Fetal and Pediatric Pathology, 33:127–134, 2014 C Informa Healthcare USA, Inc. Copyright  ISSN: 1551-3815 print / 1551-3823 online DOI: 10.3109/15513815.2013.839013


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Sinonasal Pure Yolk Sac Tumor: A Case Report and Literature Review Huei Chieh Chuang,1 Chung-Jan Kang,2 and Li-yu Lee1 1

Department of Pathology, Chang Gung Memorial Hospital, Kwei Shan, Taoyuan County, Taiwan; 2 Department of Otolaryngology, Chang GungMemorial Hospital, Kwei Shan, Taoyuan County, Taiwan

Extragonadal pure yolk sac tumor of sinonasal origin is very rare. We report herein a case with sinonasal yolk sac tumor in a 1 year and 3 months old girl. The initial complaint was persistent nasal bleeding for about 2 months. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a lobulated soft tissue mass in paranasal sinus that extended to oral cavity, nasopharynx, and oropharynx. The histology showed typical features of yolk sac tumor and the positive immunohistochemical staining of SALL4 and α-fetoprotein. After tumor excision, adjuvant chemotherapy of JEB regimen was prescribed. After the follow-up for 13-months, α-fetoprotein was normal and neither tumor progression nor metastasis was found. We review the previous literature and discuss the etiology, histology, treatment, and the prognosis of the rare sinonasal yolk sac tumor. Keywords: sinonasal yolk sac tumor, endodermal sinus tumor, extragonadal germ cell tumor

INTRODUCTION Extragonadal germ cell tumors account for 20% of all germ cell tumors. The location is usually the midline of the body, such as the sacrococcygeal region, vagina, vulva, mediastinum, and central nervous system [1–5]. Germ cell tumors arising from the head and neck are extremely rare, representing only approximately 5% to 6% of all germ cell tumors [6]. However, head and neck germ cell tumors are primarily mixed germ cell tumors, and are mostly found in the neck. A pure yolk sac tumor of sinonasal origin is rarely reported. The origin of yolk sac tumor is known to be a heterogeneous germ cell tumor differentiating into multiple endodermal structures; a yolk sac tumor can produce α-fetoprotein (AFP) and can be differentiated from other nongerm cell tumors via SALL4 expression [3]. We present a case of yolk sac tumor in the unusual location of the soft palate and nasopharynx, as confirmed by immunohistochemical staining of SALL4. A girl at 1 year and 3 months of age without previous systemic disease and associated family history suffered persistent nasal bleeding for approximately 2 months. In addition, a soft mass over the soft palate was found by her parents. She received tumor excision in another hospital, and the initial pathology showed glial heterotopia Received 5 February 2013; Revised 25 August 2013; accepted 26 August 2013. Address correspondence to Li-yu Lee, Department of Pathology, Chang Gung Memorial Hospital, No. 5, Fusing St., Kwei Shan Township, Taoyuan County 333, Taiwan. E-mail: [email protected]


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H. C. Chuang et al.

Figure 1. Photomicrograph of previous excisional biopsy showed neuroglial tissue separated by fibrovascular core and scant ganglion cells. (Original magnification ×100.)

(Figure 1). Unfortunately, the recurrent and rapid growth of the soft mass over the left soft palate was found 3 weeks later. Hematoma formation over the left nostril and bleeding from the right nostril and left eye were also noted later. The girl was then admitted to our hospital and received facial bone computed tomography (CT) and magnetic resonance imaging (MRI). The images revealed a 3.9 × 3.7 × 3.4-cm lobulated and isointensity soft tissue mass centering in the left palatal region, extending to the left nasal cavity, left oral cavity, and nasopharynx with bony erosion. The mass showed mild heterogeneous contrast enhancement after contrast medium intravenous injection (Figure 2). The initial impression was nasopharyngeal angiofibroma or rhabdomyosarcoma, and surgical resection and flap reconstruction

Figure 2. The T2-weighted magnetic resonance imaging showed heterogeneous intensity mass after Gadolinium injection at soft palate and extending to sinonasal cavity. Fetal and Pediatric Pathology

