CASE REPORT

Malignant extragonadal yolk sac tumor of the cervix in a 2-year-old female: case report

SPMC J Health Care Serv. 2016;2(1):6 ARK: http://n2t.net/ark:/76951/jhcs27fmx8


Aeia R Agarano,1 Andrew U Alvarez,1 Chastitee M Amora,1 Alvin P Arreola,1 Catherine E Autida,1 Tessa Marie R Balboa,1 Glennilyn L Bantilan,1 Rocelyn M Barrientos,2 Benjamin Alejandro R Untalan,1 Cheryl Lyn A Diez,3 Maria Theresa T Sanchez,4 Mae Concepcion Dolendo3


1Davao Medical School Foundation, Medical School Drive, Bajada, Davao City, Philippines;
2Central Philippine University, Jaro Iloilo City, Philippines; 3
3Children's Cancer and Blood Diseases Unit, Department of Pediatrics, Southern Philippines Medical Center, Bajada, Davao City, Philippines;
4Department of Radiological and Imaging Sciences, Southern Philippines Medical Center, Bajada, Davao City, Philippines


Correspondence Aeia R Agarano, agaranoaeia@yahoo.com
Received 31 May 2016
Accepted 22 July 2016
Cite as Agarano AR, Alvarez AU, Amora CM, Arreola AP, Autida CE, et al. Malignant extragonadal yolk sac tumor of the cervix in a 2-year-old female: case report. SPMC J Health Care Serv. 2016;2(1):6. http://n2t.net/ark:/76951/jhcs27fmx8


Abstract

Extragonadal germ cell tumors (EGGCT) are rare neoplasms. Yolk sac tumors (YST), a histologic variant of EGGCT, is rarely found in the cervix, especially among infants. We report a 2-year-old girl who presented with a 6-week history of foul smelling vaginal discharge and a cervical mass on computed tomography. Diagnosis of YST was established through biopsy, positive immunohistostaining with SALL4, placental alkaline phosphatase (PLAP) and alpha-fetoprotein (AFP), and an elevated serum AFP level. Because surgery can possibly affect the patient’s reproductive capacity adversely, we initially decided to aim for remission with chemotherapy. The presence of a residual mass post-chemotherapy and an increasing trend in serum AFP levels prompted us to do radiotherapy for local control of the mass with incomplete tumor response.


Keywords. cervico-uterine mass, germ cell tumor, radiotherapy, chemotherapy, immunohistostaining


Introduction

Malignant germ cell tumors (MGCT) are rare. Their incidence varies according to age and sex. They occur in the <20-year-old group with the incidence of 12 cases per million.1 Pediatric MGCT account for less than 3% of pediatric malignancies.2 In children less than three years of age, MGCT are most commonly extragonadal or testicular in males and ovarian in females.1 Extragonadal germ cell tumors (EGGCT) are germ cell neoplasms characterized by one of the histologies associated with gonadal origin, but are located outside of the gonads. Commonly, EGGCT are located in the mediastinum and retroperitoneum. On rare occasions, EGGCT can be found in the pineal region, prostate, vagina, sacrococcygeal region, orbital region, liver and gastrointestinal tract.3 Cervical yolk sac tumor, a variant of EGGCT, is extremely rare, with only three cases in children less then three years old reported worldwide.4 5 6 We present a young girl who came in due to bloody vaginal discharge and was eventually diagnosed as having malignant extragonadal yolk sac tumor of the cervix.

Clinical features

A two-year-old girl from Southern Mindanao came to our institution for a six-week history of occasional bloody, brownish, foul smelling vaginal discharge, with passage of meaty tissues and blood clots. This was associated with occassional vaginal pain. There was no reported fever, loss of appetite, weight loss, vomiting, dyspnea, abdominal pain, diarrhea and easy bruising. The patient’s parents brought her to a local clinic, and she was initially prescribed with antibiotics, which did not stop the symptoms. During a second consult in a local hospital, a pelvic ultrasonography done on the patient revealed an echogenic solid structure, measuring 2.8 x 2.4 cm, and located in the pelvic region. She was then referred to a pediatric oncologist in our institution for further evaluation and management. The patient’s past medical, family, birth, and maternal histories were all unremarkable. She had complete immunizations for a two-year-old, and her growth and developmental milestones have been at par with age.

