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Abstract

Malignant tumors of the female reproductive system are a serious health and social problem, as they are the second most common cause of death among women, after breast cancer. Vulvar tumors represent only 4% of all gynecological neoplasms, and they are fourth in frequency after tumors of the cervix, uterus, and ovary. Ninety-eight percent of all vulvar tumors are benign and only 2% are malignant. Sarcomas of the vulva comprise approximately 1–3% of all vulvar cancers. They are characterized by rapid growth, high metastatic potential, frequent recurrences, aggressive behavior, and high mortality rate. In Part 1 of this paper, we presented the most common forms of sarcoma of the vulva: leiomyosarcoma, epithelioid sarcoma, malignant rhabdoid tumor, and rhabdomyosarcoma. The second part of this review will focus mainly on the rarest variants of vulvar sarcoma: low-grade fibromyxoid sarcoma, synovial sarcoma, monophasic synovial sarcoma, carcinosarcoma, Ewing sarcoma, myeloid sarcoma, dermatofibrosarcoma protuberans, malignant fibrous histiocytoma, angiomatoid fibrous histiocytoma, liposarcoma, malignant peripheral nerve sheath tumor, and malignant mesothelioma.

Keywords

dermatofibrosarcoma protuberans liposarcoma sarcomas synovial sarcoma vulva

Introduction

Sarcomas are comparatively rare tumors of mesenchymal origin, which may arise from the soft tissues and viscera.¹ They account for about 2% of all cancers and only 1–3% of all malignant neoplasms with vulvar location.^2,3

Vulvar sarcomas are often misdiagnosed, because of their non-specific clinical manifestations and rare occurrence. The median age of onset is 50 years, but it depends on the specific variant.^1–3 Usually they are asymptomatic or present with non-specific local discomfort associated with a vulvar mass, chronic vulvar pruritus of longstanding, while pain, bleeding, or ulceration are late symptoms associated with an adverse outcome. The prognosis is generally poor for these tumors, and depends mainly on the size of the tumor, tumor involvement of adjacent tissues, and mitotic activity.

The most common vulvar sarcomas were discussed in part 1.^1,2 The second part of this review will mainly consider the rare variants of vulvar sarcomas: low-grade fibromyxoid sarcoma, synovial sarcoma, monophasic synovial sarcoma, carcinosarcoma, Ewing sarcoma, myeloid sarcoma, dermatofibrosarcoma protuberans, malignant fibrous histiocytoma, angiomatoid fibrous histiocytoma, liposarcoma, malignant peripheral nerve sheath tumor, and malignant mesothelioma.

Low-grade fibromyxoid sarcoma of the vulva is a rare disease that only infrequently affects the female genital tract.¹ It presents clinically as a painless, slowly growing non-specific nodule or tumor.¹ Radical excision after histological confirmation of the diagnosis is mandatory, as well as long-term follow-up of the patients, since the disease tends to develop late metastases years after the initial diagnosis.¹

Synovial sarcoma is the fourth most common sarcoma, representing up to 10% of all sarcomas.² Its onset is characteristic in young women of reproductive age.² It is derived from pluripotent stem cells and is usually associated with a specific chromosomal translocation t (X; 18) (p11, q11).³ Vulvar localization of biphasic and monophasic synovial sarcomas is extremely rare, with few cases described in the literature.^4,5

Monophasic synovial sarcoma is a rare soft tissue tumor more commonly affecting the head, neck, and abdomen.⁴ Vulvar localization is exceptional, with fewer than five cases described in the literature.⁵ Clinically it presents with a painless tumor mass located in the deep soft tissues of the vulva.⁶ Its expression has been reported in women of reproductive age (average age, 30 years).^5,6 Histologically, it is characterized by a monotonous proliferation of spindle cells with a hemangiopericytoma-like vascular pattern. The presence of SYT-SSX2 gene fusion in molecular analysis confirms the diagnosis and is associated with a better prognosis.^6,7

