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Case Report Uncommon of Ovarian : A Case Report and Review of the Literature

Mihaela Camelia Tîrnovanu 1, Irina Daniela Florea 2, Adina Tănase 1, Bogdan Florin Toma 1, Elena Cojocaru 2,* , Carmen Ungureanu 2,* and Ludmila Lozneanu 2

1 Department of Mother and Medicine, “Grigore. T. Popa” University of Medicine and Pharmacy, 700115 Ia¸si,Romania; mihaela.tirnovanu@umfiasi.ro (M.C.T.); [email protected] (A.T.); bogdan-fl[email protected]fiasi.ro (B.F.T.) 2 Department of Morphofunctional Sciences I, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Ia¸si,Romania; irina.florea@umfiasi.ro (I.D.F.); ludmila.lozneanu@umfiasi.ro (L.L.) * Correspondence: elena2.cojocaru@umfiasi.ro (E.C.); carmen.ungureanu@umfiasi.ro (C.U.); Tel.: +40-745-367-144 (E.C.); +40-752-114-139 (C.U.)

Abstract: Ovarian malignant tumors (OMGCT) represent less than 10% of all ovarian tumors. Dysgerminoma is the most common malignant primitive in young women, known for its curability and low propensity to invade and metastasize when diagnosed early. Herein, we report an unusual type of ovarian dysgerminoma (OD) metastasis with a brief review of the literature, lacking similar reported cases. To our knowledge, although there are several case reports of dysgerminoma metastases with variable anatomic location and presentation, vaginal metastasis   has not been previously described. The local or systemic relapse together with local and distant metastasis is considered as an independent predictor of poor survival in patients with OD. In light Citation: Tîrnovanu, M.C.; Florea, of the absence of mutations status, our patient successfully responded to therapy. Currently, the I.D.; T˘anase,A.; Toma, B.F.; Cojocaru, patient remains in clinical remission. A specific follow-up plan is ongoing knowing that ovarian E.; Ungureanu, C.; Lozneanu, L. Uncommon Metastasis of Ovarian tend to recur most often in the first 2–3 years after treatment. Dysgerminoma: A Case Report and Review of the Literature. Medicina Keywords: dysgerminoma; ; metastasis; follow-up 2021, 57, 534. https://doi.org/ 10.3390/medicina57060534

Academic Editor: 1. Introduction Masafumi Koshiyama Ovarian dysgerminoma (OD) is a malignant tumor originating from the ovarian primordial germ cells. Unlike other ovarian tumors, dysgerminomas have no precursor Received: 18 May 2021 lesions. The etiology of OD is not well established. They are defined by the World Accepted: 25 May 2021 Health Organization (WHO)as tumors composed of primitive germ cells that do not Published: 27 May 2021 have a specific pattern of differentiation [1,2]. Dysgerminoma constitute about 0.9–2% of all ovarian and is about half of malignant ovarian germ cell Publisher’s Note: MDPI stays neutral (33–37%) [1–5]. According to a survey performed in the United States comprising 1262 with regard to jurisdictional claims in cases of ovarian malignant germ cell tumors (OMGCTs) registered from 1973 to 2002, the published maps and institutional affil- age-adjusted incidence of ovarian dysgerminoma per 100,000 women-years was 0.109 [4]. iations. Dysgerminoma is known as ovarian correspondent of testicular . Germinal cell tumors occur at all ages, but develop especially in children and adolescents with a peak incidence between 10–30 years. Epidemiological data prove that 90% of patients are under 30 years of age, similar to our patient. Tumors diagnosed under the age of five or after Copyright: © 2021 by the authors. menopause are far less common [6]. Still, the literature reports cases of OD in patients aged Licensee MDPI, Basel, Switzerland. 7 months to 70 years [7]. Dysgerminoma are responsible for 10% of developed in This article is an open access article women younger than 20 years [8]. distributed under the terms and conditions of the Creative Commons 2. Case Presentation Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ We present a case of a 22-year-old virgin woman admitted to the First Obstetrics- 4.0/). Gynecology Clinic of “Cuza Vodă” Hospital, Iasi, Romania, for subacute pain, palpable

Medicina 2021, 57, 534. https://doi.org/10.3390/medicina57060534 https://www.mdpi.com/journal/medicina Medicina 2021, 57, x FOR PEER REVIEW 2 of 12 Medicina 2021, 57, x FOR PEER REVIEW 2 of 12