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Sinonasal Pure Yolk Sac Tumor


Figure 3. The gross specimen showed a white, soft, and infiltrative tumor measuring 1.9 × 1.6 × 1.3 cm with a piece of overlying sinonasal mucosa.

were prescribed; however, the tumor could not be excised completely due to the deep location. The resection specimen consisted of a protruding tumor with central extensive ulceration measuring 1.9 × 1.6 × 1.3 cm (Figure 3). The microscopic features showed an infiltrative tumor composed of primitive tumor cells arranged in a solid, microcystic, reticular, and papillary pattern. The tumor cells showed vesicular nuclei, prominent nucleoli, and vacuolated cytoplasm with frequent hyaline globules (Figure 4). Subsequent immunohistochemical studies showed strong nuclear staining of SALL4 (Figure 5) and positivity of AFP, pancytokeratin (AE1/AE3), and glypican-3; CD30 and β-hCG were negative. The diagnosis of pure yolk sac tumor was confirmed by the absence of other germ cell components. Due to the highly elevated serum level

Figure 4. Photomicrographs of a typical Schiller–Duval body composed of pleomorphic tumor cells with distinct nucleoli and clear cytoplasm and central vascular core. (Original magnification ×400.) C Informa Healthcare USA, Inc. Copyright 

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H. C. Chuang et al.

Figure 5. Photomicrographs of intensive and diffuse SALL4 nuclear staining of tumor cells. (Original magnification ×400.)

of AFP (2243 ng/mL) after operation and positive surgical margin, the patient received adjuvant chemotherapy of the JEB regimen (carboplatin, VP-16 and bleomycin) for three cycles. AFP gradually decreased to the normal range (12.2 ng/mL) during the patient’s 13-month follow-up period. There was neither recurrence nor metastasis at the most recent visit. DISCUSSION Germ cell tumors of gonadal and extragonadal areas account for 3% of malignant disease in children and adolescents [1, 4]. Extragonadal sites typically include the head and neck and the midline of trunk, such as the vagina, vulva, central nervous system, mediastinum, sacrococcygeal region, stomach, prostate, urinary bladder, and mesentery [4, 5, 7–11]. Only 5% of germ cell tumors are found in the head and neck region (except for the central nervous system) and rarely arise from the sinonasal tract [12]. The most common pediatric germ cell tumors in the head and neck are teratomas and mixed germ cell tumors. Pure pediatric yolk sac tumor in the head and neck origin is extremely rare. According to the WHO classification of head and neck tumors, only two published yolk sac tumor occurrences have been reported in the sinonasal tract to date, and both patients were adults (aged 34 and 43 years) [13]. The clinical presentation of extragonadal yolk sac tumor depends on the tumor location, and patients who have sinonasal yolk sac tumor usually complain of nasal obstruction, epistaxis, and continuous nasal discharge. The clinical characteristic of yolk sac tumor is elevated serum AFP due to the excess production and secretion of tumor cells; lactic dehydrogenase (LDH) may also be elevated. The tumor may extend to the cranial cavity, orbital region, and exhibit local invasion [14]. Although yolk sac tumor of the sinonasal tract is rare, it is still found combined with a carcinomatous component, teratoma, and other germ cell tumors in adult and early-childhood patients. Furthermore, pure yolk sac tumor is even more rare and predominantly occurs in early-childhood and pediatric patients. English language literature from PubMed was surveyed and only seven cases of pure yolk sac tumors involving the sinonasal cavity were found (Table 1), though there were no available Fetal and Pediatric Pathology







3 [5]

4 [7]

5 [8] 6 [9]

7 [11]

8 (our case)




10 m

3y 4y


4y 6m


Nasal cavity Maxillary sinus, nasal cavity, cheek Maxillary sinus, ethmoid sinus, orbit, palate, and nasopharynx Left nasopharynx and nasal cavity

Right maxillary sinus and extension to orbit

Maxillary sinus Orbit and extending to ethmoid and maxillary sinus Maxillary sinus