Carcinosarcomas of the vulva

Carcinosarcoma represents a rare mixed mesodermal tumor called malignant mixed Mullerian tumor (MMMT).^8,9 It is characterized by a dual component both of sarcoma and carcinoma: carcinoma elements are usually glandular, while the sarcomatous element may resemble normal stroma (homologous or so-called carcinosarcoma).¹⁰ It is found more commonly in the digestive system, liver, and urinary tract, but the most common location is the reproductive system – mainly the uterus and ovaries, and only extremely rarely in the vulva.⁸ Due to its aggressive nature and infiltrative growth, initial presentation as a non-specific tumor mass in the uterus is possible.⁹ Mullerian adenosarcoma is described as a variant of MMMT of the uterus, normally composed of benign but sometimes mildly atypical glandular epithelial elements admixed with malignant sarcomatous stroma.¹¹ There are reports in elderly patients (aged 50–60 years).⁹ It can present clinically as a polyp, with endophytic or exophytic growth in the vulva and vagina, accompanied by metrorrhagia.^11,12

Mixed histological findings can be discerned – intermixtures of carcinomatous or adenocarcinomatous with sarcomatous elements, which may include osteosarcoma, chondrosarcoma, and leiomyosarcoma.¹⁰ Several lobules of typical eccrine spiradenoma may be present in the same lesion.¹⁰ Normally, lymph node metastases are characteristic of the carcinomatous component only.^12,13 Sarcomatoid carcinoma of epidermal origin is a very aggressive neoplasm and it should be considered in the differential diagnosis.¹³

Ewing sarcoma of the vulva

Ewing sarcoma (EwS) and primitive neuroectodermal tumor (PNET) are similar to the high-grade malignant neoplasms that affect the skeletal system.¹⁴ Extraosseous location of EwS and PNETs is unusual and vulvar involvement is extremely rare, with 15 cases reported in the literature to date.^15,16

Association with a number of chromosomal translocations is known, most often t (11; 22) (q24; q12), as well as translocations associated with the EwS gene on chromosome 22, commonly found in Ewing family of tumors (EFTs).^17,18

Usually EwS occurs in young women (aged 15–16 years) and women of reproductive age (aged 20–40 years).¹⁵ It is aggressive with a highly malignant course and development of early metastasis.¹⁴ Morphologically EwS usually displays a lobulated architecture, composed of solid aggregates of cells, sometimes forming rosettes.¹⁹ Histologically it shows the typical features of EwS: monomorphic population of small round blue cells with cytoplasmic glycogen, which is confirmed by periodic acid-Schiff.^16,18 Immunohistochemistry shows membranous positivity for CD99 and Fli-1 in a nuclear pattern.^16,20 A EwS / Fli-1 fusion transcript can be evidenced by polymerase chain reaction.²⁰

Treatment includes surgery, chemotherapy, and radiation.²¹ The prognosis is poor, with frequent development of recurrence and high mortality, mainly associated with respiratory failure due to early development of lung metastases.^21,22 Median survival is about 9 months to 1 year.^21,22

Myeloid sarcoma of the vulva

Myeloid sarcomas are rare tumors arising from myeloblasts or immature myeloid cells occurring in an extramedullary site.²³ Their localization on the female genitalia is extremely rare, with few cases reported – mainly in the vagina and vulva.²⁴

Myeloid sarcomas can occur in up to 1.4% of patients with acute myeloid leukemia (AML), and 1.1% of patients with high-risk myelodysplastic syndrome in transformation to AML.²⁵ Their appearance is associated with a number of chromosomal aberrations, including trisomy 8, trisomy 4, monosomy 7, 16q-, 5q-, 20q-, and trisomy 11.²⁶

Myeloid sarcoma of the vulva may occur as the first manifestation of myeloid leukemia.²³ Cases heralding relapse of myeloid leukemia have been described after bone marrow transplantation (allogeneic hematopoietic stem cell transplant).^22,23

MS of the vulva presents clinically as a slow-growing non-specific vulvar mass, accompanied by subjective voiding dysfunction in advanced cases.^22,23 Differential diagnosis includes primarily cysts and abscesses of Bartholin’s gland.²⁷ Histological findings can be non-specific, with the presence of round cells with uniform chromatin and small nucleoli, but immunohistochemistry shows positivity for myeloperoxidase (MPO), CD34, CD15, CD56, CD117, and lysozyme.^23,27 Bone marrow biopsy is recommended, as it usually shows the presence of a dominant population of blasts, with Auer rods.²⁵ Cytochemical studies reveal positivity for peroxidase and α-naphthol butyrate esterase, and negativity for naphthol AS-D chloroacetate esterase.²⁵

Disease associations have been described with 45, X, -X, t (8; 21) (q22; q22), identified by cytogenetic analysis of bone marrow.^26,27 In cases associated with acute myeloid leukemia, dual fluorescence in situ hybridization demonstrates positivity for the AML1 / ETO gene.²⁵

