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Introduction

Ewing's sarcoma and primitive neuroectodermal tumor (PNT) are considered sarcomas with round cells and fluctuating levels of neuroectodermal differentiation. These types of cancer are distinguished by genetic translocation, wherein the Ewing's sarcoma breakpoint region 1 (EWSR1) gene binds to the DNA-fusing domain of an erythroblast transformation-specific (ETS) transcription factor gene. In Ewing's sarcoma, although there are five different ETS factors that fuse with EWSR1, FLI1 is the most common factor reported in up to 95% of cases (1).

Friend leukemia virus-induced erythroleukemia-1 (FLI-1) is an ETS transcription factor that acts as a key regulator of normal development and malignant transformation. There is evidence that FLI-1 serves an important role in the maintenance, differentiation, hematopoiesis, vasculogenesis, and angiogenesis of stem cells (2). Consequently, any perturbation of ETS factor activity will induce tumor initiation, progression and metastasis. Studies have also demonstrated that the major cause of aberrant ETS expression in leukemia is chromosomal translocation (2,3). In addition, ETS factors have been demonstrated to have implication in the development of various solid tumors (2,3).

Therefore, Ewing's sarcoma and PNT have chromosomal aberration, which is expressed by translocation, wherein one gene from the Ewing's sarcoma gene on 22q12 is fused with another gene, a member of the ETS group of transcription factors. More precisely, the most recurrent gene involved in this process is t(11;22)(q24;q12), which is a result of the fusion of the FLI1 gene with the Ewing's sarcoma gene (4). The entire molecular mechanism occurs in 85% of the Ewing's sarcoma cases or PNTs, with the other 15% of cases involving t(21;22)(q22;q12) translocation. These translocations result in the formation of certain fusion genes that encode various novel chimeric transcription factors (5). These factors are considered to be vital to the tumor biology because they alter the critical control points of cell differentiation and proliferation through aberrant regulation of gene expression (6).

Therefore, given that Ewing's sarcoma and PNT share numerous genetic features, they are considered members of the same family of tumors, i.e., the Ewing's family of tumors. However, the two entities differ in that PNTs refer to neoplasms that present with neuroectodermal differentiation, as determined using various methods, including microscopy, ultrastructural studies or immunohistochemistry, which Ewing's sarcoma refers to tumors that lack evidence of this type of differentiation (7).

The Ewing's family of tumors is a group of tumors of mesenchymal origin, which account for 4% of all neoplasms and occur more commonly in the first two decades of life (8). There are several main types of tumor belonging to the Ewing's family of tumors. However, the most well-known tumor from this family is Ewing's sarcoma of the bone, which was first described in 1921 by the American pathologist James Ewing, who found differences between this tumor and osteosarcoma, the most common malignant bone tumor (9).

Another tumor from the Ewing's family of tumors is the extraosseous Ewing's sarcoma. The first case of extraosseous Ewing's sarcoma was reported in 1975 when Angervall and Enzinger validated the diagnosis of this tumor after analyzing 39 cases (10).

Furthermore, PNT is a type of tumor that belongs to the Ewing's family of tumors. PNT was first mentioned in 1918 by Arthur Stout, who described a tumor of the ulnar nerve that had small, round cells (11).

Of all these types, PNT and extraosseous Ewing's sarcoma of the female genital tract are more aggressive. However, regarding the location of the PNT and extraosseous Ewing's sarcomas of the female genital tract, the most common sarcoma is one that develops in the ovaries. PNT and Ewing's sarcoma of the cervix, vagina and vulva are extremely rare (12,13). Data regarding these tumors are very limited, and there are no standard guidelines for the pathology, diagnosis or treatment of these types of cancer (14–16).

Therefore, the main objective of the present review was to investigate the limited available data and to emphasize the clinical and paraclinical aspects and the recommended treatment for PNT and extraosseous Ewing's sarcoma located in the vulva and vagina.

Methodology

The inquired databases (from 1960 until July 2020) were Medline, Embase, Cancerlit, DARE and Cochrane Database of Systematic Reviews. The keywords used in the search strategy were ‘extraosseous Ewing's sarcoma’, ‘primitive neuroectodermal tumor’, ‘PNT’, ‘extraosseous Ewing's sarcoma case report’, ‘primitive neuroectodermal tumor case report’ and ‘PNT case report’.