Persistent nasal bleeding

– –

Conjunctiva injection, ptosis, and bloody rhinorrhea

– Epistaxis, ptosis, eyelid edema, and chemosis of left eye

Initial symptoms


Surgery + chemotherapy

Combination of chemotherapy: bleomycin, cisplatin, and etoposide Neoadjuvant chemotherapy (cisplatin, etoposide, ifosfamide), wide excision and adjuvant chemotherapy Chemotherapy Chemotherapy and radiotherapy Nil

RT and Chemotherapy Orbital exenteration and tumor excision

R, reference; –, without available data; M, male; F, female; y, year; m, month, CR, complete remission; DOD, dead of disease


1 [1] 2 [6]

Reported cases of pure yolk sac tumor in sinonasal cavity.


Table 1.

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No recurrence and metastasis (13 m)

DOD (1 m)

DOD:10 m CR (5.7 y)

Recurrence (6 m)

CR (3 y)

CR (17 y) DOD (5 m)

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H. C. Chuang et al.

data for the gender and age in the third case. The prevalence was slightly increased in females (five of seven known cases), and the onset was generally in early childhood (6 months to 4 years old; mean of 2.36 years old). If it was found with another component, including carcinoma, teratoma, and other germ cell tumors, the age of onset became bimodal (middle age and early childhood) [7, 10, 12, 27, 28]. Of the eight indentified cases, four showed no disease recurrence or metastasis in the following years (1 month to 17 years; mean of 3.57 years). In three cases, the patients died of the disease: one at 1 month after the diagnosis without any treatment and another in only 10 months while receiving chemotherapy; the remaining patient was dead within 5 months after tumor excision. Almost all cases received treatment, including chemotherapy (adjuvant or neoadjuvant), radiotherapy, and surgery as needed. Tumor progression of sinonasal yolk sac tumor was mostly noted during the first years after surgery. Yolk sac tumor, also known as endodermal sinus tumor, is a primitive germ cell neoplasm forming multiple endodermal structures in the placenta and typically arising from the gonads [15]. Although yolk sac tumor is commonly found in the gonads, extragonadal sites of origin are reported in 20% of the cases. The etiology of extragonadal germ cell tumors is uncertain. There are three hypotheses: the inappropriate migration of primordial germ cells during embryonic development; malignant transformation of undifferentiated pluripotent embryonic cells; or malignant transformation of extraembryonic cells that have escaped from the influence of primary development factors [15]. There are similar histological findings in yolk sac tumors of gonadal and extragonadal origins, such as specific growth patterns and AFP immunoreactivity. Yolk sac tumor cells display vacuolated cytoplasm, a single large nucleolus, and some small eosinophilic hyaline globules. The tumor cells commonly form a mesh work of microcystic, labyrinthine spaces within loose, basophilic, and myxoid stroma [16]. There are some histological variants of pseudopapillary, polyvesicular, glandular, hepatoid, and solid patterns [4]. The pseudopapillary pattern is the characteristic pattern of yolk sac tumor commonly known as “Schiller–Duval body” (papillary fibrovascular projections lined by epithelium) [14, 17]. Pure sinonasal yolk sac tumor in children needs to be differentiated from teratoma and teratoma with malignant transformation, whereas teratocarcinosarcoma chiefly occurs in adults [18–21]. We analyzed the entire specimen and found no teratomatous component. We also reviewed previous slides of the first surgery, but no mesodermal or endodermal component of teratoma, despite the glial heterotopia, was found. The malignant transformation of teratoma is usually revealed as a focal malignant component with synchronous teratoma in the same lesion. However, no teratomatous component was detected in the present case. In addition, the recurrence of teratoma with a malignant component generally does not occur until 2 years later, yet occurred at only 3 weeks from the first excision in our case [20]. Therefore, recurrent yolk sac tumor from teratoma was unlikely. Other differential diagnoses of sinonasal yolk sac tumor include rhabdomyosarcoma and other germ cell tumors in pediatric patients, with metastatic carcinoma and undifferentiated carcinoma tendencies in older patients. An immunohistochemistry staining panel for AFP, placental alkaline phosphate (PLAP), pan-cytokeration (AE1/AE3), CD30, β-hCG, glypican-3, and SALL4 can assist in the confirmation of yolk sac tumor diagnosis. SALL4 is a transcription factor involved in the maintenance of self-renewal and pluripotency in embryonic stem cells. SALL4 is known as a sensitive marker for yolk sac tumor in both gonadal or extragonadal germ cell tumors, though it is not specific enough to differentiate yolk sac tumor from other germ cell tumors [3, 22–24]. SALL4 staining in teratoma is typically weak and focal but diffuse Fetal and Pediatric Pathology

