmin. Potential immunohistochemical pitfalls include rare SMA expression in spindle cell carcinomas [45], occasional cytokeratin expression in leiomyosarcoma [46], and rare desmin expression in melanoma [36].


Table 15.2
The differential diagnosis of vulvar smooth muscle tumors








































































 
Smooth muscle tumors

Cellular angiofibromaa

Aggressive angiomyxoma

Clinical features

• Wide age range of adult women

• Wide age range of adult women

• Women of reproductive age

• Usually circumscribed

• Usually circumscribed

• Poorly circumscribed, infiltrative, displaces pelvic structures

• Benign > malignant

• Benign

Histopathology

• Intersecting fascicles of spindle cells (sometimes epithelioid) with cigar-shaped nuclei

• Short fascicles of spindle cells with scant, fibrillary cytoplasm and fusiform nuclei (resemble spindle cells of spindle cell lipoma)

• Paucicellular proliferation of small, bland, ovoid, or stellate-shaped cells

• Myxoid background

• Variably sized vessels from which bundles of smooth muscle radiate

• Myxohyaline extracellular matrix

• Fibrous stroma, wispy collagen

• No mitotic figures or atypia

• Numerous thick-walled, hyalinized blood vessels

• Mitotic figures inconsequential

• Regard mitotic figures with concern
 

Ancillary studies

• SMA +

• Most SMA −

• Desmin +/−

• Desmin +

• Most desmin −

• SMA +/−

• H-caldesmon +

• Most h-caldesmon −

• CD34 +/−

• Usually ER/PR +

• CD34 + in up to 60 %

• ER/PR +

• HMGA2 +/− (up to 43 %

• Usually ER/PR +

• HMGA2 + (most)

of vulvar leiomyomas are +)

• Loss of RB1 and FOXO1 (13q14 region)
 

• Rare, focal CD34 expression reported in leiomyosarcoma


Data from: Refs. [1, 4, 5, 8, 4043]

aLeiomyomatous nodules have been reported within cellular angiofibromas [44]


Summary





  • Clinical Presentation



    • Patients are usually adults with a mass of the labia majora, but any vulvar site can be involved.


    • Leiomyomatosis presents as a diffuse or multinodular proliferation.


    • The patient may report enlargement during pregnancy or hormone therapy.


  • Histologic Features



    • Intersecting fascicles of spindled, sometimes epithelioid cells with eosinophilic cytoplasm


    • Cigar-shaped (sometimes corkscrew) nuclei, with occasional adjacent paranuclear vacuoles


    • Myxohyaline extracellular matrix separates fascicles, imparting a plexiform appearance


  • Differential Diagnosis



    • Vulvar-specific neoplasms cellular angiofibroma and aggressive angiomyxoma are often considered.


    • Leiomyosarcoma can mimic other spindle cell sarcomas, spindle cell carcinoma, and spindle cell melanoma.


Takeaway Essentials





  • Clinically Relevant Pearls



    • These lesions must be excised widely for thorough microscopic evaluation to exclude malignancy and to reduce the risk of recurrence.


    • Any mass can recur, regardless of histologic features.


  • Pathology Interpretation Pearls



    • Although smooth muscle neoplasms at all body sites are united by common morphologic characteristics of their constituent cells, each anatomic location must be considered separately owing to different criteria for predicting behavior.


    • Worrisome features in smooth muscle tumors of the vulva:



      • Size > 5 cm


      • ≥ 5 mitotic figures per 10 high-power fields


      • Infiltrative edges


      • Moderate or severe cytologic atypia


      • Coagulative necrosis


  • Immunohistochemical/Molecular Findings



    • A supportive immunohistochemical panel includes desmin, smooth muscle actin, and h-caldesmon.


    • Smooth muscle tumors of the vulva express ER and PR, unlike their skin and soft tissue counterparts.




Tumors of Skeletal Muscle



Rhabdomyoma



Clinical Features


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 [4751]. 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, 5860, 62].


Prognosis or Course


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].


Etiology/Pathogenesis


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].


Histopathology


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].

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Fig. 15.5
Genital rhabdomyoma. Low-power examination shows unremarkable, glycogenated, non-keratinizing, squamous epithelium overlying stroma containing loosely interweaving, brightly eosinophilic, polymorphous cells (Images by authors, from case of Dr. Thomas Krausz)


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Fig. 15.6
Genital rhabdomyoma. (a) Polygonal and strap-like cells are present. Some cells have multiple, peripheral nuclei. (b) Cross-striations can be seen (Images by authors, from case of Dr. Thomas Krausz)


Immunohistochemical Features


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.