A total of 38 cases of PNT or Ewing's sarcoma with vulvar localization were identified. The majority of the identified patients were young (<30 years old), and the youngest and the oldest of the patients were 3 years and 87 years, respectively (Table I) (5,9,13,16–43). Regarding vaginal PNT and extraosseous Ewing's sarcoma, 15 cases (14 and 1, respectively) have been recorded in the literature, and they were reported to occur in patients aged 12–54 years, and the first case was described in 1970 (Table II) (12,21,25,44–54).

Table I. Available case reports of vulvar extraosseous Ewing's sarcoma or primitive neuroectodermal tumors.

Table I.

Available case reports of vulvar extraosseous Ewing's sarcoma or primitive neuroectodermal tumors.

Year of publication	Author(s)	Patient's age	Location	Symptoms	Reference
2014	Narayanan et al	17	Clitoris	Swelling	(7)
2017	Yang et al	20	Left labium majus	Growing painful mass	(9)
2010	Dadhwal et al	20	Right labium majus	Growing tumor	(13)
2014	Xiao et al	20	Left labium majus	Painful tumor	(16)
		36	Right labium majus	Painful tumor
1994	Scherr et al	10	Left labium majus	Painless tumor	(18)
1995	Paredes et al	29	Left labium majus	Painful tumor	(19)
1995	Nirenberg et al	35	Right labium majus	Painless tumor	(20)
		31	Right labium majus	Painless tumor
		30	Right vulva	Painless tumor
		54	Right vulva	Painless tumor
		51	Clitoris	Painless tumor
		41	Left labium majus	Painless tumor
		29	Right labium majus	Growing painless tumor
		44	Right labium minus	Growing Painless tumor
		87	Mons pubis	Painless tumor
		20	Right labium majus	Growing Painless tumor
2000	Vang et al	28	Dermis of the vulva	Painless tumor	(21)
2001	Takeshima et al	45	Right labium majus	Painless tumor	(22)
2001	Lazure et al	29	Dermis of the vulva	Painless tumor	(23)
2005	Moodley and Jordaan	26	Lower right labium majus	Painless tumor	(24)
2007	McCluggage et al	40	Right labium minus	Painless tumor	(25)
		20	Right labium	Painless tumor
		19	Dermis of the vulva	Painless tumor
2008	Fong et al	17	Left vulva	Painless tumor	(26)
2009	Cetiner et al	23	Left labium majus	Painful tumor	(27)
		29	Left vulva	Painless tumor
2012	Kelling et al	18	Right labium majus	Growing painless tumor	(28)
2010	Boldorini et al	52	Lower right labium majus	Painless tumor	(29)
2018	Pei et al	33	Right vulva	Painless tumor	(30)
2017	Chiang et al	65	Vulva	Painless tumor	(31)
2019	Xu et al	3	Vulva	Painless tumor	(32)
2015	Tunitsky-Bitton et al	15	Left labium minus	Painful tumor	(33)
2015	Rekhi et al	10	Left vulva	Painless swelling	(35)
2014	Matsuda et al	60	Right vulva	Painless tumor	(36)
2013	Che et al	38	Left labium majus	Painless tumor	(37)
2019	Cantos et al	52	Clitoris	Growing painless tumor	(40)
2017	Kakoti et al	16	Left vulva	Growing tumor with severe pain	(41)

Table II. Available case reports of vaginal extraosseous Ewing's sarcoma or primitive neuroectodermal tumors.

Table II.

Available case reports of vaginal extraosseous Ewing's sarcoma or primitive neuroectodermal tumors.

Year of publication	Author(s)	Patient's age	Location	Symptoms	Reference
2000	Vang et al	35	Vagina	Painless tumor	(21)
2000	Farley et al	35	Vagina	Painless tumor	(44)
2002	Petković et al	45	Recto-vaginal septum	Painful tumor	(50)
2003	Gaona-Luviano et al	34	Vagina	Painless tumor	(45)
2004	Liao et al	30	Vagina	Painless tumor	(46)
2007	McCluggage et al	30	Vagina	Painless tumor	(25)
2009	Al-Tamimi et al	47	Vagina	Painless tumor	(47)
2009	Yip et al	28	Vagina	Painless tumor, discharge	(48)
2010	Rekhi et al	17	Vagina	Painless tumor, discharge	(12)
2013	Machado et al	32	Vagina	Painless tumor, discharge	(51)
2012	Bancalari et al	39	Vagina	Bleeding tumor	(49)
2012	Pang et al	54	Vagina	Bleeding two tumors	(52)
2016	Modi et al	34	Vagina	Painless tumor, bleeding	(53)
2017	Cross et al	12	Vagina	Painless tumor, discharge, bleeding	(54)
		15	Vagina	Abdominal discomfort, bleeding, discharge, painless tumor	(54)

Clinical and paraclinical evaluation

The clinical findings in vulvar PNT or extraosseous Ewing's sarcoma vary from the presence of a rapidly growing tumor to a cystic or peduncled appearance on the labia majora, labia minora or clitoris, or to the presence of ulceration or inguinal lymphadenopathy (16–43,55).