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Sinonasal Pure Yolk Sac Tumor


and strong in yolk sac tumor [3, 24]. In our case, the results of diffuse and strong SALL4 staining, AE1/AE3 positivity, CD30 negativity, and β-hCG negativity were able to exclude teratoma, dysgerminoma, embryonal carcinoma, and choriocarcinoma, respectively. However, SALL4 was also recently reported to show positive staining in hepatocellular carcinoma (HCC) [22], which might indicate a diagnostic pitfall between yolk sac tumor and HCC. Clinical history and typical morphological findings would be helpful in distinguishing between the two entities. The treatment of yolk sac tumor involves the combination of resection and chemotherapy. However, combined chemotherapeutic regimens including cisplatin were suggested to have more effect against yolk sac tumor [25, 26]. According to the previous cases reports, yolk sac tumor of the head and neck shows a highly aggressive behavior, which might be due to the difficulty of tumor approach and excision [11, 14, 27]. The poor prognosis is related to incomplete resection and anterior skull base involvement. Although the metastasis of lymph nodes is not considered to be related to the prognosis, distant metastasis to the liver, lung, regional‘ lymph nodes, and bone have been reported. Therefore, close monitoring of the AFP level can help to monitor the recurrence and metastasis status of extragonadal and gonadal yolk sac tumors. Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. REFERENCES [1] Gangopadhyay K, McArthur PD, Martin JM, Saleem M. Endodermal sinus tumor of the maxillary sinus: a case report. Ear Nose Throat J 1999;78(5):376–377, 381–382. [2] Kutluhan A, U˘gras¸ S, Akman E. Endodermal sinus (yolk sac) tumor of oral cavity originating from gingival. Auris Nasus Larynx 1998;25(4):459–462. [3] Wang F, Liu A, Peng Y, et al. Diagnostic Utility of SALL4 in extragonadal yolk sac tumors. An immunohistochemical study of 59 cases with comparison to placental-like alkaline phosphatase, alphafetoprotein, and glypican-3. Am J Surg Pathol 2009;33(10):1529–1539. [4] Dehner LP. Gonadal and extragonadal germ cell neoplasia of childhood. Hum Pathol 1983;14(6):493–511. [5] Nair R, Krishnamurthy S, Advani SH. Maxillary extragonadal germ cell tumor: a case report. Indian J Cancer 1993;30(4):202–204. [6] Kusumakumari P, Geetha N, Chellam VG, Nair MK. Endodermal sinus tumor in the head and neck. Med Pediatr Oncol 1997;29(4):303–307. [7] Bresters D, Zwaan CM, Veerman AJ, et al. A three-year-old girl with a yolk sac tumor in the orbit/maxillary sinus. Med Pediatr Oncol 2003;40(1):70–71. [8] Westerveld GJ, Quak JJ, Bresters D, et al. Endodermal sinus tumor of the maxillary sinus. Otolaryngol Head Neck Surg 2001;124(6):691–692. [9] Shebib S, Sabbah RS, Sackey K, et al. Endodermal sinus (yolk sac) tumor in infants and children. A clinical and pathologic study: an 11 year review. Am J Pediatr Hematol Oncol 1989;11(1):36–39. [10] Manivel C, Wick MR, Dehner LP. Transitional (cylindric) cell carcinoma with endodermal sinus tumor-like features of the nasopharynx and paranasal sinuses. Clinicopathologic and immunohistochemical study of two cases. Arch Pathol Lab Med 1986;110(3):198–202. [11] Weedon D, Musgrave J. Endodermal sinus tumour of the face. Pathology 1974;6:365–369. [12] Ahmad Z, Khurshid A, Qureshi A. Primary oribital yolk sac tumour in a 14-year-old girl. BMJ Case Rep 2009. Epub 2009, Nov 18. [13] Barnes L, Eveson JW, Reichart P, Sidransky D. Pathology and Genetics of Head and Neck Tumours(IARC WHO Classification of Tumours, volume 9). Lyon: IARC publishing, 2005. [14] Mishra A, El-Naggar AK, DeMonte F, Hanna EY. Endodermal sinus tumor of the paranasal sinuses. Head Neck 2008;30(4):539–543. [15] Filho BC, McHugh JB, Carrau RL, Kassam AB. Yolk sac tumor in the nasal cavity. Am J Otolaryngol 2008;29(4):250–254. C Informa Healthcare USA, Inc. Copyright 