On physical examination during the initial admission, the patient was awake but was pale and weak looking. She had pale conjunctivae. The abdomen was globular. A firm, palpable hypogastric mass, measuring 7 x 3 cm, and bilateral inguinal lymph nodes were noted. The external genitalia showed no lesions. Vaginoscope also revealed an intact hymen. The rest of the physical and neurological examination findings were unremarkable. Our primary consideration then was vaginal bleeding secondary to a urogynecological tumor.

Diagnostic approaches

Blood workup revealed anemia of 94 g/L and leukocytosis of 10.60 x 103/µL with 77% neutrophilic predominance. We requested for alpha-fetoprotein (AFP), lactate dehydrogenase (LDH) and beta human chorionic gonadotropin (beta-hCG), which all turned out to be elevated: >3000 ng/mL (normal 0-9 ng/mL), 736 U/L (normal: 266-500 U/L) and 0.710 mIU/mL (normal: 0.5-1350 mIU/mL), respectively. Computed tomography (CT) of the whole abdomen with oro-rectal contrast (Figure 1) showed a large cervico-uterine mass, measuring 6.4 x 5 x 4.3 cm, and compressing the sigmoid colon and urinary bladder. At this point, we were considering either a germ cell tumor or a sarcoma.

Figure 1    Abdominal computed tomography taken on admission, showing a large, fairly defined, heterogeneously enhancing soft tissue, measuring 6.4 x 5 x 4.3 cm, noted at the region of the cervix and uterus (A, B, and C: red arrows). Cystic components are seen contiguous to the enhancing mass (A, B, and C: yellow arrows). The sigmoid colon is compressed, which shows wall thickening. The mass causes compression and displacement of the urinary bladder anteriorly (A, B, and C: green arrows). Multiple enhancing lymph nodes are seen in the left and right inguinal areas (B: blue arrows).


From the mass noted on initial CT scan, we did a biopsy by transvaginal approach. Histopathologic findings revealed areas with reticular, cord-like and microcystic patterns (Figure 2). The neoplastic cells demonstrate immunoreactivity to SALL4, PLAP and AFP. These findings are consistent with a malignant germ cell tumor, specifically yolk sac tumor (YST). We staged the patient’s malignancy as Stage 2, due to the involvement of the regional lymph nodes, as seen on physical examination and CT scan and based on the Childhood Extragonadal and Extracranial Germ Cell Tumor Staging.7

Figure 2    Histopathology of the cervico-uterine mass, which revealed a malignant neoplasm, displaying reticular, cord-like (A and B: yellow ring), and microcystic patterns (A, B, and C: red rings). The tumor is composed of polygonal cells with eosinophilic cytoplasm, round nuclei and occasional prominent nucleoli (hematoxylin-eosin stain, A: x200, B: x200, C: x400). The neoplastic cells demonstrate immunoreactivity for SALL4 with nuclear staining of tumor cells (D: red ring, x400) and for AFP with cytoplasmic staining of tumor cells (F: red ring, x400), consistent with a yolk sac tumor. Immunohistostaining with placental alkaline phosphatase (PLAP) shows very weak membranous and cytoplasmic staining of few tumor cells (positive) (E: x400).



Therapeutic approaches

Our initial goal was to achieve remission by chemotherapy to preserve our patient’s reproductive structures. We started the patient on a platinum-based chemotherapy regimen, consisting of six cycles of carboplatin, etoposide and bleomycin (JEB) every 28 days. AFP level monitoring throughout the JEB course showed a gradual decrease from the baseline level of >3,000 ng/mL to its normal range of 9-10 ng/mL. By the end of the sixth cycle, AFP level was 4.6 ng/mL (Figure 3).