Genetics and Molecular Findings


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.


Differential Diagnosis


The two entities that most commonly enter the differential for rhabdomyoma are embryonal rhabdomyosarcoma and fibroepithelial polyp [4749, 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].


Table 15.3
The differential diagnosis of genital rhabdomyoma























































 
Genital rhabdomyoma

Rhabdomyosarcoma (embryonal/botryoid)

Fibroepithelial polyp

Clinical features

• Adult with a polypoid lesion

• Young female with a mass

• Adult with a polypoid lesion

• Non-ulcerated mucosal covering

• Rapid growth

• Non-ulcerated mucosal covering

• Ulceration of overlying mucosa

• May be multiple and large

Histopathologic features

• Differentiated, eosinophilic cells, ranging from polygonal to fusiform to strap-like

• Mostly primitive mesenchymal cells

• Scattered fibroblastic cells

• Cross-striations often present

• Limited myogenic differentiation, with occasional eosinophilic cells with cross-striations

• May contain markedly atypical stromal cells, with increased mitotic rate in pregnancy (termed cellular pseudosarcomatous fibroepithelial polyps or pseudosarcoma botryoides)

• No cambium layer

• Cambium layer (condensation of neoplastic cells below epithelium)

• No nuclear atypia

• Nuclear atypia present

• No mitotic figures

• Mitotic figures present

Ancillary studies

• Desmin +

• Desmin +

• ER/PR + (almost always)

• Myogenin +

• Myogenin +

• Pitfall: rarely focally positive for desmin, myogenin
 
• t(1;13), t(2;13)


Data from: Refs. [4749, 55, 62, 66, 69]


Summary





  • Clinical Presentation



    • Polypoid vulvovaginal mass in women in their 4th decade, either asymptomatic or with symptoms relating to mass effect


  • Histologic Features



    • A spectrum of differentiated skeletal muscle cells appears as interweaving, polymorphous cells with abundant, brightly eosinophilic cytoplasm.


    • Cells can be polygonal, fusiform, or strap-like, with or without cross-striations.


    • Nuclear atypia and mitotic figures are always absent.


  • Differential Diagnosis



    • Consider embryonal rhabdomyosarcoma and fibroepithelial polyp.


Takeaway Essentials





  • Clinically Relevant Pearls



    • This is a benign lesion with no metastatic potential.


  • Pathology Interpretation Pearls



    • Recognition of a range of muscle cells in later stages of differentiation is key.


    • Any atypia, mitotic figures, or primitive mesenchymal cells should raise suspicion for embryonal rhabdomyosarcoma.


  • Immunohistochemical/Molecular Findings



    • Immunohistochemistry does not distinguish rhabdomyoma from rhabdomyosarcoma, but recognition of the mature striated muscle elements usually obviates the need for ancillary studies.


    • An immunohistochemical pitfall is presented by focal myogenin and desmin expression in fibroepithelial polyp.


Rhabdomyosarcoma



Clinical Features


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 [7376]. 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 [7375, 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 [7880]. 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 [8389]. 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].

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Fig. 15.7
This case of vulvar rhabdomyosarcoma resembled childhood asymmetric labium majus enlargement (Used with permission from Youngstrom EA, Bartkowski DP et al. Vulvar embryonal rhabdomyosarcoma: A case report. J Pediatr Urol. 2013;9(4):e144–6)


Prognosis or Course


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, 8385].


Etiology/Pathogenesis


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 [9496].


Histopathology


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, 8587, 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].

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Fig. 15.8
Embryonal RMS. (a) Low-power view shows alternating zones of cellularity. Note the absence of a cambium layer. (b) High-power view of the hypocellular regions reveals the stellate-shaped, primitive mesenchymal cells. (c) High-power view of a cellular condensation


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Fig. 15.9
Spectrum of myogenic differentiation. (a) Spidery cells. (b) Polygonal and strap-like cells. (c) Strap-like cells with cross-striations (center)

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].

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Fig. 15.10
Alveolar RMS. (a) Fibrous septa compartmentalize the cells. (b) The neoplastic cells align along the fibrous septa. (c) The solid variant consists of sheets of neoplastic cells. (d) A multinucleated giant cell with a wreath-like nuclear configuration is seen (Images by authors, from case of Dr. Thomas Krausz)

The pleomorphic type constitutes a small fraction of RMS cases in the gynecological tract, mainly affecting the uterus [8183, 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].