Therefore, complete clinical examination is essential to assess local extension, and more attention must be paid to the inguinal lymph nodes. In locally advanced cases, magnetic resonance imaging or computed tomography should be performed (56). In the case of suspected lymphadenopathy, fine needle aspiration may be performed under ultrasound guidance (56). Distant metastases present at the time of diagnosis are rare and indicate a reserved prognosis, as most often, these lesions are located in the lungs (19,24,25,28,42,56).

Regarding the differential diagnosis of vulvar PNT or extraosseous Ewing's sarcomas, the diagnoses of genital herpes, inguinal granuloma caused by Klebsiella granulomatis, chancroid due to Haemophilus ducreyi, rhabdomyosarcoma, malignant fibrous histocytoma, leiomyosarcoma, epithelioid sarcoma, neuroblastoma, Paget's disease of the vulva, lymphoma, small cell carcinoma, malignant melanoma (~10% of vulvar tumors), Merkel cell carcinoma, squamous cell carcinoma of the vulva, Bartholin's gland cyst, Bartholin's gland carcinoma, basal cell carcinoma of the vulva, vulvar wart carcinoma and metastases from other organs should first be excluded (26,33,56).

In addition, vaginal PNT or extraosseous Ewing's sarcoma may cause various symptoms, including vaginal bleeding or a painless intravaginal tumor (36). Therefore, the differential diagnosis of vaginal PNT and extraosseous Ewing's sarcoma should be made with benign vaginal lesions, extrauterine leiomyomas or lipomas (33).

Furthermore, PNT and extraosseous Ewing's sarcoma are histologically characterized by the presence of small blue cells with a rosette-like pattern, but diagnosing is difficult due to, not only the similar findings on the usual staining, but also their similarity with other types of small cell tumors, including rhabdomyosarcoma, osteosarcoma, non-Hodgkin's lymphoma, Merkel cell tumors, malignant melanoma and other primary small cell tumors and their metastases (19).

Therefore, once the diagnosis of PNT or extraosseous Ewing's sarcomas is made, the next step is to differentiate between the two. The differences between PNT and extraosseous Ewing's sarcoma are that, unlike PNT, Ewing's sarcomas have no neuroectodermal differentiation (12). Therefore, in electron microscopy, the presence of neurosecretory granules may differentiate PNT from Ewing's sarcoma.

Immunohistochemical and genetic aspects in differential diagnosis

From an immunohistochemical perspective, the CD99 marker may be found in 97% of cases of PNT and extraosseous Ewing's sarcoma (57). Another immunohistochemical characteristic of PNT and extraosseous Ewing's sarcoma is the lack of expression of the CD20 marker, which is specific for B-cell lymphoma, and CD15, which occurs in several types of leukemia and Hodgkin's lymphoma (16).

In terms of the differences from other types of cancer, cytokeratin (AE1/AE3) expression is positive in Merkel cell carcinoma and small cell lung cancer, is rarely positive in Ewing's sarcoma and malignant melanoma, and is negative in lymphoma (58). Cytokeratin 20 (CK20) expression is positive in Merkel cell carcinoma, but negative in small cell lung cancer, lymphoma, malignant melanoma and Ewing's sarcoma (58). Cytokeratin 7 (CK7) expression is positive in small cell lung cancer, but negative in Merkel cell carcinoma, lymphoma, malignant melanoma and Ewing's sarcoma (58).

Furthermore, the expression of thyroid transcription factor or the mammalian achaete-scute homolog 1 gene is positive in non-small cell lung cancer, but negative in small cell lung cancer, malignant melanoma, lymphoma and Ewing's sarcoma (59). In addition, S-100 protein expression is positive in Merkel cell carcinoma, lymphoma, lung cancer and Ewing's sarcoma (60). However, S-100 protein expression is negative in malignant melanoma (60).