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[16] Nogales-Fernandez F, Silverberg SG, Bloustein PA, et al. Yolk sac carcinoma (endodermal sinus tumor): ultrastructure and histogenesis of gonadal and extragonadal tumors in comparison with normal human yolk sac. Cancer 1977;39(4):1462–1474. [17] Teilum G. Endodermal sinus of the ovary and testis: comparative morphogenesis of the so-called mesonephroma ovarii (Schiller) and extraembryonic (yolk sac allantoic) structures of the rat’s palcenta. Cancer 1959;12:1092–1105. [18] Cukurova I, Gumussoy M, Yaz A, et al. A benign teratoma presenting as an obstruction of the nasal cavity: a case report. J Med Case Rep 2012;6(1):147. [19] Ohno Y, Kanematsu T. An endodermal sinus tumor arising from a mature cystic teratoma in the retroperitoneum in a child: is a matureteratoma a premalignant condition? Hum Pathol 1998;29(10):1167–1169. [20] Utsuki S, Oka H, Sagiuchi T, et al. Malignant transformation of intracranial mature teratoma to yolk sac tumor after late relapse. Case report. J Neurosurg 2007;106(6):1067–1069. [21] Thomas J, Adegboyega P, Iloabachie K, et al. Sinonasal teratocarcinosarcoma with yolk sac elements: a neoplasm of somatic or germ cell origin? Ann Diagn Pathol 2011;15(2):135–139. [22] Gonzalez-Roibon N, Katz B, Chaux A, et al. Immunohistochemical expression of SALL4 in hepatocellular carcinoma, a potential pitfall in the differential diagnosis of yolk sac tumors. Hum Pathol 2013;7(7):1293–1299. [23] Ota Y, Iihara K, Ryu T, et al. Metastatic seminomas in lymph nodes: CD10 immunoreactivity can be a pitfall of differential diagnosis. Int J Clin Exp Pathol 2013;6(3):498–502. [24] Bai S, Wei S, Ziober A, et al. Expression of SALL4 and SF-1 in gonadoblastoma: useful markers in the identification of the invasive germ cell component. Int J Gynecol Pathol 2013;32(4):379–383. [25] Aziz MF. Current management of malignant germ cell tumor of the ovary. Gan To Kagaku Ryoho 1995;22(Suppl 3):262–376. [26] Kawai M, Kano T, Furuhashi Y, et al. Prognostic factors in yolk sac tumors of the ovary. A clinicopathologic analysis of 29 cases. Cancer 1991;67(1):184–192. [27] Devaney KO, Ferlito A. Yolk sac tumors (endodermal sinus tumors) of the extracranial head and neck regions. Ann Otol Rhinol Laryngol 1997;106(3):254–260. [28] Bernbeck B, Schneider DT, Bernbeck B, et al. Germ cell tumors of the head and neck: report from the MAKEI group. Pediatr Blood Cancer 2009;52(2):223–226.

Fetal and Pediatric Pathology

Sinonasal pure yolk sac tumor: a case report and literature review.

Extragonadal pure yolk sac tumor of sinonasal origin is very rare. We report herein a case with sinonasal yolk sac tumor in a 1 year and 3 months old ...
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