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CASE REPORT  
Year : 2015  |  Volume : 58  |  Issue : 3  |  Page : 341-344
Primary Ewing sarcoma of vulva, confirmed with molecular cytogenetic analysis: A rare case report with diagnostic and treatment implications


1 Department of Surgical Pathology, Tata Memorial Centre, Parel, Mumbai, Maharashtra, India
2 Department of Medical Oncology, Tata Memorial Centre, Parel, Mumbai, Maharashtra, India
3 Department of Nuclear Medicine and Molecular Imaging, Tata Memorial Centre, Parel, Mumbai, Maharashtra, India

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Date of Web Publication14-Aug-2015
 

   Abstract 

Primary vulvar Ewing sarcoma (ES)/PNET is an uncommonly documented tumor, especially with molecular results. A 10-year-old girl presented with left vulvar swelling, a year ago. Her abdominopelvic ultrasound revealed a 12 cm × 8 cm sized, mixed echogenic blood-filled lesion in the left vulva; radiologically considered as a hematoma. Vulvectomy revealed a multinodular grey-brown tumor, microscopically comprising malignant round cells. Immunohistochemically, tumor cells diffusely expressed MIC2/CD99 and Fli1 and subsequently displayed EWSR1 rearrangement, confirming diagnosis of ES/PNET. Subsequently, PET-CT scan revealed residual local lesion with lung metastases. The patient was induced on EFT 2001 chemotherapy protocol. Three months after chemotherapy completion, there was no metabolically active disease on PET scan. Four months later, MRI disclosed recurrent primary and metastatic pulmonary lesions. She was planned for scar excision and adjuvant radiotherapy, but unfortunately defaulted further treatment. This forms the eighth case of primary vulvar ES/PNET confirmed with molecular cytogenetic result, underscoring therapeutic value of objective diagnosis in such cases.

Keywords: Ewing sarcoma/primitive neuroectodermal tumor, EWSR1 rearrangement, female genital tract sarcomas, vulvar tumors

How to cite this article:
Rekhi B, Chinnaswamy G, Vora T, Shah S, Rangarajan V. Primary Ewing sarcoma of vulva, confirmed with molecular cytogenetic analysis: A rare case report with diagnostic and treatment implications. Indian J Pathol Microbiol 2015;58:341-4

How to cite this URL:
Rekhi B, Chinnaswamy G, Vora T, Shah S, Rangarajan V. Primary Ewing sarcoma of vulva, confirmed with molecular cytogenetic analysis: A rare case report with diagnostic and treatment implications. Indian J Pathol Microbiol [serial online] 2015 [cited 2022 Aug 11];58:341-4. Available from: https://www.ijpmonline.org/text.asp?2015/58/3/341/162869



   Introduction Top


Primary Ewing sarcoma (ES) and primitive neuroectodermal tumor (PNET) constitute as Ewing sarcoma family of tumors (ESFT), characterized by a t(11;22) (q24;q12) chromosomal translocation leading to a chimeric transcript EWS-FLI1 in 85% such cases. [1] ES/PNET is an aggressive malignant round cell tumor yet is chemosensitive. Therefore, its correct identification is vital, including at unusual sites. ES/PNET is uncommon in the female genital tract. It is objective confirmation necessitates the application of necessary immunohistochemical stains and molecular and or molecular cytogenetic analysis. [2],[3],[4],[5],[6],[7],[8],[9],[10] Primary ES/PNET of the vulva is as extremely rare tumor with only 7 such reported cases, objectively confirmed with molecular techniques. [3],[4],[5],[6]


   Case Report Top


A 10-year-old girl presented with left vulvar swelling since a year ago, un-associated with pain. She underwent radiological examination; a biopsy, followed by surgical excision, elsewhere. The paraffin blocks were submitted to us for review.

During her initial presentation, a swelling was noted over her vulvar region measuring 20 cm × 12 cm. At our center, she was found to be moderately undernourished with body mass index of 13.3. Her basic laboratory values were within normal limits.

Radiological findings

Abdominopelvic ultrasonogram revealed a 12 cm × 8 cm sized mixed echogenic mass lesion in the left vulva, filled with blood. The possibility of vulvar hematoma was suggested [Figure 1].
Figure 1: Real-time ultrasonogram pelvis showing a large sized, mixed echogenic mass lesion in the left vulva, filled with blood and containing septae


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Postoperative computed tomography scan showed irregular fluid collection in the left side of vulva extending into left perineum along with surrounding edema.

Pathological findings

As per referring laboratory reports, grossly the vulvectomy specimen comprised two irregular masses weighing 140 g and measuring 8.3 cm × 5.7 cm × 3.7 cm and 7.2 cm × 4.6 cm × 4.5 cm, respectively. On cutting open, multiple tumor nodules were identified with gray brown surfaces, varying in area from 0.2 cm × 0.2 cm to the largest measuring 3 cm × 2.8 cm.