Medicina 2021, 57, 534 We present a case of a 22-year-old virgin woman admitted to the First Obstetrics-2 of 12 We present a case of a 22-year-old virgin woman admitted to the First Obstetrics- Gynecology Clinic of “Cuza Vodă” Hospital, Iasi, Romania, for subacute pain, palpable Gynecology Clinic of “Cuza Vodă” Hospital, Iasi, Romania, for subacute pain, palpable abdominal mass with rapid growth and vaginal for a week. In addition, the abdominal mass with rapid growth and for a week. In addition, the abdominalpatient declared mass withprimary rapid amenorrhea. growth and She vaginal was born bleeding from forhealthy a week. non-consanguineous In addition, the patient declared primary amenorrhea. She was born from healthy non-consanguineous patientparents declared without primarysignificant amenorrhea. family history. She was Informed born from consent healthy was non-consanguineous obtained from the parents without significant family history. Informed consent was obtained from the parentspatient withoutinvolved significant in the case. family The history.study was Informed approved consent by the was Hospital obtained Ethics from theCommittee patient patient involved in the case. The study was approved by the Hospital Ethics Committee involved(protocol in according the case. to The the study Order was 865/22 approved January by the2021). Hospital Ethics Committee (protocol (protocol according to the Order 865/22 January 2021). accordingPhysical to the examination Order 865/22 revealed January an 2021).abdominopelvic solid mass, with irregular borders Physical examination revealed an abdominopelvic solid mass, with irregular borders whichPhysical extended examination to approximately revealed 2 an cm abdominopelvic above the umbilicus. solid mass, Gynecological with irregular examination borders which extended to approximately 2 cm above the umbilicus. Gynecological examination whichcould extendednot be performed to approximately because 2she cm had above not the had umbilicus. sexual intercourse Gynecological yet. examinationWe used for could not be performed because she had not had sexual intercourse yet. We used for coulddiagnosis not be the performed IOTA because(International she had Ovar not hadian sexualTumor intercourse Analysis) yet. criteria We used based for diag- on diagnosis the IOTA (International Analysis) criteria based on nosistransabdominal the IOTA (International ultrasound (US), Ovarian computer Tumor tomography Analysis) criteria (CT), and based tumor on transabdominal markers [9,10]. transabdominal ultrasound (US), computer tomography (CT), and tumor markers [9,10]. ultrasoundThe US (US), showed computer a large tomography heterogeneous (CT), solid and mass tumor on markers the right [ 9ovary,10]. (Figure 1), about The US showed a large heterogeneous solid mass on the right (Figure 1), about 130 Themm USwith showed a septate a large cystic heterogeneous component, solid showing mass on thickened the right ovary walls (Figure (Figure1), about2) and 130 mm with a septate cystic component, showing thickened walls (Figure 2) and 130prominent mm with flow a septate signal cystic within component, the septa, showing suggestive thickened for . walls (Figure 2According) and prominent to the prominent flow signal within the septa, suggestive for malignancy. According to the flowrecommendation signal within theprovided septa, suggestiveby the IOTA, for malignancy.the first image According corresponds to the to recommendation the IOTA forth recommendation provided by the IOTA, the first image corresponds to the IOTA forth providedcriteria of by malignancy, the IOTA, the namely first image an irregular, corresponds multilocular to the IOTA solid forth tumor criteria with of malignancy, the largest criteria of malignancy, namely an irregular, multilocular solid tumor with the largest namelydiameter an ≥ irregular,100 mm. The multilocular US showed solid no peritoneal tumor with effusion. the largest Evaluation diameter with≥ 100color mm. Doppler The diameter ≥ 100 mm. The US showed no peritoneal effusion. Evaluation with color Doppler USrevealed showed blood no peritoneal vessels inside effusion. the solid Evaluation part of withthe tumor color Doppler(Figure 3), revealed with a vascular blood vessels score revealed blood vessels inside the solid part of the tumor (Figure 3), with a vascular score insideof 2. The the left solid ovary part was of the slightly tumor increased (Figure3), in with dimensions a vascular with score a ofhypoechoic 2. The left image ovary about was of 2. The left ovary was slightly increased in dimensions with a hypoechoic image about slightly50 × 29 mm increased (Figure in 4). dimensions with a hypoechoic image about 50 × 29 mm (Figure4). 50 × 29 mm (Figure 4).

FigureFigure 1.1.Ovarian Ovarian ultrasoundultrasound (US)(US) revealingrevealing aa largelarge heterogeneous heterogeneous solid solid mass mass (right (right ovary). ovary). Figure 1. Ovarian ultrasound (US) revealing a large heterogeneous solid mass (right ovary).

Figure 2. Ovarian US showing a thickened septation with prominent flow signal (right ovary). FigureFigure 2. 2.Ovarian Ovarian USUS showingshowing aa thickenedthickened septation septation with with prominent prominent flow flow signal signal (right (right ovary). ovary).

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FigureFigure 3.3. OvarianOvarian color color Doppler Doppler revealing revealing blood blood vessels vessels inside inside the solid the part solid of partthe tumor of the (right tumor Figure 3. Ovarian color Doppler revealing blood vessels inside the solid part of the tumor (right (rightovary). ovary). ovary).