Immunohistochemical Features


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 [102105]. 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 [102106]. However, the frequent background cytoplasmic staining for MyoD1 limits interpretation of this marker [102105]. 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 [102104]. Data are limited on the pleomorphic subtype, but expression of nonspecific muscle markers and at least one skeletal-muscle-specific marker is expected [81].


Genetics and Molecular Findings


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, 110112], supporting the use of fusion status to assess risk and to guide therapy.


Differential Diagnosis


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.


Table 15.4
Review of rhabdomyosarcoma of the gynecological tract
































































 
Embryonal

Alveolar

Other

Clinical features

• Children < 10 years

• Children and adolescents

• Pleomorphic type arises in the extremities of adults

• Only one case report describes a vulvar origin (the vulva is more likely to be indirectly involved)

• More common than embryonal in the vulva

• Spindle cell/sclerosing variant is not clearly a subtype

• Botryoid: bunch of grapes

Behavior

• Relatively favorable

• Relatively aggressive

• Pleomorphic → aggressive

Histopathology

• Primitive mesenchymal cells with stellate shape

• Primitive mesenchymal cells with a round shape

• Pleomorphic type has large cells with pleomorphic nuclei

• Range of myogenesis (gain of eosinophilic nuclei, peripheral nucleus, strap-like cells)

• Restricted range of myogenic differentiation

• Spindle cell/sclerosing morphology has fascicles of fusiform cells intermixed with variable amounts of collagen

• Myxoid background, variable cellular condensations

• Fibrovascular septa compartmentalizes dishesive cells
 

• Botryoid: cambium layer (condensation of neoplastic cells below epithelium)

•  ±Wreath-like multinucleated giant cells

• Solid variant: sheets of cells

Differential diagnosis

• Rhabdomyoma, fibroepithelial polyp

• Small round cell tumors

• Spindled morphology → smooth muscle neoplasms

• Small round cell tumors
 

Ancillary studies

• Lack recurrent abnormalities

• Often more diffuse myogenin expression than embryonal

• Spindled can be SMA +

• Chromosome gains and losses

• Recurrent translocations t(2;13), t(1;13)

• Lack recurring abnormalities


Takeaway Essentials





  • Clinically Relevant Pearls



    • Consider RMS as a rare cause of a vulvovaginal mass, vulvar asymmetry, or vaginal bleeding.


    • Although vulvar RMS is most commonly alveolar, the embryonal type can protrude into the vulva from more proximal sources.


    • This aggressive neoplasm requires prompt institution of multimodal therapy.


  • Pathology Interpretation Pearls



    • Histologic classification carries prognostic value, with a relatively favorable outcome for embryonal RMS compared with the aggressive alveolar RMS.


    • The solid variant of alveolar RMS is particularly susceptible to morphologic overlap with other neoplasms, requiring ancillary studies to confirm the diagnosis.


  • Immunohistochemical/Molecular Findings



    • Because embryonal RMS lacks recurrent cytogenetic abnormalities, molecular testing is less useful as a diagnostic aid than in alveolar RMS.


    • Demonstration of recurrent translocation t(2;13) or t(1;13) in alveolar RMS corresponds to more aggressive behavior, whereas cases lacking a recurrent translocation behave more favorably, similar to embryonal RMS.


Tumorlike Conditions



Traumatic Neuroma



Clinical Features


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 [119123].

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Fig. 15.11
Traumatic neuroma. This painful clitoral nodule developed after female genital mutilation (Used with permission from Abdulcadir J. et al. Clitoral neuroma after female genital mutilation/cutting: a rare but possible event. J Sex Med. 2012;9(4):1220–5)


Etiology/Pathogenesis


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.


Histopathology


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].

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Fig. 15.12
Traumatic neuroma. (a) A disrupted nerve segment (upper right) gives rise to haphazardly arranged nerve fascicles. (b) The nerve fascicles are embedded within a fibrotic stroma


Immunohistochemistry/Special Techniques


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].

