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Ewing’s sarcoma/PNET of the cervix is an extremely rare entity. Our review shows that
there have been only 18 cases reported so far in the English literature; we report
the 19th case (Table 1). In two cases, PNET was reported in association with another malignancy. Horn et al. reported PNET with squamous cell carcinoma of the cervix, and Tsao et al. reported carcinoma in addition to PNET, and described their case as a “carcinosarcoma”
2], 3]. The ages at presentation ranged between 19 and 60 years, with the mean age being
39.

Table 1. Clinical and pathologic features, diagnosis, treatment, and outcome of peripheral
neuroectodermal tumors of the cervix

The most common symptom reported was irregular vaginal bleeding. Other symptoms included
dysuria, lower abdominal pain, vaginal discharge, and in one case, urinary frequency.
The most common physical findings were nodular lesions extending into the anterior
vaginal wall and enlarged uterus. The vaginal bleeding with enlarged uterus led to
the preliminary diagnosis of fibroid in two patients 3], 4]. One patient had vaginal stenosis and necrotic tissue on the cervix 5].

Stage was not reported in three cases. Ten (62.5 %) patients were stage IB1 or IB2,
one (6.25 %) stage IIA, two (12.5 %) stage IIB, one (6.25 %) stage IIIB, and two stage
IV (12.5 %).

In the reported cases, multiple imaging modalities including ultrasound, CT, and MRI
were used for diagnosis and staging. Our review shows that PNET tumors are highly
fludeoxyglucose avid. PET scan may be a useful imaging modality in diagnosis, staging,
and monitoring response to therapy.

The diagnosis of EFTs is difficult by routine microscopy because they have small blue
cell morphology that can be seen in several malignancies. On histology examination,
there are sheets of small blue cells with “stippled salt and pepper chromatin” in
the nuclei and absence of nucleoli 6]. Necrosis and nuclear molding of adjacent cells is common. Additionally, the cells
easily become crushed during processing of the specimen, producing smudged and streaked
extra nuclear chromatin (crush artifact). Small round blue cells can be seen in a
wide variety of malignancies which can be remembered using the pneumonic “LEMON” (lymphoblastic
lymphoma, Ewing’s sarcoma, medulloblastoma, oat cell/small cell neuroendocrine, and
neuroblastoma). Other soft tissue sarcomas and rhabdomyosarcoma should also be considered
in the differential diagnosis. Lymphoblastic lymphomas closely resemble PNET because
they have sheets of small cells with a lack of glandular or squamous differentiation.

Immunohistochemistry is critical in the diagnosis. Small cell neuroendocrine carcinomas
are usually positive for chromogranin, synaptophysin, and neuron-specific enolase,
and overlap highly with PNET. The vast majority of EFTs express high levels of a cell
surface glycoprotein CD99 or MIC2 surface antigen that is encoded by the CD99 (MIC2X)
gene 7], 8]. The finding of membrane-localized MIC2 expression in a small blue cell malignancy
is a sensitive diagnostic marker for the EFTs. MIC2 lacks specificity because other
tumors, like rhabdomyosarcoma, can be MIC2 positive. However, small cell carcinomas
are negative for MIC2. Benbrahim et al. reported a case of cervical PNET that was initially misdiagnosed as lymphoma 9]. Lymphoid markers, leucocyte common antigen, CD20, and CD3 can be utilized to differentiate
lymphoma from PNET 9].

Molecular genetic characterization of chromosomal anomalies specific to EFT has led
to increased detection. The characteristic signature translocation involving the EWS gene at 22q12.2 and various erythroblast transcription specific-family genes, like
FLI (friend leukemia virus integration 1) at 11q24.1-q24.3, is seen in 85–90 % of cases
10], 11]. ESWR encodes a multifunctional protein that regulates multiple cellular processes. FLI1 encodes the FLI1 protein, which controls cellular development, proliferation, and
carcinogenesis 12]. The EWSR1–ERG translocation [t (21; 22) (q22; q12)] is present in 5–10 % of EFTs, while other translocations
are less common 13].

Most of the cases reported were diagnosed based on histopathology and immunohistochemistry
(Table 1). Cytogenetic analysis 14] was done in one case. Fluorescent in situ hybridization 14] was used in two cases including our case, while reverse transcriptase polymerase
chain reaction 15], 16] was used in two cases.

Currently there is no uniformity of treatment, owing to the rarity of this neoplasm.
Snijders-Keilholz et al. recommended a multidisciplinary approach similar to that used in osseous PNETs with
induction chemotherapy, surgery, adjuvant chemotherapy, and radiation 17]. When surgery is feasible, wide excision performed at a sarcoma center is preferable.

Most patients (Table 1) with early stage disease underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy.
Pelvic lymph node dissection was performed in 11 out of 19 cases. Of these 11 cases,
eight patients are alive without recurrence, the outcome of two cases is unknown,
and one patient died from metastatic disease 4 years later. Of the eight cases that
did not use lymph node dissection, two tumors were inoperable owing to stage IIIB
5] and IV 16] disease. The stage of one patient is unknown. The remaining five cases were early
stage (three stage I B2, two stage IIB). Of these five cases, one patient did not
receive any chemotherapy and died 4 years later. Our patient (stage IIB) died 10 months
later despite chemotherapy and radiation. The other three cases received chemotherapy
and are alive without relapse. The contribution of Pelvic lymph node dissection (PLND)
to overall survival, especially in patients who had chemoradiation, is unclear.

Chemotherapy was used in 16 of the 19 cases (Table 1). Two patients who were metastatic at diagnosis received palliative chemotherapy.
Although adjuvant chemotherapy was used in the earlier reported cases, a combined
regimen of neoadjuvant and adjuvant chemotherapy has been used frequently in recent
years, with favorable results. The chemotherapy regimens and schedules used varied
considerably. The use of ifosfamide and etoposide alternating with vincristine, doxorubicin
(Adriamycin) and cyclophosphamide, which is the regimen of choice for Ewing’s sarcoma
of the bone, has increased in recent years with good outcomes. The overall survival
appears to have dramatically improved with the use of chemotherapy.

Eight of 19 patients (Table 1) received radiation therapy. The intent of radiation was palliative in one case,
definitive in three, and adjuvant in four. The definitive chemoradiation given to
our patient was part of the small cell carcinoma regimen owing to an initial small
cell diagnosis, but she subsequently developed pelvic recurrence 9 months after diagnosis.
Another case death from pelvic recurrence 9 months after diagnosis was reported by
Xiao et al. 18], but the authors did not report if radiation was given. Radiation doses ranged from
40 to 55 Gy with the fractionation schedule of 180–200 cGy over 4–5 weeks. Overall,
we conclude that adjuvant radiation may have a role in preventing local recurrence
and should be considered when appropriate.

The follow-up of these cases ranged between 5 months and 8 years, with 15 of the 19
cases being alive and recurrence-free at the time of follow-up. Two patients died
of metastatic disease 12 days and 4.2 years after presentation, respectively. Our
patient developed metastatic disease while on adjuvant chemotherapy and died 10 months
after diagnosis. The outcome of a case reported by Goda et al. 19] is unknown.

The best outcomes were noted in patients who underwent tri-modality therapy with surgery,
chemotherapy, and radiation; although owing to the paucity of cases the best approach
is still unknown.

Similar to skeletal Ewing’s sarcoma, the most unfavorable prognostic factor is the
presence of distant metastasis, with stage IV disease being universally fatal. A recent
review by Baldini et al. 20] suggested that age may be a prognostic factor in survival and elderly patients do
poorly.