Figure 4. Ovarian US revealing a hypoechoic image (left ovary). FigureFigure 4. 4.Ovarian Ovarian USUS revealingrevealing a a hypoechoic hypoechoic image image (left (left ovary). ovary). Abdominal CT scan before admission showed: (1) large right ovarian mass (137 × 63 × 54 Abdominalmm),Abdominal with solid CT CT scan scanand before liquid before admissioncomponents, admission showed with showed: :vessels (1) large (1) and right large contrast ovarian right medium ovarian mass (137 uptake; mass × 63 (137(2)× 54 left× mm),63 ovary× with54 showing mm) solid, with and a lesion solidliquid andwith components, liquid polycyc components,lic with contour, vessels with measuring and vessels contrast and56 × contrast 62medium × 53 mediummm uptake; with uptake;prominent(2) left (2)ovary left hypodense showing ovary showing acomponent, lesion a lesion with withpolycyc polycyclicperipherallic contour, contour, solid measuring zones measuring and 56 ×56calcifications 62× ×62 53× mm53 mmwithin a withspeckledprominent prominent pattern. hypodense hypodense Abdominal component, component, CT did with not with displayperipheral peripheral fluid solid in solid the zones zonesperitoneal and and calcificationscalcificationscavity. inin aa speckledspeckledTaking pattern. pattern. into account AbdominalAbdominal the age CTCT of diddid the notnot patient, displaydisplay our fluidfluid first in inhypothesis the the peritoneal peritoneal was cavity.ovarian cavity. malignant germTakingTaking cell tumor into into account account (OMGCTs). the the age age With of of the the this patient, patient, in regard, our our firstfirst we hypothesishypothesis assessedwas wasvarious ovarian ovarian serum malignant malignant tumor germgermmarkers cell cell tumoruseful tumor (OMGCTs).for (OMGCTs). the diagnosis, With With this therapy inthis regard, in su regard,rveillance, we assessed we andassessed various post-treatment serumvarious tumor serum follow-up markers tumor in usefulOMGCT.markers for useful theIt is diagnosis, known for the that diagnosis, therapy increased surveillance, therapy values suare andrveillance, linked post-treatment to certainand post-treatment components follow-up in offollow-up OMGCT. OMGCTs. Itin is known that increased values are linked to certain components of OMGCTs. We found WeOMGCT. found It anis knownincrease that in increased the serum values level are of linkedlactate to dehydrogenase certain components (LDH) of ofOMGCTs. 485U/L an increase in the serum level of (LDH) of 485 U/L (normal values: We(normal found values: an increase 120–246U/L in the and serum human level chorio of lactatenic gonadotropin dehydrogenase (hCG) (LDH) of 56.9 of mIU/mL 485U/L 120–246 U/L and human chorionic gonadotropin (hCG) of 56.9 mIU/mL (normal values: (normal values: 120–246U/L<5 mIU/mL). and The human patient chorio had normalnic gonadotropin levels of alpha-fetoprotein (hCG) of 56.9 mIU/mL (AFP) <5 mIU/mL). The patient had normal levels of alpha-fetoprotein (AFP) (1.67 IU/mL) and (1.67(normal IU/mL) values: and <5 cancer mIU/mL). antigen The 125 patient (CA-125) had (11.6 normal U/mL). levels Two of alpha-fetoproteinweeks after surgery, (AFP) the antigen 125 (CA-125) (11.6 U/mL). Two weeks after surgery, the value for lactate value(1.67 IU/mL) for lactate and dehydrogenase cancer antigen (LDH)125 (CA-125) decreased (11.6 to U/mL). 310U/L. Two weeks after surgery, the dehydrogenase (LDH) decreased to 310 U/L. value Complete for lactate blood dehydrogenase count (CBC) (LDH) revealed decreased important to 310U/L. anemia with hemoglobin (Hb) Complete blood count (CBC) revealed important anemia with hemoglobin (Hb) values values Complete of 8.6 g/dL blood before count surgery (CBC) and revealed 7.6 g/dL importantafter surgery. anemia with hemoglobin (Hb) of 8.6 g/dL before surgery and 7.6 g/dL after surgery. valuesA ofsurgical 8.6 g/dL approach before surgery was decided and 7.6 asg/dL the after first-line surgery. treatment. During the median A surgical approach was decided as the first-line treatment. During the median laparo- ,A surgical a bilateral approach ovarian was decided tumor wasas the identified, first-line with treatment. no . During The the maximum median tomy, a bilateral ovarian tumor was identified, with no ascites. The maximum dimension of dimensionlaparotomy, of a the bilateral right ovary ovarian tumor tumor was was 170 mmidentified, with regular with no surface ascites. and The the maximumleft ovary thedimension right ovary of the tumor right was ovary 170 mmtumor with was regular 170 mm surface with andregular the leftsurface ovary and was the very left brittle ovary was very× brittle with 60 × 50 mm, adherent to the posterior wall of the uterus. Frozen withwas 60very 50brittle mm, with adherent 60 × 50 to mm, the posterior adherent wall to the of theposterior uterus. wall Frozen of the section uterus. revealed Frozen malignancysection revealed and confirmed malignancy bilateral and confirmed dysgerminoma. bilateral Consequently, dysgerminoma the. patient Consequently, underwent the sectionpatient revealedunderwent malignancy comprehensive and confirmed surgical bilateral procedures, dysgerminoma including. Consequently,total abdominal the comprehensivepatient underwent surgical comprehensive procedures, includingsurgical procedures, total abdominal including , total abdominal bilateral salpingo-oophorectomyhysterectomy, bilateral withsalpingo-oophorectom bilateral pelvic lymphadenectomyy with bilateral pelvic and peritoneal lymphadenectomy lavage. A hysterectomy, bilateral salpingo- with bilateral pelvic lymphadenectomy