Microscopic sections displayed a malignant round cell tumor with monomorphic cells arranged in a diffuse manner, containing fine chromatin, scanty indistinct cytoplasm, and inconspicuous nucleoli. At places, tumor cells were seen around blood vessels [Figure 2]a.
Figure 2: (a) Microscopically, a malignant tumor composed of fairly monomorphic round cells with fine nuclear chromatin and scanty cytoplasm, arranged in a diffuse pattern (H and E, ×200). (b) Immunohistochemically, diffuse staining with CD99/MIC2 (DAB, ×400). (c) Diffuse intranuclear staining with Fli1 DAB, ×400. (d and e) Fluorescent in-situ hybridization. Two tumor nuclei, respectively, displaying EWSR1 rearrangement, indicated by red and green "split signals" DAPI ×1000


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By immunohistochemical staining, tumor cells displayed diffuse cytoplasmic membranous staining with CD99/MIC2; intense, intranuclear staining with Fli-1, while these showed negative staining with desmin, MyoD1, myogenin, leukocyte common antigen, smooth muscle actin, desmin, AE1/AE3, epithelial membrane antigen and CD56. INI1/SMARCB1 was retained [Figure 2]b and c. In view of the lack of representative sections, margins of resection could not be commented upon. Diagnosis of ES/PNET was offered.

Subsequently, the tumor was subjected to molecular cytogenetic analysis by fluorescent in-situ hybridization (FISH) that showed 100% rearrangement, confirming the diagnosis of ES/PNET [Figure 2]c and d. Molecular analysis by reverse transcriptase-polymerase chain reaction (RT-PCR) was negative for EWS-FLI1 and ESW-ERG transcripts.

Management and outcome

Two months post-excision, positron emission tomography computed tomography (PET-CT) scans showed a soft tissue thickening involving the left vulva with focal fluorodeoxyglucose uptake in the left perineum (maximum standardized uptake value 4.60). Additionally, a 6 mm sized nodule was seen in the lower lobe of the right lung; 5 mm nodule in the left lower lobe and another nodule in the lingular lobe, indicative of metastatic lesions.

The patient was induced on ESFT 2001 chemotherapy (CT) protocol, including 5 cycles of injectable vincristine (1.6 mg), ifosfamide (2.2 g), mesna (440 mg) and etoposide (110 mg). Three months after her initial PET-CT scan, subsequent to completion of CT cycles, her whole body PET-CT scan showed complete metabolic regression of primary and metastatic lesions, indicative of complete response to CT [Figure 3]a-d.
Figure 3: (a) Positron emission tomography-computed tomography (PET-CT) scan post tumor excision and pre chemotherapy induction showing residual primary disease (arrow). (b) PET-CT scan post chemotherapy induction showing complete resolution of residual primary disease. (c) PET-CT scan pre chemotherapy induction showing metastatic lung nodule (arrow). (d) PET-CT scan post chemotherapy induction showing complete resolution of metastatic lung nodule


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Four months after chemotherapy completion, magnetic resonance imaging disclosed a sizable, ill-defined heterogeneous, postcontrast enhancing lesion involving the left labia majora and mons pubis, indicative of recurrent disease. Additionally, metastatic nodules were noted in bilateral lungs. The patient was planned for surgical re-excision with interstitial radiotherapy, including "lung bath." However, she defaulted for further treatment.


   Discussion Top


Primary ES/PNET of vulva is a rare and an aggressive tumor with nearly 16 such documented cases, including 7 cases confirmed with molecular analysis. Reported mean and median age of occurrence was 22.8 and 20 years, respectively [Table 1]. [2],[3],[4],[5],[6],[7],[8],[9],[10] The present case is the second most young such patient, who presented with vulvar swelling that was radiologically considered as a hematoma. [2]
Table 1: Cases of primary vulvar Ewing sarcomas/PNETs, confirmed by ancillary tests, published in English literature