There are reports of granulocytic sarcomas on the female genital tract associated with acute myeloid leukemia,^23,28 found mainly on the cervix, ovaries, rarely on the vagina, and very rarely on the vulva.²⁶ Immunohistochemistry and Giemsa staining with Leder’s reaction are useful in diagnosis.^28,29 Immunoreactivity to chloroacetate esterase, lysozyme, myeloperoxidase, CD68, and CD43 is characteristic.²⁷

Therapy is identical to that of myeloid sarcomas in acute myeloid leukemia and consists of surgical excision, with subsequent treatment of the underlying myeloid leukemia.^25,27

Dermatofibrosarcoma protuberans of the vulva

Dermatofibrosarcoma protuberans of the vulva (DFSP) represents a low- to intermediate-grade well-differentiated sarcoma of dermal origin,³⁰ which is rarely localized in the area of the vulva.^31,32 Vulvar localization has been reported in elderly women.³³

The typical clinical picture consists of a firm plaque with surrounding red to blue discoloration, or less often with multiple small subcutaneous nodules.³⁴ Histological study shows a storiform pattern of uniform cytologically bland spindle cells, with a characteristic honeycomb pattern of infiltration into the subcutaneous fat (Figure 1).^31,32 Strong positivity for vimentin and CD34 (Figure 2) is revealed by immunohistochemistry.³⁵ Relapses are common after excision, but metastatic potential is low.^35,36

Figure 1.

Dermatofibrosaroma protuberans. Proliferation of monomorphous spindle-shaped cells in a storiform pattern infiltrating the adipose tissue (hematoxylin/eosin, original magnification x100).

Figure 2.

Dermatofibrosarcoma protuberans. Strong and diffuse positivity for CD34 (immunohistochemistry, original magnification x100).

Wide and deep excision with tumor-free margins is the optimal therapeutic approach, in order to avoid the risk of relapse.³⁷ Mohs microsurgery has been reported as an appropriate therapeutic option.^32,33,37

Malignant fibrous histiocytoma of the vulva

Malignant fibrous histiocytoma of the vulva (MFH) is an aggressive tumor with an extremely rare location in the area of the vulva.^38,39 It was described for the first time by O’Brien and Stout in 1964, as the most common soft tissue sarcoma of late adult life accounting for 20–24% of all soft-tissue sarcomas.³⁹ Currently, there are fewer than 10 cases described in women of younger and middle age (average, 30–40 years).⁴⁰ It is usually localized in the labia majora and it presents clinically as a slow-growing painful tumor mass measuring about 3–6 cm in diameter.^40,41 The pathogenesis of this type of neoplasm is not entirely understood, but contribution of genetic alterations is suggested, although they are not always identified.⁴² The development of metastasis via hematogenous spread is typical of MFH, primarily to the lungs and rarely to the bones.³⁸ Lymph node metastases and relapses occur less frequently.⁴³

The diagnosis is based on histological examination with the identification of atypical spindle or pleomorphic cells with focal myxoid or storiform patterns.⁴² The histological picture can include a mixture of fibroblastic and histiocytic cells with haphazardly interspersed collagen fibers. The histiocytic cells show granular and vacuolated cytoplasm due to the presence of lipid.^40,42 Characteristic findings include pleomorphic neoplastic cells and bizarre tumor giant cells as well as mitotic figures, many of which are atypical.⁴² Vimentin reactivity and negativity for keratins and leukocyte common antigen can be seen on immunohistochemistry.³⁸

Treatment includes wide surgical excision followed by radio- or chemotherapy, depending on the location of the primary tumor and the presence of metastasis.⁴³ Partial or total vulvectomy with bilateral lymphadenectomy is the treatment of choice in the case of larger lesions and advanced local stages.⁴³ Angiogenesis inhibitors have been described, and other biological therapies are used less frequently.^40,42 The prognosis depends on the size of the primary tumor and the presence of metastasis.^39,43 The 5-year survival rate is 80% for lesions <5 cm, 65% for tumors in the range of 5–10 cm in size, and 50% for tumors >10 cm.⁴⁴

Angiomatoid fibrous histiocytoma (AFH) represents a soft-tissue neoplasm with low malignant potential. Its characteristic location is in the deep dermis or subcutis of the extremities and the superficial soft tissues, occurring more commonly in children and young adults.⁴⁵ Only rarely does AFH occur outside of these locations, but it has been reported in the lungs, mediastinum, brain, omentum and bones, vulva, retroperitoneum, and ovary.^45,46 Although it is typical of young age, the age range may vary within wide limits (range, 20–60 years).⁴⁵