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and peritoneal lavage. A sample of peritoneal lavage fluid was obtained and sent for histological evaluation. No malignant cells were confirmed on cytological findings. samplePathological of peritoneal examination lavage fluid described was obtained the following and sent gross for histological findings: (i) evaluation. the right ovary No malignanthad a solid cells tumor were confirmedof 170 × 100 on cytologicalmm with findings.central cystic area of 6 cm, and hemorrhage;Pathological the examinationcut surface of described solid part the was following uniform, gross pale, findings: gray–pink (i) thewith right a lobe-like ovary hadpattern a solid (Figure tumor 5); of (ii) 170 the× 100left mmovary with measured central cystic60 × 50 area mm, of with 6 cm, large necrosis area and of necrosis hemor- rhage;(more thethan cut 75%) surface and ofcalcification; solid part was (iii) uniform, the uterus pale, had gray–pink serosa involvement; with a lobe-like (iv) the pattern right (Figurefallopian5); (ii)tube the showed left ovary tumor measured invasion 60 × 50at mm,serosa with level large and area necrotic of necrosis detritus (more thanwith 75%)intraluminal and calcification; tumor cells, (iii) while the uterus the left had fallopian serosa involvement; tube did not (iv)present the right tumor fallopian invasion; tube (v) showeddeposits tumor of necrotic invasion detritus at serosa and level aggregates and necrotic of tumor detritus cells with (with intraluminal same tumor tumor features) cells, whilewere theidentified left fallopian on cervical tube did adventitia; not present (vi) tumor infracolic invasion; omentectomy—omentum (v) deposits of necrotic without detri- tusmetastases; and aggregates (vii) pelvic of tumor lymph cells nodes (with without same tumormetastases features) (including were identified three lymph on cervicalnodes at adventitia;aortic bifurcation). (vi) infracolic omentectomy—omentum without metastases; (vii) pelvic lymph nodes without metastases (including three lymph nodes at aortic bifurcation).

FigureFigure 5. 5.Gross Gross appearance appearance of of cut cut surface surface of of the the solid solid part part (right (right ovary). ovary).

MicroscopicMicroscopic aspects aspects were were consistent consistent with with the diagnosisthe diagnosis of dysgerminoma of dysgerminoma (Figure (Figure6A–D ), 6 demonstratingA–D), demonstrating variably variably sized nests sized of uniformnests of polygonaluniform polygonal cells with cells abundant with granularabundant eosinophilicgranular eosinophilic or clear cytoplasm or clear and cytoplasm distinct cell and membranes distinct cell that membranes resemble primordial that resemble germ cells.primordial The cells germ have cells. a central The cells large have round a orcentral flattened large nucleus round that or flattened contains onenucleus or a fewthat prominentcontains one nucleoli. or a few The tumorprominent proliferation nucleoli. hasThe a trabecular,tumor proliferation cordonal andhas pseudoglan-a trabecular, dularcordonal pattern. and Thepseudoglandular tumor architecture pattern. presented The tumor fibrous architecture septa, with presented mature .fibrous septa, Areaswith mature of hemorrhage, lymphocytes. coagulative Areas necrosisof hemorrhag and cystice, coagulative changes were necrosis seen. and High cystic mitotic changes rate waswere observed seen. (15High mitoses/10 mitotic highrate powerwas observ fields).ed Histopathological (15 mitoses/10 examinationhigh power revealed fields). tumorHistopathological emboli in adjacent examination vessels. revealed Final diagnosis tumor emboli was bilateral in adjacent dysgerminoma, vessels. Final infiltrating diagnosis thewas right bilateral fallopian dysgerminoma, tube, serosa infiltrating of the uterus the and right cervical fallopian adventitia. tube, serosa of the uterus and cervicalThe adventitia. patient was diagnosed according to the latest International Federation of Gyne- cology and Obstetrics (FIGO) classification with FIGO II A and according to the TNM classification (T—tumor, N—node, M—metastases) with pT2aN0MxL1V1 (p—pathological, T—tumor, N—node, M—metastases, LV—lymphovascular invasion) [1]. No metastases were demonstrated microscopically in any of the retroperitoneal lymph nodes examined. confirmed the bilateral ovarian dysgerminoma. AFP, calre- tinin, cluster of differentiation 30 (CD30), and inhibin were negative in tumor cells while PLAP (placental ) and c-/cluster of differentiation 117 (CD117) showed strong positive staining (with membrane enhancement and cytoplasmic expres- sion) in both (Figure7A,B). For the left ovary the positivity for PLAP and c-kit was weaker (Figure8). A B

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and peritoneal lavage. A sample of peritoneal lavage fluid was obtained and sent for histological evaluation. No malignant cells were confirmed on cytological findings. Pathological examination described the following gross findings: (i) the right ovary had a solid tumor of 170 × 100 mm with central cystic area of 6 cm, necrosis and hemorrhage; the cut surface of solid part was uniform, pale, gray–pink with a lobe-like pattern (Figure 5); (ii) the left ovary measured 60 × 50 mm, with large area of necrosis (more than 75%) and calcification; (iii) the uterus had serosa involvement; (iv) the right fallopian tube showed tumor invasion at serosa level and necrotic detritus with intraluminal tumor cells, while the left fallopian tube did not present tumor invasion; (v) deposits of necrotic detritus and aggregates of tumor cells (with same tumor features) were identified on cervical adventitia; (vi) infracolic omentectomy—omentum without metastases; (vii) pelvic lymph nodes without metastases (including three lymph nodes at aortic bifurcation).

Figure 5. Gross appearance of cut surface of the solid part (right ovary).

Microscopic aspects were consistent with the diagnosis of dysgerminoma (Figure 6 A–D), demonstrating variably sized nests of uniform polygonal cells with abundant granular eosinophilic or clear cytoplasm and distinct cell membranes that resemble primordial germ cells. The cells have a central large round or flattened nucleus that contains one or a few prominent nucleoli. The tumor proliferation has a trabecular, cordonal and pseudoglandular pattern. The tumor architecture presented fibrous septa, Medicina 2021, 57, x FOR PEER REVIEW with mature lymphocytes. Areas of hemorrhage, coagulative necrosis and cystic changes5 of 12 were seen. High mitotic rate was observed (15 mitoses/10 high power fields). Medicina 2021, 57, 534 Histopathological examination revealed tumor emboli in adjacent vessels.5 of Final 12 diagnosis was bilateral dysgerminoma, infiltrating the right fallopian tube, serosa of the uterus and cervical adventitia.