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Fig. 15.13
Epithelial membrane antigen immunohistochemistry highlights the perineurium that surrounds each nerve fascicle in traumatic neuroma (×10)


Differential Diagnosis


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


Table 15.5
The differential diagnosis of traumatic neuroma















































 
Traumatic neuroma

Solitary circumscribed neuroma

Neurofibroma

Clinical differences

• History of trauma

• No clear association with trauma

• In neurofibromatosis, the vulva can be affected as part of a multifocal process

• Usually painful

• Asymptomatic

• Can be pruritic

• Develop at sites of nerve transection

• Genital involvement has been reported

Morphologic differences

• Overall lesion is not encapsulated

• Circumscribed and partially encapsulated by thin perineurium

• Some are circumscribed

• Haphazard nerve bundles compartmentalized by fibrous tissue

• Compact bundles of Schwann cells without intervening fibrous tissue

• Encapsulation depends on typea
 
• Frequent interfascicular clefting

• Proliferation of neural elements in a fibrillary or myxoid background

• Fibrotic stroma is not a feature; if collagen is present, it is usually dispersed in loose clusters

• Mast cells are common

Immunohistochemical differences

• EMA + perineurium surrounds individual nerve fascicles

• Discontinuous EMA + perineurium restricted to periphery of the lesion

• EMA expression in few cells, usually scattered throughout the lesion


aIntraneural neurofibroma is ensheathed by a thick epineurium or perineurium (EMA +)

Data from: Refs. [51, 128, 132, 133]


Summary





  • Clinical Presentation



    • Patients experience pain ranging from mild to excruciating.


    • The painful site may be a palpable nodule or thickening, or it may not be palpable at all.


  • Histologic Features



    • Cross-sectioning through a tangle of nerve fibers appears microscopically as a haphazard arrangement of nerve fascicles.


    • The contents of the nerve fascicles mirror those of a normal nerve.


    • The stroma surrounding the fascicles is usually fibrotic but can show myxoid change.


  • Differential Diagnosis



    • Solitary circumscribed neuroma and neurofibroma may be considered.


Takeaway Essentials





  • Clinically Relevant Pearls



    • Suspect traumatic neuroma for any painful vulvar lesion accompanied by a history of episiotomy, female genital mutilation, or other trauma.


  • Pathology Interpretation Pearls



    • This tumorlike condition can be distinguished from other neural lesions by recognizing the fibrotic stroma separating discrete nerve fascicles.


  • Immunohistochemical/Molecular Findings



    • Within the fascicles, immunostains for neurofilament, S100, and CD34 highlight axons, Schwann cells, and dendritic stromal cells, respectively.


    • Surrounding each fascicle is a perineurial layer, which expresses EMA and GLUT-1 (also D2-40 and claudin-1).


Langerhans Cell Histiocytosis



Clinical Features


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) [142144]. 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, 144146].

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Fig. 15.14
Vulvar Langerhans cell histiocytosis. This painful and pruritic ulceration involves mainly the vestibular portion of the vulva (Used with permission from El-Safadi et al. Management of adult primary vulvar Langerhans cell histiocytosis: review of the literature and a case history. Eur J Obstet Gynecol Reprod Biol. 2012;163(2):123–8)


Prognosis or Course


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 [146151]. 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 [142144].


Etiology/Pathogenesis


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].


Histopathology


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].

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Fig. 15.15
Langerhans cell histiocytosis. (a) Clusters and aggregates of histiocytoid cells intermingle with numerous eosinophils, which may appear granulomatous. (b) Within this field are reniform and convoluted nuclei. Depending on the plane of tissue sectioning, the reniform nuclei may resemble coffee beans


Immunohistochemical Features


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, 162164]. 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, 165167]. CD68 expression is usually less intense than that seen in macrophages (Fig. 15.16c) [158].

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Fig. 15.16
Immunophenotype of Langerhans cell histiocytosis. (a) Strong, membranous CD1a expression illustrates the round, rather than dendritic, shape of the LCH cells. (b) Langerin expression is observed in a membranous and cytoplasmic distribution. A reniform nucleus stands out in the bottom right corner. (c) Faint CD68 positivity is seen in some of the cells bearing reniform nuclei


Genetics and Molecular Findings


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].


Differential Diagnosis


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.


Table 15.6
Differential diagnosis of vulvar LCH
































































 
LCH

Xanthogranuloma

Rosai-Dorfman disease

Erdheim-Chester diseasea

Morphology

• Cytoplasm abundant and pale

• Cytoplasm moderate to abundant and pale to lipid laden

• Cytoplasm abundant and pale or clear with emperipolesis

• Cytoplasm abundant and foamy

• Nuclei reniform or convoluted

• Nuclei round to ovoid, sometimes indented

• Nuclei round to oval; can be reniform

• Fibrous tissue present

• Nucleoli small to inconspicuous

• May have eosinophils

• Prominent nucleoli

• Variable numbers of eosinophils; occasional microabscesses

• Touton giant cells

• Mixed inflammatory component

• Mixed inflammatory component

• Giant cells usually of foreign-body or Langerhans configuration

• Touton giant cells

Immunohisto chemistry

• S100 +

• S100 −

• S100 +

• S100 −

• CD1a +

• CD1a −

• CD1a −

• CD1a −

• Langerin +

• Langerin −

• Langerin −

• Langerin −

• CD68 +/−

• CD68 +

• CD68 +

• CD68 +
 
• Factor XIIIa +
   


Data from: Refs. [51, 139, 162166, 171, 172]

aLCH and Erdheim-Chester disease can coexist, leading some to propose that they exist on a continuum [173, 174]