The typical histological picture includes a peritumoral lymphoplasmacytic cuff⁴⁵ and an incomplete fibrous pseudocapsule around the tumor.⁴⁷ The peritumoral lymphoid tissue may comprise reactive lymphoid follicles separated by abundant small lymphocytes and plasma cells.^45,48 Multiple discrete or coalescent pale-staining nodules that sometimes exhibited a plexiform or serpentine pattern are seen in the central region of the tumor, separated by a sclerotic stroma richly infiltrated by plasma cells.^45,49 The immunohistochemical study is contributory but not entirely diagnostic, due to the lack of a specific diagnostic panel.⁵⁰ Immunohistochemical expression of epithelial membrane antigen, CD68, and CD99 are typical, with desmin and smooth muscle actin being less common.⁵¹ Focal CD21 expression is also a possible feature.^50,51

Chromosomal translocations are typical of this neoplasm.⁴⁷ EWS/CREB1 fusion is detected in more than 75% of cases, rarely EWS/ATF1 and FUS/ATF1.^52,53 The therapy consists of surgical excision, followed by radiotherapy.⁵³

Liposarcoma (atypical lipomatous tumors) of the vulva

Liposarcoma (LS), the most common soft-tissue sarcoma, normally occurs on the limbs, trunk, or abdomen, but very rarely on the vulva.^54,55 It mainly affects women of middle age, aged approximately 50 years, presenting with different sized tumor masses with a characteristic focal infiltrative growth.⁵⁵ A non-specific, asymptomatic tumor mass, with a long duration, localized usually on the labia is seen clinically.^55,56 The myxoid variant of liposarcoma was reported to arise in the area of the vulvar perineum in a 15-year-old girl.⁵⁷ Typical histological features of well-differentiated liposarcoma/atypical lipomatous tumor include variation in adipocyte size, adipocytic nuclear atypia, and occasional lipoblasts.^54,58 Atypical histologic variants are also described, with an admixture of neoplastic bland spindle and round cells along with adipocytes showing variation in size as well as numerous mainly bivacuolated lipoblasts.^57,58 Cytogenetic abnormalities have been identified, mainly in the MDM2 and CDK4 genes.^59,60

In the differential diagnosis of LS, lipomas and lipoblastomas should be taken into account.⁵⁹ Bartholin’s gland cysts are also included in the clinical differential diagnosis.⁵⁵

Therapy consists of wide surgical excision with the objective of attaining negative margins.⁵⁴ Post-surgical radiotherapy can also be considered, although it is not relevant in reducing the risk of recurrence.^55,56 Lymphatic and hematogenous metastases are possible.^55,60

The prognosis is generally good after total resection of the tumor, and the mortality rate is relatively low.^57,58

Malignant peripheral nerve sheath tumor of the vulva: Neurogenous sarcoma (malignant schwannoma) of the vulva

Neurogenous sarcoma (NS), also called ‘Neurofibrosarcoma’ and ‘Neurosarcoma’ represents a slow-growing nerve sheath neoplasm, originating from Schwann cells of the nerve sheath – the connective tissue surrounding nerves.^61,62 They rarely occur on the vulva, as the reported cases are mainly in the area of the clitoris in women of middle age.⁶³ At least half of the cases described are in association with neurofibromatosis, as the risk of development of malignant peripheral nerve sheath tumor (MPNST) in patients with neurofibromatosis type 1 is 8–13%.^63,64 A particular variant of this type of tumor that contains a rhabdomyoblastomatous component is called a malignant triton tumor.⁶⁴

MPNST in general is the most common soft-tissue sarcoma in childhood.⁶⁵ It usually occurs in association with major nerve trunks, most often affecting the proximal portions of the upper and lower extremities and the trunk.⁶⁶ Vulvar localization, however, is uncharacteristic, with the incidence in the general population of 0.001%.^61,62 The risk of development, however, increases to 5–42% in patients with neurofibromatosis type 1.^63–65 MPNST may arise de novo, and the prognosis is usually more favorable in these cases.⁶⁶

MPNST of the vulva affects mainly young girls and women (age range, 20–50 years), with NF1 being present in half of them.⁶⁷ NF1 is an autosomal dominant disorder, with genetic mutations on the NF1 gene in chromosome 17, associated with the development of tumors along the nervous system.^63–65 The risk of inheritance for the offspring is 50/50.⁶⁸