Medicina 2021, 57, x FOR PEER REVIEW 5 of 12 C A D B Figure 6. Histologic features of dysgerminoma. (A) Nests and nodules of uniform tumor cells separated by. fine connective tissue containing inflammatory cells. Hematoxylin and eosin stain (HE × 10), (B) fibrous septa of connective tissue containing lymphocytes (HE × 10), (C) large zones of necrosis and hemorrhage (HE × 10), (D) tumor cells with nucleus increased in volume with enlarged nucleoli and lymphocytes (HE × 40).

The patient was diagnosed according to the latest International Federation of Gynecology and Obstetrics (FIGO) classification with FIGO II A and according to the TNM classification (T—tumor, N—node, M—metastases) with pT2aN0MxL1V1 (p— pathological, T—tumor, N—node, M—metastases, LV—lymphovascular invasion) [1]. No metastases were demonstrated microscopically in any of the retroperitoneal lymph nodes examined. ImmunohistochemistryC confirmed the bilateralD ovarian dysgerminoma. AFP, Figure 6. HistologicFigurecalretinin, features 6. Histologic cluster of dysgerminoma. features of differentiation of dysgerminoma. (A) Nests and 30 nodules (CD30), (A) Nests of uniformand and inhibin nodules tumor cellswere of uniform separated negative tumor by. infine cells tumor connective cells tissue containing inflammatory cells. Hematoxylin and eosin stain (HE × 10), (B) fibrous septa of connective tissue separatedwhile PLAP by. fine connective(placental tissue alkaline containing phosphatase) inflammatory cells.and Hematoxylinc-kit/cluster and of eosin differentiation stain (HE 117 containing lymphocytes (HE × 10), (C) large zones of necrosis and hemorrhage (HE × 10), (D) tumor cells with nucleus × 10), (B) fibrous septa of connective tissue containing lymphocytes (HE × 10), (C) large zones of increased in volume(CD117) with showed enlarged nucleolistrong andpositive lymphocytes staining (HE (with × 40). membrane enhancement and cytoplasmic necrosisexpression) and hemorrhage in both (HEovaries× 10), (Figure (D) tumor 7A,B). cells with Fo nucleusr the left increased ovary in the volume positivity with enlarged for PLAP and nucleolic-kit was and lymphocytesweakerThe (Figure patient (HE × 8).40). was diagnosed according to the latest International Federation of Gynecology and Obstetrics (FIGO) classification with FIGO II A and according to the TNM classification (T—tumor, N—node, M—metastases) with pT2aN0MxL1V1 (p— pathological, T—tumor, N—node, M—metastases, LV—lymphovascular invasion) [1]. No metastases were demonstrated microscopically in any of the retroperitoneal lymph nodes examined. Immunohistochemistry confirmed the bilateral ovarian dysgerminoma. AFP, calretinin, cluster of differentiation 30 (CD30), and inhibin were negative in tumor cells while PLAP (placental alkaline phosphatase) and c-kit/cluster of differentiation 117 (CD117) showed strong positive staining (with membrane enhancement and cytoplasmic expression) in both ovaries (Figure 7A,B). For the left ovary the positivity for PLAP and A c-kit was weaker (Figure 8). B

FigureFigure 7. 7.Immunohistochemical Immunohistochemical staining staining positive positive for (A for) placental (A) placental alkaline alkaline phosphatase phosphatase (PLAP), (PLAP), (B()B c-kit/cluster) c-kit / cluster of differentiation of differentiation 117 (CD117), 117 (CD117) right ovary, right (original ovary (original magnification magnification× 10). × 10).

A B

Figure 7. Immunohistochemical staining positive for (A) placental alkaline phosphatase (PLAP), (B) c-kit / cluster of differentiation 117 (CD117), right ovary (original magnification × 10).

A B

A B

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C D Figure 6. Histologic features of dysgerminoma. (A) Nests and nodules of uniform tumor cells separated by. fine connective tissue containing inflammatory cells. Hematoxylin and eosin stain (HE × 10), (B) fibrous septa of connective tissue containing lymphocytes (HE × 10), (C) large zones of necrosis and hemorrhage (HE × 10), (D) tumor cells with nucleus increased in volume with enlarged nucleoli and lymphocytes (HE × 40).

The patient was diagnosed according to the latest International Federation of Gynecology and Obstetrics (FIGO) classification with FIGO II A and according to the TNM classification (T—tumor, N—node, M—metastases) with pT2aN0MxL1V1 (p— pathological, T—tumor, N—node, M—metastases, LV—lymphovascular invasion) [1]. No metastases were demonstrated microscopically in any of the retroperitoneal lymph nodes examined. Immunohistochemistry confirmed the bilateral ovarian dysgerminoma. AFP, calretinin, cluster of differentiation 30 (CD30), and inhibin were negative in tumor cells while PLAP (placental alkaline phosphatase) and c-kit/cluster of differentiation 117 (CD117) showed strong positive staining (with membrane enhancement and cytoplasmic expression) in both ovaries (Figure 7A,B). For the left ovary the positivity for PLAP and c-kit was weaker (Figure 8).

A B

Medicina 2021, 57, 534 6 of 12 Figure 7. Immunohistochemical staining positive for (A) placental alkaline phosphatase (PLAP), (B) c-kit / cluster of differentiation 117 (CD117), right ovary (original magnification × 10).