Finally, the expression of chromogranin A and B, proteins located in the secretory vesicles, and CD56 is positive in malignant melanoma, neuroendocrine tumors, small cell lung cancer, and Merkel cell carcinoma, but negative in lymphoma (Table III) (61). However, from a genetic perspective, PNT and extraosseous Ewing's sarcomas exhibit the chromosomal abnormality t(11;22)(q24;q12), which involves the binding of the EWSR1 gene with the FLI1 gene, which encodes the EWS/FLI fusion protein. This translocation is essential to confirm the diagnosis of rare tumors, including PNT and extraosseous Ewing's sarcoma of the vulva or vagina (13,18,33,49).

Table III. Immunohistochemical aspects in differential diagnoses of Ewing's sarcoma.

Table III.

Immunohistochemical aspects in differential diagnoses of Ewing's sarcoma.

Positive in Ewing's sarcoma	Negative in Ewing's sarcoma
CD99 markers	CD20 markers
S-100 protein expression	CD15 markers
CD56 expression	Cytokeratin expression
	(AE1/AE3)
	Cytokeratin 20
	Cytokeratin 7
	Thyroid transcription factor

Location

Although the literature has extremely limited data regarding the incidence, information on the location of extraosseous Ewing's sarcoma and PNT demonstrates that ~30% of the tumors are located in the paravertebral region (62), 25% in the lower extremities (62), 20% in the chest wall (63), 10% in the pelvic region (64–66), 10% in the retroperitoneum (63), 5% in the head and neck (67), and <1% in the upper extremities (10).

Prognostic factors

Extraosseous Ewing's sarcomas have a generally reserved prognosis, but patients with vulvar localization appear to have a better prognosis, possibly due to localization and detection at an early stage, and the ability to perform surgery with negative margins (37).

PNTs appear to be more aggressive than Ewing's sarcomas (18). Furthermore, Serlo et al (68) demonstrated that younger patients have a better prognosis, and the use of adjuvant chemotherapy also improves prognosis. As in Ewing's sarcoma of the bone, the most unfavorable prognosis is determined by the presence of secondary disseminations, locally advanced disease, surgical resection with positive margin and resistance to chemotherapy (69).

Treatment

Given the rarity of cases, there are no guidelines for the treatment of these types of tumors. The treatments are often multimodal, depending on the location, extent and characteristics of the tumors. The recommended treatments include surgery, radiotherapy and systemic chemotherapy. Chemotherapy may be neoadjuvant, adjuvant or palliative. However, when feasible, surgery is always recommended first. Adjuvant chemotherapy has demonstrated significant survival benefit. The main chemotherapeutic agents used in the treatment of PNT and extraosseous Ewing's sarcomas are those that are also used for Ewing's sarcoma of the bone. The chemotherapeutic agents that have been used successfully on PNT and extraosseous Ewing's sarcoma are vincristine, doxorubicin, cyclophosphamide, actinomycin-D, ifosfamide and etoposide. Furthermore, the use of the oral tyrosine kinase inhibitor, pazopanib, has shown beneficial effects (33,70).

In addition, there is an increased interest in developing a treatment approach based on redox-modulating chemotherapeutics (71). This in-development type of treatment is based on the idea that oxidative stress and redox regulation may serve vital causative roles in the initiation and progression of numerous cancer types. The therapy is based on direct or indirect pro-oxidant approaches, which are referred to as redox therapeutics (72). Two distinct directions have been proposed for the development of the therapy: the first one is oxidant-generating therapy, which refers to the possibility of enhancing the intracellular concentration of reactive oxygen species (ROS), while the second one is antioxidant-inhibitor therapy, which involves inhibiting the antioxidant defense systems of cancer (73). The assumption underlying these two treatments is that enhancing intracellular levels of ROS above the capacity of endogenous antioxidant defenses will destroy the tumor cells.

Conclusions

Although PNT and extraosseous Ewing's sarcoma are very rare tumors, they should be taken into consideration when making a differential diagnosis for tumors of the lower gynecological tract. In addition, Ewing's sarcomas and PNTs are more commonly described as a painless mass in the older age group than in the younger age group. The diagnosis should be made using histological and immunohistochemical analyses and should be confirmed by molecular techniques, given its rarity. However, further molecular and histopathological studies are essential for a better understanding of these conditions and for an early, accurate diagnosis. Although the gathered and presented information from the present review is limited, the literature demonstrates that the outcomes of these types of cancer appear to be more favorable than those observed for carcinomas in more typical locations.

Acknowledgements

Not applicable.

Funding

No funding was received.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Authors' contributions

AT, BD, EA and CA made substanțial contributions to the conception of the study. DG, GS, RM and CI acquired data. AT, BD, EA and CA contributed to analysis and interpretation of data. DG, GS RM and CI wrote the paper. All authors have read and approved the manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

References