Summary





  • Clinical Presentation



    • Vulvar LCH most commonly presents as part of a multisystem process, but localized disease can affect a wide range of ages.


    • Ulceration is most common, followed by erythematous plaques, irregular nodules, papules, and macules.


  • Histologic Features



    • The sine qua non of LCH is the histiocytoid LCH cell, characterized by its round shape, abundant, pale cytoplasm, and a reniform or convoluted nucleus.


    • Inflammatory elements are present, with eosinophils providing a helpful clue.


  • Differential Diagnosis



    • The clinical differential for the vulva includes eczema, venereal disease (such as herpes simplex or syphilitic chancres), and Paget disease.


    • The microscopic differential includes histiocytic proliferations such as juvenile xanthogranuloma, Rosai-Dorfman disease, and Erdheim-Chester disease.


Takeaway Essentials





  • Clinically Relevant Pearls



    • The polymorphous clinical spectrum lends itself to a diagnostic challenge, resulting in frequent delays in diagnosis.


    • Consider LCH in any persistent, atypical, or multifocal vulvar lesion.


  • Pathology Interpretation Pearls



    • Careful evaluation must be undertaken to discern the LCH cells within the inflammatory background.


    • There are no histologic features that can predict LCH behavior, which ranges from spontaneous remission to fatal dissemination.


  • Immunohistochemical/Molecular Findings



    • The majority of LCH cells express S100, CD1a, and langerin (langerin immunohistochemistry has largely replaced the need to seek Birbeck granules by electron microscopy).


    • Histiocytic proliferations in the differential diagnosis are ruled out by expression pattern of CD1a and langerin.


Tumors of Unknown Origin



Epithelioid Sarcoma



Clinical Features


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 [175177]. 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 [182184]. The mons pubis [184, 185] and labia minora may be involved [186]. Rarely, ulceration accompanies the vulvar mass [187].


Prognosis or Course


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].


Etiology/Pathogenesis


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].


Histopathology


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 [175177, 179, 194]. Mitotic count varies in both types [188, 196], with > 20 per 10 high-power fields portending a worse prognosis (see above).

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Fig. 15.17
Epithelioid sarcoma. The mass is irregular, is white-tan, and has foci of hemorrhage and necrosis


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Fig. 15.18
Distal-type epithelioid sarcoma. (a) A low-power view discloses a pseudogranulomatous appearance. (b, c) The epithelioid appearance of cells (right) transitions subtly into spindle cells (left)


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Fig. 15.19
Proximal-type epithelioid sarcoma. (a) Low-power view shows sheetlike growth. (b, c) Higher magnification shows increased pleomorphism compared to the distal type. A rhabdoid cell is present (center)


Immunohistochemical Features


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].

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Fig. 15.20
Immunophenotype of epithelioid sarcoma, compiled from several references [175, 176, 178, 188, 195, 197]


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Fig. 15.21
(a) Pan-cytokeratin immunostaining highlights epithelioid and spindle cells. (b) INI-1 expression is lost in the tumor cells but retained in lymphocytes and stromal cells


Genetics and Molecular Findings


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.


Differential Diagnosis


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.


Table 15.7
Mimickers of epithelioid sarcoma







































 
Epithelioid sarcoma

Carcinoma

Melanoma

Necrobiotic granuloma

Morphology

• Epithelioid cells

• Epithelioid cells

• Can be epithelioid, spindled, or rhabdoid

• Histiocytes can be epithelioid, non-epithelioid, or foamy

• +/− Pleomorphism

• Pleomorphism

• +/− Rhabdoid features

• Intercellular bridges

• Spindled component

• Intraepithelial component
 
       
• Variable giant cells

Immunohistochemistry

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Nov 11, 2017 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Tumors of Smooth Muscle, of Skeletal Muscle, and of Unknown Origin and Tumor-Like Conditions of the Vulva
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