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FigureA 8. Immunohistochemical staining B positive for (A) PLAP, (B) c-kit (CD117), left ovary (originalFigure 8. magnificationImmunohistochemical ×10). staining positive for (A) PLAP, (B) c-kit (CD117), left ovary Figure(original 8. Immunohistochemical magnification ×10). staining positive for (A) PLAP, (B) c-kit (CD117), left ovary (original magnification ×10). At 8 days post-surgery, the patient continued to present vaginal bleeding. With At 8 days post-surgery, the patient continued to present vaginal bleeding. With generalAt 8 daysanesthesia, post-surgery, a speculum the patient vaginal continued examin to presentation vaginal was performed, bleeding. With identifying general a vaginal general anesthesia, a speculum vaginal examination was performed, identifying a vaginal anesthesia,tumor (Figure a speculum 9). Subsequent vaginal examination histological was examination performed, identifying described avaginal a friable, tumor bloody vaginal (Figuretumor9 ).(Figure Subsequent 9). Subsequent histological histological examination examination described a friable, described bloody a vaginalfriable, metas-bloody vaginal metastasis from ovarian dysgerminoma with extensive area of tumor necrosis and tasismetastasis from ovarian from dysgerminoma ovarian dysgerminoma with extensive with area ofextensive tumor necrosis area andof tumor hemorrhage necrosis and (Figurehemorrhage 10). She (Figure(Figure received 10). 10). blood She She transfusions received received blood and blood after transfusions transfusions the final pathological and and after after resultthe the final she final waspathological pathological transferredresult she to waswas the transferredtransferred Regional Oncological to to the the Region Region Institute,alal Oncological Iasi,Oncological Romania. Institute, Institute, Iasi, Iasi, Romania. Romania.

FigureFigure 9. 9.Vaginal VaginalVaginal metastases metastases metastases of anterior of of anterior anterior wall. wall. wall.

Figure 10. Microscopical aspect of vaginal biopsy with nuclear atypia, pleomorphism, and. FigureFigureprominent 10. 10.Microscopical Microscopicalnecrosis, HE aspect × 10.aspect of vaginal of vaginal biopsy with biopsy nuclear with atypia, nuclear pleomorphism, atypia, pleomorphism, and prominent and. necrosis,prominent HE × necrosis,10. HE × 10. Thoracic CT after surgery showed multiple pulmonary metastatic micronodular area, Thoracicdisseminated CT after on bothsurgery showed in full multiple parenchyma pulmonary and subpleural metastatic (Figure micronodular 11). area,Abdomino-pelvic disseminated CT ondid bothnot identify lungs liverin full metastasis parenchyma and retroperitoneal and subpleural lymph (Figure node. 11). Abdomino-pelvic CT did not identify metastasis and retroperitoneal .

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Figure 8. Immunohistochemical staining positive for (A) PLAP, (B) c-kit (CD117), left ovary (original magnification ×10).

At 8 days post-surgery, the patient continued to present vaginal bleeding. With general anesthesia, a speculum vaginal examination was performed, identifying a vaginal tumor (Figure 9). Subsequent histological examination described a friable, bloody vaginal metastasis from ovarian dysgerminoma with extensive area of tumor necrosis and hemorrhage (Figure 10). She received blood transfusions and after the final pathological result she was transferred to the Regional Oncological Institute, Iasi, Romania.

Figure 9. Vaginal metastases of anterior wall.

Medicina 2021, 57, 534 7 of 12 Figure 10. Microscopical aspect of vaginal biopsy with nuclear atypia, pleomorphism, and. prominent necrosis, HE × 10. Thoracic CT after surgery showed multiple pulmonary metastatic micronodular area, Thoracic CT after surgery showed multiple pulmonary metastatic micronodular disseminated on both lungs in full parenchyma and subpleural (Figure 11). Abdomino- area, disseminated on both lungs in full parenchyma and subpleural (Figure 11). pelvic CT did not identify liver metastasis and retroperitoneal lymph node. Abdomino-pelvic CT did not identify liver metastasis and retroperitoneal lymph node.

Figure 11. Computer tomography (CT) scans revealed metastases.

The next step in the management was , including BEP: , cis- platin and with administration at 3 weeks. The patient tolerated well the induction chemotherapy. The first complete chemotherapy course was started 18 days after surgical intervention. A total of 7 days after the first chemotherapy treatment, only Bleomycin was administered, because the patient presented a severe neutrope- nia and anemia (Hb = 5.6 g/dL). During this period, the patient was diagnosed with SARS-COV-2 infection.