Figure 3    Chart showing temporal relationships of the therapeutic interventions, serum alpha-fetoprotein (AFP) levels, serum lactate dehydrogenase (LDH) levels, and the patient’s tumor sizes by computed tomography (CT) scan, ultrasonography, and magnetic resonance imaging (MRI).


Repeat CT scan after the JEB course showed a residual mass measuring 2.5 x 3.3 x 1.4 cm (Figure 4), hence we decided to extend the patient’s chemotherapy regimen to 4 more cycles. The AFP level taken 11 weeks after the end of the tenth cycle was again elevated at 67.49 ng/ml. A repeat CT scan 3 months after the tenth JEB cycle did not show any significant reduction in the size of the mass (2.33 x 1.81 x 1.99 cm). The patient also started to have hypogastric pain. At this point, we decided to proceed with radiotherapy for local control. The patient underwent 28 fractions of external beam radiation therapy within 50 days. The tumor received a total radiation dose of 5040 cGy. After the radiotherapy, repeat ultrasonography revealed a reduction in the size of the mass to 1.2 x 0.9 x 0.8 cm.

The repeat AFP level taken three months after the end of radiotherapy showed further elevation at 143.9 ng/mL (Figure 3). We performed an abdominal magnetic resonance imaging (MRI), which revealed the presence of a residual mass measuring 1.8 x 1.2 x 0.7 cm (Figure 4).

Figure 4    Axial views of abdominal computed tomography (CT) pre-chemotherapy (A), CT post-chemotherapy (B) and magnetic resonance imaging (MRI) 12 weeks post-radiotherapy (C), demonstrating a decrease in the size of the mass in the cervico-uterine region (A, B, and C: red rings). R – right; P – posterior.



Outcomes

Due to the persistence of the mass and elevated AFP levels, we held a mutidisciplinary meeting with the Obstetrics-Gynecology, Pathology, Radiology, General Surgery, Urology, Pediatric Surgery and Pediatric Oncology services. The consensus was to perform a total hysterectomy with vaginal exploration after obtaining the informed consent of the patient’s family. Thorough preparation of the patient for the procedure is underway as of this writing.

Discussion

Bloody vaginal discharge is a common and distressing complaint in the vast majority of women, especially during their reproductive years. But when it occurs in a two-year-old girl whose reproductive tract has not yet fully developed, a variety of conditions must be considered as possible diagnoses.

Vulvovaginitis is the most common gynecologic problem for prepubertal children presenting with abnormal vaginal discharge, genital pain, pruritus, erythema and dysuria.8 Although this was initially considered in our patient, she did not improve when antibiotics were given. Other considerations that merit further investigation are trauma, the presence of foreign bodies or sexual abuse. We ruled out these conditions when the vaginoscopy done on the patient revealed an intact hymen and did not reveal any foreign body.

Genital tumors are uncommon among children and adolescents, accounting for only 1.5 to 2.0% of all malignancies in this age group.9 Vaginal bleeding in the premenarcheal girl is an early symptom and warrants investigation, including vaginoscopy.10 An ultrasonography that was initially done on our patient was able to elucidate the underlying cause and allowed us to perform timely interventions.

Vaginal malignancies are usually embroyogenic rhabdomyosarcomas, yolk sac tumors, or vaginal adenocarcinoma.9 11 In our patient, transvaginal biopsy initially revealed malignant germ cell tumor. We initially entertained either an embryonal carcinoma or yolk sac tumor. Immunohistotostaining, turned positive for SALL4, PLAP and AFP stains, confirmed the diagnosis of a yolk sac tumor.12 It is expected that PLAP staining in YST is often focal, with stain uptake of less than 30% of tumor cells.12

Perivascular Schiller-Duval bodies are the most distinctive features of yolk sac tumor12 13 but these structures were not found in the biopsy specimen that we took from our patient. Tumor markers may also help differentiate the germ cell tumors. An elevated serum AFP level is mostly consistent with yolk sac tumor, while germinomas and choriocarcinomas mostly produce beta-human chorionic gonadotropin (beta-HCG).14

Germ cell tumors, such as YST, mostly occur in the ovaries and testes.4 EGGCT, such as YST in the cervix, are extremely rare especially in the pediatric population. This is the first case of YST in the cervix that we have seen in our institution. A review of literature that we did revealed only three reported cases of cervical YST among children less than three years old.4 5 6 Our patient is the fourth reported case worldwide.

