Extragonadal germ cell tumors represent approximately 1% Unusual Presentations of Gynecologic Tumors. Extragonadal Yolk Sac Tumor of the Vulva

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1 Special Article Unusual ations of Gynecologic Tumors Extragonadal Yolk Sac Tumor of the Vulva Extragonadal germ cell tumors are uncommon, and although they morphologically resemble their gonadal counterparts, unexpected gonadal presentation increases the potential for erroneous diagnoses. Yolk sac tumor is a malignant germ cell tumor characterized by an extraembryonic yolk sac line of differentiation, and relative to other germ cell tumors, is characterized by varied and diverse histologic patterns. When occurring outside of typical age parameters or in extragonadal locations, the histologic variability of yolk sac tumor and its tendency to mimic somatic tumors pose diagnostic challenges. Because extragonadal yolk sac tumor of the vulva is very rare, with only isolated case reports and small series in the literature, it is often not considered in the differential diagnosis. As both prognosis and management of yolk sac tumor differ significantly from those of somatic tumors, accurate diagnosis is essential. This review discusses histologic features of extragonadal yolk sac tumor, addresses somatic tumors arising in the vulva for which yolk sac tumor may be confused, and provides guidance with respect to the use of immunohistochemistry in the diagnosis of yolk sac tumor. (Arch Pathol Lab Med. 2017;141: ; doi: / arpa sa) 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 Accepted for publication June 15, Published as an Early Online Release December 13, From the Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston. The author has no relevant financial interest in the products or companies described in this article. ed in part at the 56th Annual Spring Symposium of the Houston Society of Clinical Pathologists; April 18, 2015; Houston, Texas. Reprints: Elizabeth D. Euscher, MD, Department of Pathology, The University of Texas MD Anderson Cancer Center, Box 85, 1515 Holcombe Blvd, Houston, TX ( edeusche@ mdanderson.org). Elizabeth D. Euscher, MD 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) polyvesicularvitelline 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 Arch Pathol Lab Med Vol 141, February 2017 Extragonadal Yolk Sac Tumor of the Vulva Euscher 293

2 Table 1. Source, y Summary of Reported Cases of Extragonadal Yolk Sac Tumor (YST) Primary in the Vulva Age, y Location Size, cm FIGO Stage Histologic Pattern Schiller-Duval Bodies Ungerleider et al, Right labium majus 4 IB Reticular/microcystic Unk Castaldo et al, Clitoris 1.5 IB Reticular/microcystic Unk Krishnamurthy and Sampat, Left labium majus 7 IB Reticular/microcystic, solid Dudley et al, Right labium majus 1.8 IIIAi Reticular/microcystic Unk Penkar et al, Right labium majus 10 II Reticular/microcystic Absent Craighead and du Toit, Left labium majus 4 IB Reticular/microcystic, solid Flanagan et al, Right labium majus 5 IB Hepatoid, papillary, glandular Traen et al, Right labium majus 2.5 IB Reticular/microcystic Khunamornpong et al, Right labium majus 3.5 IB Reticular/microcystic, solid Basgul et al, Right labium majus 6 IIIB Reticular/microcystic, Niwa et al, Right labium majus 3 IB Reticular/microcystic, glandular Subrahmanya et al, Right labium majus 6 IB Reticular/microcystic, Chang et al, Left labium majus 5?IIIB Reticular/microcystic, solid Mochizuki et al, Right labium majus 3 IB Not described Unpublished case, MDACC 17 Right labium majus 1.2 IIIB Reticular/microcystic, Abbreviations: AFP, a-fetoprotein; CEA, carcinoembryonic antigen; DOD, dead of disease; AWD, alive with disease; FIGO, International Federation of Gynecology and Obstetrics; IHC, immunohistochemistry; Ker, keratin; LTF, lost to follow-up; MDACC, University of Texas MD Anderson Cancer Center, Houston; NED, no evidence of disease; Unk, unknown; WNL, within normal limits. Figure 1. A, Yolk sac tumor; pseudoglandular and trabecular structures surrounded by myxoid-appearing material mimicking adenocarcinoma. B, Microcystic pattern of yolk sac tumor with cribriform architecture mimicking the punched-out spaces of adenoid cystic carcinoma. C, Solid pattern of yolk sac tumor. D, Schiller-Duval body (hematoxylin-eosin, original magnifications 3100 [A, C, and D] and 3200 [B]). 294 Arch Pathol Lab Med Vol 141, February 2017 Extragonadal Yolk Sac Tumor of the Vulva Euscher

3 Table 1. Extended Non-YST Component IHC Initial Treatment Follow-up, mo Embryonal carcinoma Not done Excision DOD 23 Unk None Not done Excision NED 42 WNL None Not done Excision DOD 11 Unk None AFPþ Neoadjuvant therapy, excision DOD 6 Unk None Not done Excision LTF 335 ng/ml None AFPþ, Ker Excision, chemotherapy, radiation NED 15 WNL None AFPþ Excision, chemotherapy, radiation NED ng/dl Immature teratoma AFPþ Excision, chemotherapy NED 40 WNL None AFPþ, CEAþ, Ker20þ, Ker7 Excision, chemotherapy NED 90 WNL None AFPþ Excision AWD 42 WNL None AFPþ Excision, chemotherapy NED ng/dl None AFPþ, Kerþ Excision LTF 13.4 lg/l Embryonal carcinoma Not done Neoadjuvant therapy, excision NED ng/ml None AFPþ Excision, chemotherapy NED ng/dl None AFPþ, glypican3þ, SALL4þ, Ker20þ, CDX2þ, Ker7 Excision, non germ cell chemotherapy AWD 36 Unk AFP 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 a-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- Table 2. Immunoperoxidase Studies Used to Diagnose Yolk Sac Tumor and to Exclude Entities in the Differential Diagnosis Yolk Sac Tumor Clear Cell Endometrioid Mucinous (Gynecologic Origin) Adenoid Cystic EMA /þ þþþ þþþ þþ þþ Cytokeratin 7 /þ þþþ þþþ þþþ þþþ Cytokeratin 20 þ/ /þ þþ /þ SALL-4 þþþ /þ Unk Unk AFP þþ þ/ Unk Unk Glypican 3 þþþ þ/ /þ Unk CDX2 þþ /þ þþ Napsin þþþ /þ Unk PAX8 þ/ þþþ þþþ þþ GATA3 þþþ /þ Unk Unk mcea Unk þ/ þ/ þþ þþþ CD117 þþ þþþ Unk þþþ Abbreviations: AFP, a-fetoprotein; EMA, epithelial membrane antigen; mcea, monoclonal carcinoembryonic antigen; Unk, unknown; /þ, rarely reported or focally positive; þ/, occasional cases have focal to patchy expression; þþ, most cases with patchy to diffuse expression; þþþ, most cases have strong, diffuse expression. Arch Pathol Lab Med Vol 141, February 2017 Extragonadal Yolk Sac Tumor of the Vulva Euscher 295

4 Figure 2. Immunoperoxidase studies used to arrive at a correct diagnosis for the last case described in Table 1. A, Cytokeratin 7. B, Cytokeratin 20. C, CDX2. D, a-fetoprotein. E, Sall-4. F, Glypican 3 (original magnification 3100). 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 296 Arch Pathol Lab Med Vol 141, February 2017 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 Extragonadal Yolk Sac Tumor of the Vulva Euscher

5 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. 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