Unusual Presentations of Gynecologic Tumors: Extragonadal Yolk Sac Tumor of the Vulva Open Access

Extragonadal germ cell tumors represent approximately 1% to 5% of all germ cell tumors and are characterized by varied and diverse histologic patterns.^1–3  They morphologically resemble their gonadal counterparts and classically have a midline distribution.³  Although these neoplasms often contain mature teratoma (either pure or admixed with a malignant germ cell component), many lack such a component and instead are composed solely of malignant germ cell components either in combination or in pure form.³  It is estimated that 10% to 15% of yolk sac tumors will be of extragonadal origin, with the most common reported sites including sacrococcygeal, thorax (predominantly mediastinum), vagina, brain (predominantly pineal), and retroperitoneum.^3–5  At some sites there is a proclivity for certain ages: vaginal yolk sac tumor is seen almost exclusively in young (≤2 years old) girls, whereas mediastinal tumors are typically seen in young adult males.^3,6,7  In addition to classic midline extragonadal locations, isolated case reports and small series of yolk sac tumors arising in the head/neck region (thyroid, maxillary sinus, nasopharynx, mandible, orbit), omentum, pancreas and hepatobiliary system, stomach, bladder, uterus (endometrium, cervix), and vulva^4–30  have been published. This review details the body of literature with respect to extragonadal yolk sac tumor of the vulva.^6,18–30 

There are several theories regarding the histogenesis of extragonadal yolk sac tumor, including (1) arrested migration of or misplaced germ cells during embryogenesis, (2) reverse migration of germ cells, (3) abnormal differentiation of somatic cells, (4) derivation from pluripotential stem cells within a somatic tumor, (5) origination from residual fetal tissue following incomplete abortion (for primary endometrial yolk sac tumor), and (6) metastasis from an occult gonadal primary.^1,4,5,21,25  The association with somatic tumors such as endometrioid adenocarcinoma or carcinosarcoma, seen in some cases arising in the gynecologic tract of older patients, supports a non–germ cell origin (points 3, 4) for a subset of extragonadal yolk sac tumors.¹  However, in the case of yolk sac tumor primary in the vulva, misplaced/aberrant germ cell migration along the gubernaculum is the leading hypothesis.²⁴ 

Whether of germ cell or somatic origin, yolk sac tumors may display a variety of patterns that resemble both endodermal extraembryonic and somatic patterns, including (1) reticular/microcystic pattern, characterized by a loose meshwork of anastomosing, small cystic spaces lined by flattened, primitive cells; (2) pseudopapillary, labyrinth, tubular, and “festoon” patterns, the latter characterized by interconnecting cords of cells with a drapelike arrangement; (3) Schiller-Duval bodies, a relatively uncommon feature present in approximately 20% of yolk sac tumors, characterized by a papillary structure with a central vascular core lined by primitive cuboidal to columnar cells occupying a space lined by flat, hobnail, or cuboidal cells; (4) polyvesicular-vitelline pattern, in which cystic spaces, often with eccentric constriction, lined by flattened cells in the larger (primary) vesicle merge with columnar cells in the smaller (secondary) vesicle are separated by dense spindle cell stroma; (5) parietal pattern, characterized by deposits of abundant basement membrane; (6) glandular pattern, which may mimic somatic gastrointestinal or endometrial carcinomas; (7) hepatoid pattern; and (8) solid pattern.^1,2,7,31  It is not uncommon to find multiple patterns within the same tumor.