Management of tumors in pediatric gynecology remains challenging, as it aims not only to be lifesaving but also to preserve all capabilities for future pregnancy. The management of extragonadal YST may require the prudent combination of surgery, chemotherapy and radiotherapy.

Our patient’s pre-treatment tumor extended from the cervix to the uterus, displacing the bladder anteriorly and compressing the sigmoid colon. Due to the extent of the tumor in our patient, surgical resection of the mass will entail total hysterectomy eliminating any hopes of future childbearing. The decision to originally avoid surgery and to achieve remission by chemotherapy alone was based on our attempt to preserve our patient’s sexual and reproductive functions. When chemotherapy alone failed, we pursed radiotherapy, despite the added cost, to achieve local control of the residual tumor.

Chemotherapy with cisplatin, etoposide and bleomycin is the first line of chemotherapy and is the most effective regimen, with a greater than 90% overall survival outcome.15 In our patient, we used the equally efficacious carboplatin instead of cisplatin in order to avoid the renal toxicity of cisplatin, which commonly occurs among children.16

Radiotherapy is an acceptable alternative option to surgery for local control following first-line chemotherapy in EGGCT, particularly in the mediastinum.17 However, its role is less certain among patients with YST in the cervix. In previous case reports on EGGCT, most patients underwent surgical resection with neoadjuvant or adjuvant chemotherapy.4 5 6 Our patient is the first reported case of YST in the cervix where remission by chemotherapy and local control by radiotherapy were attempted. However, because of the residual tumor and rising AFP levels despite this approach, we decided to do surgical removal of the tumor.

The rarity of malignant extragonadal yolk sac tumor in the cervix compelled us to approach our patient’s management with limited information regarding effective treatments or evidence-based management guidelines, and with lack of experience among healthcare providers. We strongly considered our patient’s age, the site of the tumor, and the patient’s potential for childbearing when we opted to follow a chemotherapy and radiotherapy course, yet the patient’s incomplete response to chemoradiotherapy convinced us to resort to surgery.

In essence

Yolk sac tumor of the cervix is rare among children less than three years old.


In this case report, a two-year-old patient was diagnosed to have a cervico-uterine yolk sac tumor. Because of the location and possible complications or consequences of surgery, chemotherapy was initiated. The lack of a complete response prompted us to proceed with radiotherapy for local control. However, persistence of a residual mass and rising tumor markers made us decide to pursue surgery.


Based on limited case reports, complete remission and local control of yolk sac tumors may require chemotherapy, radiotherapy and surgery.


Acknowledgments

Our heartfelt gratitude goes to: the Department of Radiological and Imaging Sciences in Southern Philippines Medical Center (SPMC) for providing us the CT and MRI images used in this report; Dr Je-Ann Fabian-Tan of the Department of Radiology in Davao Doctors Hospital for evaluating and providing the labels in the CT and MRI images; the Division of Clinical Pathology, Department of Pathology in St Jude Children’s Research Hospital in Memphis, Tennessee, USA for performing the immunohistostaining and for preparing the histopathologic report; and to Dr Oscar P Grageda and the residents of the Department of Pathology and Laboratories in SPMC for reviewing the histopathologic images and for their additional inputs in the histopathologic report.


Patient consent

Obtained through the patient’s legally acceptable representative


Reporting guideline used

CARE Checklist (http://www.care-statement.org/downloads/CAREchecklist-English.pdf)


Article source

Submitted


Peer review

External


Competing interests

None declared


Access and license

This is an Open Access article licensed under the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to share and adapt the work, provided that derivative works bear appropriate citation to this original work and are not used for commercial purposes. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/


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Copyright © 2016 Agarano AR, et al.

     

Published
October 19, 2016

Issue
Volume 2 Issue 1 (2016)

Section
Case report