The clinical picture depends mainly on the location of the primary tumor.⁶⁶ It usually presents with a painful swelling, accompanied by paresthesia.^66,67 Slow-growing non-specific, longstanding painful swelling is observed when the tumor is located on the vulva, more commonly in the clitoris.⁶⁹ Besides pain, subjective complaints are associated with neural involvement and manifest with paresthesia, difficulty in walking or sitting, and a periodically burning sensation, numbness, or tingling.⁷⁰ The diagnosis of MPNST is based on histological examination that reveals a predominant spindle cell proliferation, frequently with nerve involvement. Immunohistochemistry, clinical features, and the possible association with neurofibromatosis all contribute to the establishment of an accurate diagnosis.^70,71 The characteristic histological findings include fascicles of spindled cells with marked hypercellularity and high mitotic activity.^66,71 Immunohistochemical study usually discloses focal positivity for S-100 protein and negativity for cytokeratins, smooth muscle actin, HMB45, and alpha-1-antitrypsin.^71,72

Therapy consists of wide surgical excision of the primary tumor.^70,72 Postsurgical radiotherapy has been reported with good effect in order to prevent the risk of recurrence.⁷³ In cases involving locally advanced disease and large tumors, external-beam radiation, anterior pelvic exenteration with pelvic reconstruction, and adjuvant chemotherapy represent the treatment of choice.^70,73 In cases where surgery is contraindicated, high-dose radiation therapy can be considered.⁷³

The prognosis is generally poor, especially for children.^65,71 Besides age, factors that are indicative of a poor prognosis are large primary tumor (over 5 cm), high-grade disease, co-existent neurofibromatosis, and the presence of metastases.^61,65 Distant metastases occur in 40% of patients, mainly to the lungs.^61,62

Malignant mesothelioma of the vulva

Malignant mesothelioma is a rare soft-tissue sarcoma that develops from cells of the mesothelium.⁷⁴ It usually occurs in the pleura, less frequently in the peritoneum and tunica vaginalis testis, and exposure to asbestos is considered to be a predisposing factor.⁷⁵ Vulvar localization is extremely rare, reported as anecdotal cases presenting in the labia minora.^75,76

According to these cases, the tumor clinically presents as 3–4 cm encapsulated soft tumor located in the superior and outer margin of the labium minus.⁷⁵ It is histologically characterized by spindled and polygonal cells presenting in a variety of patterns, with focal areas of collagenous eosinophilic matrix seen in between the tumor cells.⁷⁶ Staining with PAS and alcian blue can contribute for the diagnosis.^74,76 Currently, there is no specific immunohistochemical panel to confirm the diagnosis.⁷⁷ Immunoreactivity with EMA (epithelial membrane antigen), mesothelin-1, and HBME-1 (anti-mesothelioma antibody) has been established, and there is negativity for CEA (carcinoembryonic antigen) and CD15.^74,77

Treatment consists of wide excision with postoperative radiotherapy to prevent recurrences, which are rare.^75,76

Conclusion

Sarcomas of the vulva are rare malignant neoplasms which often lead to misdiagnosis. They are characterized by non-specific clinical manifestations, aggressive behavior, high metastatic potential, and mortality. Prognosis is poor, and depends mainly on the size of the primary lesion, tumor invasion, and mitotic activity. Lesions greater than 5 cm in diameter, with infiltrating margins, extensive necrosis, and with more than five mitotic figures per 10 high-power fields, are associated with even poorer prognosis, and indicative of possible recurrence after surgical resection.

It is important to consider vulvar sarcomas in the differential diagnosis of non-specific vulvar lesions in order to establish an early accurate diagnosis and appropriate treatment.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Vulvar sarcomas: Short guideline for histopathological recognition and clinical management. Part 2

Abstract

Keywords

Introduction

Carcinosarcomas of the vulva

Ewing sarcoma of the vulva

Myeloid sarcoma of the vulva

Dermatofibrosarcoma protuberans of the vulva

Malignant fibrous histiocytoma of the vulva

Liposarcoma (atypical lipomatous tumors) of the vulva

Malignant peripheral nerve sheath tumor of the vulva: Neurogenous sarcoma (malignant schwannoma) of the vulva

Malignant mesothelioma of the vulva

Conclusion

Footnotes

Declaration of conflicting interests

Funding

References