The variable appearance of these tumors may contribute to the misdiagnosis of yolk sac tumor, particularly when these tumors occur outside of typical age parameters or in extragonadal locations. In the gynecologic tract, specifically the endometrium and ovary, the most frequent differential diagnoses are clear cell carcinoma and endometrioid adenocarcinoma. In the less common presentation of primary yolk sac tumor of the vulva, other possibilities, such as mucinous adenocarcinoma and adenoid cystic carcinoma arising in association with the Bartholin gland, may be considered. Distinction of these entities from yolk sac tumor requires consideration of clinical presentation (elevated serum α-fetoprotein [AFP] for yolk sac tumor) and histologic features. Although no specific clinical features distinguish yolk sac tumor of the vulva from other labial neoplasms, review of the literature shows a tendency to a presentation in young adulthood (median age, 19 years) and a preference of the right labium. As the diagnosis of yolk sac tumor was unsuspected in some cases, information regarding serum AFP is somewhat limited. In some cases, values were obtained postoperatively. In cases in which an elevation was reported, it was mild. Although the follow-up time in some of the reported cases is limited, prolonged survival with appropriate treatment has been reported in more recent cases. The most frequent histologic patterns observed have been the reticular/microcystic and solid patterns. The reticular/microcystic pattern may be mistaken for clear cell carcinoma or other types of adenocarcinoma. Helpful distinguishing features include the primitive appearance of the nuclei and distinctive vascular network in yolk sac tumor. Occasionally, the solid component of a yolk sac tumor may display spaces that appear punched out and mimic adenoid cystic carcinoma. The presence of marked cytologic atypia, frequent cytoplasmic vacuolization, and increased mitotic activity help distinguish yolk sac tumor from adenoid cystic carcinoma, which is more typically characterized by bland, uniform, cuboidal cells with low mitotic activity. The glandular and papillary patterns have been infrequently reported in vulvar yolk sac tumor. However, it is important to be aware that these patterns can mimic mucinous adenocarcinoma, endometrioid adenocarcinoma, or clear cell carcinoma. The peculiar pattern of supranuclear and subnuclear vacuolization in combination with primitive-appearing nuclei helps to distinguish yolk sac tumor from its somatic counterpoints. Lastly, most papillae in yolk sac tumor will have a central vessel and lack the hyalinized core typical for clear cell carcinoma. In other gynecologic sites, such as in the endometrium or in ovarian yolk sac tumors of postmenopausal women, yolk sac tumor may be associated with a somatic tumor component. None of the reported vulvar yolk sac tumors to date have had an associated somatic component; however, 3 cases did have other germ cell elements.^18,25,29  Recognition of other elements is important in the event they make up the sole component of a recurrence. The clinical and histologic features of the described cases of vulvar yolk sac tumor are summarized in Table 1. Figure 1, A through D, contains representative hematoxylin and eosin images from an unpublished case (last case, Table 1) reviewed at our institution.

Although one must keep in mind that immunoperoxidase studies may have overlapping results with somatic carcinomas, use of a carefully selected panel to include markers of somatic carcinoma, markers of germ cell tumor (ie, SALL4), and more yolk sac–specific markers (ie, AFP and glypican 3) may be helpful.²  SALL4 is a stem cell nuclear transcriptional factor characterized by diffuse nuclear expression in the majority of germ cell tumors except choriocarcinoma. Although a sensitive marker of malignant germ cell differentiation, SALL4 cannot be used to subtype germ cell tumors and may be expressed in a small percentage of somatic tumors for which yolk sac tumor may be mistaken, including clear cell carcinoma and certain esophageal, gastric, and colonic adenocarcinomas.^2,32,33  AFP is an early protein secreted by primitive and secondary yolk sacs. It is considered to be the gold standard marker and is characterized by granular, cytoplasmic staining. Although highly specific, this marker is not considered particularly sensitive, with staining reported in approximately 60% of cases, which may be only focal.^2,34  Glypican 3 is a cell surface heparan sulfate proteoglycan that regulates growth and apoptosis. It is a sensitive marker, but lacks the specificity of AFP, with up to a third of clear cell carcinomas reported to have expression of glypican 3.^2,35  It should be noted that certain markers used in the evaluation of somatic adenocarcinomas, such as cytokeratin 20 and CDX2, may be expressed in yolk sac tumors exhibiting enteric differentiation.²  Because of the potential overlap in immunohistochemical profiles, a panel of markers is highly recommended. Some of the most useful immunohistochemical markers to diagnose yolk sac tumor and differentiate it from other entities are summarized in Table 2.^2,32–36  Images of immunoperoxidase studies used in the diagnosis of a previously unreported case (last case, Table 1) reviewed at our institution are found in Figure 2, A through F.

In conclusion, the infrequency of extragonadal yolk sac tumor in combination with histologic and immunohistochemical overlap with more common somatic tumors can make this a challenging diagnosis. Recognition of the wide variety of histologic features of yolk sac tumor, the use of confirmatory immunohistochemical stains, and an awareness of the unusual presentations of this type of tumor will facilitate the correct diagnosis.