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Definite diagnosis was achieved on microscopy coupled with immunohistochemical stains and molecular results. Differential diagnoses included small cell carcinoma, synovial sarcoma, and rhabdomyosarcoma. Diffuse membranous MIC2 and intranuclear Fli1 were indicative of ES/PNET, while negative desmin and MyoD1 ruled out a rhabdomyosarcoma. Lack of speckled nuclear chromatin and negative epithelial and neuroendocrine markers made the possibility of small cell carcinoma, less likely. MIC2 and Fli1 positivity is also seen in a blastic non-Hodgkin's lymphoma and synovial sarcoma. Cytoplasmic membranous MIC2 expression is more consistent with ES/PNET. In addition, the diagnosis was confirmed with molecular cytogenetic analysis. However, EWS-FLI1 and EWS-ERG transcripts were not detected, in this case, as also noted by others. [4],[5] The reason for lack of these transcripts could have been probable expression of house-keeping gene at higher level than EWS fusion transcripts or larger base pair size of the designed primers. Moreover, there are several other fusion partners/transcripts with EWSR1 gene within ESs. [1] This reinforces value of testing such cases by two techniques, namely FISH and RT-PCR. While RT-PCR identifies specific transcripts, FISH helps in identifying "basic" EWSR1 rearrangement that was detected in the present case. Therapeutically, most of the earlier documented cases were treated with surgery and specific adjuvant CT, including the present case, with optional radiotherapy in certain cases. [3],[4],[5],[6],[7],[8],[9],[10] Prognosis was fairly grim in metastatic cases, including most patients, who either died of disease or were alive with disease during their last follow-up, including the present case. [4],[7],[8],[9],[10] In cases of non-metastatic lesions, there was survival benefit ranging from 18 to 51 months. [3],[5],[6] Our patient initially underwent tumor resection with unclear margins and presented with metastatic lesions at our center. She had completed metabolic response after 6 cycles of CT adding to survival benefit. Unfortunately, she developed recurrent lesion and newer metastatic lesions for which she did not undertake further treatment.


   Conclusion Top


Ewing sarcoma/PNET should be considered as one of the suspected round cell tumors at uncommon sites, such as vulva. Exact diagnosis necessitates confirmation with necessary immunohistochemical markers and molecular analysis. A timely, correct diagnosis has therapeutic relevance and offers survival benefit.

 
   References Top

1.
Aurias A, Rimbaut C, Buffe D, Dubousset J, Mazabraud A. Chromosomal translocations in Ewing′s sacoma. C R Seances Acad Sci III 1983;296:1105-7.  Back to cited text no. 1
[PUBMED]    
2.
Scherr GR, d′Ablaing G 3 rd , Ouzounian JG. Peripheral primitive neuroectodermal tumor of the vulva. Gynecol Oncol 1994;54:254-8.  Back to cited text no. 2
    
3.
Vang R, Taubenberger JK, Mannion CM, Bijwaard K, Malpica A, Ordonez NG, et al. Primary vulvar and vaginal extraosseous Ewing′s sarcoma/peripheral neuroectodermal tumor: Diagnostic confirmation with CD99 immunostaining and reverse transcriptase-polymerase chain reaction. Int J Gynecol Pathol 2000;19:103-9.  Back to cited text no. 3
    
4.
McCluggage WG, Sumathi VP, Nucci MR, Hirsch M, Dal Cin P, Wells M, et al. Ewing family of tumours involving the vulva and vagina: Report of a series of four cases. J Clin Pathol 2007;60:674-80.  Back to cited text no. 4
    
5.
Cetiner H, Kir G, Gelmann EP, Ozdemirli M. Primary vulvar Ewing sarcoma/primitive neuroectodermal tumor: A report of 2 cases and review of the literature. Int J Gynecol Cancer 2009;19:1131-6.  Back to cited text no. 5
    
6.
Boldorini R, Riboni F, Cristina S, Allegrini S, Valentini S, Muscarà M, et al. Primary vulvar Ewing′s sarcoma/primitive neuroectodermal tumor in a post-menopausal woman: A case report. Pathol Res Pract 2010;206:476-9.  Back to cited text no. 6
    
7.
Halil S, Kucuk M, Arvas M, Aydin O, Calay ZZ. Peripheral primitive neuroectodermal tumor (PNET) of the vulva: A case report. Eur J Gynaecol Oncol 2011;32:117-8.  Back to cited text no. 7
    
8.
Kelling K, Noack F, Altgassen C, Kujath P, Bohlmann MK, Hoellen F. Primary metastasized extraskeletal Ewing sarcoma of the vulva: Report of a case and review of the literature. Arch Gynecol Obstet 2012;285:785-9.  Back to cited text no. 8
    
9.
Che SM, Cao PL, Chen HW, Liu Z, Meng D. Primary Ewing′s sarcoma of vulva: A case report and a review of the literature. J Obstet Gynaecol Res 2013;39:746-9.  Back to cited text no. 9
    
10.
Xiao C, Zhao J, Guo P, Wang D, Zhao D, Ren T, et al. Clinical analysis of primary primitive neuroectodermal tumors in the female genital tract. Int J Gynecol Cancer 2014;24:404-9.  Back to cited text no. 10
    

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Correspondence Address:
Dr. Bharat Rekhi
Department of Pathology, Tata Memorial Hospital, 8th Floor, Annex Building, Dr E.B. Road, Parel, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.162869

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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1]

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