3. Discussion Germinal cell tumors are usually unilateral, while bilateral neoplasms are rarely reported in about 10–20% [1,11]. The investigations in our case proved the bilaterality of the lesion which led to a more aggressive type of surgery. Usually the cases of bilateral tumors require additional investigations because local expansion with contralateral ovary invasion may be present [7,12]. In the pediatric setting, dysgerminoma has variable clinical manifestations, either asymptomatic (usually presented at stage I of the disease), , abdomino- pelvic mass, (adnexal torsion), menstrual abnormalities, vaginal bleeding or fever with a median of 2–4 weeks [3,13]. Commonly, the tumoral mass tends to be large at the time of diagnosis and progresses rapidly. Our patient experienced almost all these . Patients presenting with tumor mass have acute pain due to torsion, rupture of superficial tumor vessels and intra-abdominal hemorrhage. Rare cases of dysgerminoma are associated with ascites and pleurisy. The patient had a minimal bilateral pleural reaction of 9 mm on thoracic CT. Occasionally, dysgerminoma may be diagnosed during pregnancy (20%), with some tumors being fortuitously discovered during cesarean section [14,15]. Regarding imaging features, dysgerminomas are characteristically purely solid with few exceptions. At US, they show heterogeneous echogenicity, smooth lobulated contours and well-defined borders, and they are richly vascularized at color and power Doppler US [16,17]. The US images in our case revealed a heterogeneous solid ovarian mass, with a cystic component and calcifications in a speckled pattern (characteristic of dysgerminoma). The clinical features and prognosis depend on tumor stage. An overall five-year survival rate is satisfactory exceeding 75% (even 90% in stage I), decreasing to approxi- mately 63% in patients with extended disease beyond the ovaries [18]. The majority of OD are diagnosed at early stage and respond well to fertility-sparing surgery. Localized Medicina 2021, 57, 534 8 of 12

dysgerminomas are generally accepted to have long-term outcome without recurrence or metastasis. Therefore, dysgerminoma represent a group of potentially curable diseases with excellent prognosis. High responsiveness to chemotherapy may explain the favor- able prognosis typically shown in OD. However, their malignant propensity sometimes determines an aggressive course. The local invasion of advanced dysgerminoma causes the destruction of the entire ovarian tissue, the entire genital tract, the lumbar muscles, the iliac vessels, the pubic symphysis, the rectum and the spine [7,19]. Unfortunately, in our case, the involvement of serosa of the uterus, right fallopian tube, vagina along with the transition from FIGO IIA stage to FIGO IV by the presence of distant metastases proved an advanced disease. Moreover, our patient’s chemotherapy treatment was administered discontinuously and in lower doses due to COVID–19 infection during hospitalization. In addition, this unusual presentation with vaginal and lung metastasis is considered a significant predictor of unfavorable prognosis. Other factors that can be associated with reserved prognosis include: tumor stage, histological type, value of tumor markers and the presence of residual tumor. In cases where the tumor is well defined, surgical removal is not generally followed by local recurrences or metastases. Still, tumor recurrences occur in approximately 10–20% of patients in the vast majority of cases in the stage I and first two years of initial presentation [1,20,21]. The recurrence rate increases significantly after the age of 45 [12]. At the present time, there is no evidence of recurrent disease in our patient. In the advanced stage, dysgerminoma infiltrates the neighboring tissues by direct extension. It also spreads into the regional or distant lymph nodes and at the level of the pelvic and abdominal peritoneum [22,23]. Dissemination by hematogenous invasion is responsible for distant, uncommon metastasis [22]. Our case did not have lymph node metastasis. The most common metastases of dysgerminoma are the peritoneal cavity, omentum (86%), and [11,23], and retroperitoneal lymph node [11,23,24]. Furthermore, extra-abdominal lymph nodes such as para-aortic, [23,25,26], supraclavicular [11] and cervical lymph nodes [26–28] may be involved. Distant hematogenous metastases develop in the bones [29–31], lungs (15%) [24], liver [29,31], kidneys [29], adrenal glands [31], mammary glands [32], cranium, brain, dura mater and intra-axial [24,33,34], pancreas [29], heart and skin [32]. There are also a number of other uncommon distant sites that have been reported: eye, , central airways (bronchus-trachea), bladder (17%), pleura (33%), spleen (20%), bowel (50%) [22,35], and neurologic involvement such as carcinomatous meningitis [24,33,34]. Our literature search did not reveal vaginal metastasis from OD, as reported in our patient, explaining our interest for the case. Vaginal metastasis was not diagnosed at the initial presentation because the patient was a virgin. Initially, we questioned whether vagina involvement is the result of metastatic disease by lympho- vascular spread or local extension from adjacent OD. It was certain that the histological characteristics of the vaginal metastasis were similar to the primary ovarian tumor. Given the presence of vascular tumor emboli, we assumed that the vaginal infiltration represents hematogenous spread of the OD. In addition, we discovered a distant hematogenous lung metastasis. The majority of reported vaginal metastasis are derived from cervical (51%), endome- trial (13.3%), [36–38], kidney (1.3%) [39], colon [40], breast, pancreas [41] or bladder cancer. We would like to mention that some rare metastases were selected from articles that did not mention with certainty the type of ovarian tumor. A study performed in 2020 by Maekawa et al. revealed a cervical lymph node metas- tasis from OD on fine needle aspiration cytology [28]. Kumar et al. reported that the prevalence of lymph node metastasis predicts recurrences and metastasis in patients with OD [42] Epidemiological data showed that OD can be associated with some factors, such as (i) dysontogenic ; (ii) paraneoplastic hypercalcemia or (iii) endocrine disorders. Recent evidence suggests that OD is the most common malignant tumor of the gonads in Medicina 2021, 57, 534 9 of 12

patients with dysgenetic gonads. According to the WHO Classification of Tumors 2020, OD usually occurs as a part of [1]. Tumors can be discovered by chance during investigations to determine causes of primary amenorrhea in women with (i) Swyer syndrome (46 XY ), known as pure gonadal degeneration, (ii) mixed gonadal dysgenesis (45X/46XX) or (iii) partial gonadal dysgenesis (46XX) [43]. For this reason, dysgerminoma has a particularly high frequency of gonadal neoplasia, dictating early prophylactic removal of these dysgenetic gonads [1,7]. Previous findings [44] showed that patients with Swyer syndrome have a risk of dysgerminoma development, with bilateral gonadectomy being recommended in such cases. Howitt et al. reported that the incidence of dysgeminoma in people with abnormal genital development or chromosomal abnormalities is about 5–10% [45]. Even though our patient presented with primary amenorrhea, we had no data regarding genetic testing. Within this framework, we recommend a mutational screening as useful for other family members. However, diagnostic molecular has no clinical relevance in OD as stated by WHO Classification of Tumors 2020 [1]. Previous data reported associations of dysgerminoma with paraneoplastic hypercal- cemia [1,11,21,46,47]. Furthermore, a recently published study sustains that hypercalcemia is associated with elevated parathyroid hormone, parathyroid hormone-related protein (PTH-rP), 1,25 dihydroxyvitamin D [47] and hemophagocytic lymphohistiocytosis. We had no information regarding PTH level in our patient. Dysgerminoma is not a hormone-secreting tumor and is not usually accompanied by endocrine disorders. Still, in some cases it is accompanied by endocrinal manifestations such as early puberty, or signs of virility. In connection with these issues, our patient presented primary amenorrhea that could be induced by increased testosterone, but we did not investigate it. The patient reported the lack of menstruation up to 22 of age. However, she had an endocrinological consult at the age of 15, but she was not directed to a pelvic ultrasound or gynecological consult. Some patients with dysgerminoma (5%) have slightly elevated human chorionic go- nadotropin (hCG) levels secreted by syncytiotrophoblastic giant cells [1,7,13,48]. Estrogenic hormonal manifestations such as sexual pseudo precocity, menstrual disorders and vaginal bleeding or pregnancy symptoms are usually caused by elevated serum β-hCG levels [49]. Although the patient in this case did not reveal pregnancy symptoms, she presented ele- vated β-hCG level. It was proved that elevated hCG levels or elevated α-fetoprotein (αFP) concentrations suggest the association of other germ cell tumors such as , yolk sac tumor or immature . In the present case, the association was not identi- fied. In addition, serum LDH is often elevated and can also serve as a . A correlation was found between plasma level and tumor stage, similar to our patient in which LDH levels decreased almost to a normal value two weeks after surgery. Moreover, these markers are useful in monitoring therapy, but also in identifying recurrences [45]. For this reason, elevated hCG levels may raise the suspicion of ovarian cancer, but a negative result does not rule out the diagnosis. In the case of ovarian dysembryoplastic tumors, the increase in serum of β-hCG has a 86% sensitivity. Song et al., 2007, reported the case of a 6-year-old girl with and high levels of β-hCG, αFP and estradiol who was diagnosed with OD with syncytiotrophoblastic giant cells (SyTGC). After resection of the tumor, the levels of β-hCG and αFP markers became normal and precocious puberty disappeared. Our patient did not present with SyTGC. Song et al. recommend resection of the tumor because of the high risk of malignant transformation of SyTGC [50]. The morphological landscape and structural heterogeneity of these tumors is the consequence of germ cells’ ability to differentiate in divergent ways at different stages of development [49]. Histologically, dysgerminoma is divided into a pure form, having a good prognosis, and a mixed-type with a variable admixture of germinal elements (15%) (teratoma, embryonic carcinoma or yolk sac tumor) [1,4]. Even though our patient had a pure dysgerminoma, the vascular invasion dictates the prognosis. Medicina 2021, 57, 534 10 of 12

4. Conclusions To the best of our knowledge, our patient is the first reported case with vaginal metastasis of ovarian OD in the clinical scenario. The patient had genital bleeding because of vaginal tumor implants. OD should be included in the differential diagnosis for a young female who presents non-acute lower quadrant pain, palpable pelvic mass and elevated β-hCG and LDH. If the patient had been investigated for amenorrhea, the tumors could have been identified in an earlier stage. Quantification of the tumor markers β- hCG and LDH at diagnosis allows for monitoring of the tumor recurrence after treatment. Distinct histopathological features and immunohistochemistry were helpful for an accurate diagnosis for bilaterality in our case. The majority of dysgerminomas are diagnosed in early stage, unlike our case who presented in an advanced stage with lung metastasis favoring a poor outcome. Prognosis can be good with a good five-year survival after appropriate chemotherapy. The risk for recurrence increases in the first 2–3 years after treatment, so a close follow-up in our case is required.

Author Contributions: Conceptualization, M.C.T., E.C. and L.L.; methodology, E.C., I.D.F., C.U. and L.L.; software, A.T., C.U., B.F.T.; validation, M.C.T., E.C. and L.L.; formal analysis, E.C. and L.L.; in- vestigation, M.C.T., E.C., B.F.T. and L.L.; resources, A.T., B.F.T.; data curation, A.T.; writing—original draft preparation, M.C.T., A.T., E.C. and L.L.; writing—review and editing, I.D.F., B.F.T.; visualization, M.C.T.; supervision, I.D.F. All authors have equally contributed to the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Hospital Ethics Committee (protocol according to the Order 865/22 January 2021). Informed Consent Statement: Informed consent was obtained from patient involved in the case. Data Availability Statement: The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy. Acknowledgments: We thank the specialists from “Cuza Vodă” Obstetrics and Gynecological Hospi- tal Iasi who provided us the data of the functional explorations of the patient. Conflicts of Interest: The authors declare no conflict of interest.

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