Abstract

Malignant mixed germ cell tumors (MMGCTs) comprise multiple histologic germ cell components and present significant diagnostic challenges due to their atypical clinical manifestations and histopathological heterogeneity. Early recognition is imperative for optimal therapeutic outcomes. Here we present a case of a 28-year-old female with abnormal uterine bleeding and a rapidly growing uterine mass that prompted further investigation. Histopathological examination revealed a neoplasm with endometrioid-type glandular structures, immature neuroectodermal tissue with rosette formation, cartilaginous islands, and sarcomatoid differentiation with rhabdomyoblastic elements. Immunohistochemical profiling showed positivity for Pax 8, SALL 4, CD 117 (focal), Glypican 3 (focal), and p53 within the glandular component, with synaptophysin and CD 99 positivity in the neuroepithelial component. Primary uterine MMGCTs are rare, and necessitate a high index of suspicion, particularly in patients with rapidly progressive uterine masses. Comprehensive histopathological and immunohistochemical evaluation is critical for definitive diagnosis and differentiation from other uterine neoplasms. Given their aggressive nature, a multimodal treatment approach, including surgical resection and adjuvant chemotherapy, remains the mainstay of management.

Keywords:Malignant mixed germ cell tumor; Uterine neoplasm; Extragonadal germ cell tumor; Immunohistochemistry

Introduction

Germ cell tumors [GCT] are an important group of gonadal neoplasms that include a number of histologically distinct tumor types derived from the primitive germ cells of the embryonic gonad [1]. GCTs are classified as extragonadal if there is no presence of primary tumors in either tests or ovaries [2]. These account for 1-5% of the germ cell tumors [3]. These are usually located in the middle of the body [4]. Malignant GCTs are particularly rare in the uterus and endometrium, with only 14 cases of primary yolk sac tumor of the endometrium reported in literature [1]. Mixed germ cell tumors of uterus were first reported in 2020 in the endometrium of a post-menopausal female [3]. The current case report presents a case of a malignant mixed germ cell tumor in the uterus of a 28-yr old female, highlighting the rarity, unique diagnostic challenges and considerations for managing such an atypical presentation.

Case Presentation

A 28-year-old female presented with abdominal pain and per vaginal bleeding. During a per speculum examination, a necrotic polypoidal mass was observed filling the uterus and cervix. MRI pelvis revealed mass in lower portion of urinary bladder up to the rectum and vagina. There was a history of polypectomy three months prior, which was reported as a benign endometrial polyp. Hence, it was a rapidly growing cervical/ vaginal mass. A biopsy was performed, and the specimen was sent for further pathological examination. Unfortunately, it was predominantly necrotic in nature and showed only a cartilaginous island and one bit akin to hyperplastic endometrium. With the possibility of retained products, case was discussed with the referring clinician, however, serum beta HCG levels were within normal limits and the clinical presentation of a rapidly growing mass did not fit.

Hence, more material was sought. On follow up, the clinician also elicited a history of still birth 2 years prior. Unfortunately, the patient succumbed to the disease on further follow up.

Gross Examination

On gross examination the specimen consisted of multiple friable soft tissue fragments aggregating to 15 x 13 x 3 cm with surface ulceration and exudate. The cut section of the tissue revealed a gray-white appearance with hemorrhagic areas.

Microscopic examination

Extensive endometrioid-type glandular pattern was seen with presence of immature neuroectodermal tissue with rosettes. Mature and immature cartilaginous islands were observed along with stromal sarcomatoid changes and rhabdomyoblastic differentiation (Figures 1,2a,2b,2c,2d).

Immunohistochemical Examination

The tumour showed positivity for Pax 8, SALL 4, CD 117 (focal), Glypican 3 (focal) & p53 in the glandular component. Synaptophysin & CD 99 were positive in the immature neuroepithelium. Vimentin was positive in the sarcomatoid areas while Desmin positivity confirmed rhabdomyoblastic differentiation. The tumour was negative for CK 7, ER, PgR, CD 30, PLAP, and AFP (Figures 3a, 3b,3c,3d).

Final Diagnosis

The histopathological findings and IHC profile confirmed the diagnosis of a Malignant Mixed Germ Cell Tumor comprising of Yolk sac tumor (70%) and Teratocarcinosarcoma (30%) [comprising mature and immature cartilage, neuroepithelium and sarcomatoid areas with rhadomyoblastic differentiation]

Discussion

Primary extragonadal germ cell tumors, which develop outside the ovaries and testes, account for only 3-5% of all GCTs. These tumors typically emerge along the midline structures of the body along which the primitive germ cells migrate from the wall of the yolk sac to the gonadal ridge. The most common tumor sites in adults are the mediastinum, retroperitoneum, sacrococcygeal regions, pineal glands, and suprasellar regions [3-5]. Mixed germ cell tumors are tumors having two or more types of malignant, primitive, or germ cell components. As per the WHO classification, the most common subtype is GCT with a mixture of yolk sac tumor and dysgerminoma [6]. Uterine GCTs are very rare and present with non-specific symptoms, such as abnormal vaginal bleeding, abdominal pain, or a palpable mass, making early diagnosis challenging. In the current case, patients presented with an extensive uterine mass and per vaginal bleeding which aligns with the other documented cases [1-4,7]. The average age of the other patients documented in literature ranged from 24 to 87 yrs, with common occurrence seen in post-menopausal women. Zhang et al documented the first case of mixed germ cell tumor in the endometrium of a post-menopausal female [4]. Our patient is a 28-yr old female, with clinically atypical presentation, making diagnosis and further management challenging.

Primary malignant germ cell tumors of the uterus are rare and challenging to diagnose due to their atypical location and non-specific clinical presentation. Histologically, germ cell tumors often resemble ovarian GCTs, with common subtypes including yolk sac tumors and immature teratomas. Due to their rarity, uterine GCTs necessitate a high degree of clinical suspicion, along with comprehensive histopathological and immunohistochemical analysis, to distinguish them from other uterine malignancies for optimal treatment strategies. The mechanisms behind extragonadal GCT formation are not fully understood, but several theories exist. The histogenesis of extragonadal GCTs is complex, with theories suggesting aberrant germ cell migration or somatic cell differentiation within the endometrial tissue. The four proposed mechanisms for germ cell neoplasms in the endometrium include aberrant migration during embryogenesis, metastasis from an occult ovarian primary, residual fetal tissue post-abortion, or somatic cell aberrant differentiation [7,8]. Residual fetal tissue post abortion may be the cause in our patient as there is a history of still birth 2 years prior. The first case of primary YST of the endometrium was reported in 1980 [9]. Histologically, endometrial yolk sac tumors and malignant teratomas mirror their ovarian counterparts.

As described by Euscher et al, yolk sac tumors may be mistaken as more commonly encountered carcinomas due to overlapping morphologic and IHC features. Specifically, they are most likely to be mistaken for clear cell carcinomas, which express similar epithelial markers as YST (cytokeratin, EMA) but not similar tumor markers (CA-125 vs AFP) [7,10]. Also, the endometrioid variant of yolk sac tumour mimicks the endometrioid adenocarcinoma as the name suggests, however, IHC profile is different [11]. IHC markers such as Pax 8, SALL 4, and Glypican 3 help the diagnosis, while negative markers such as CK 7 and ER rule out other endometrial malignancies [7,11]. In our case, a similar immunohistochemical profile was seen with Pax 8, SALL 4, CD 117 (focal), Glypican 3 (focal) & p53 positive in the glandular component, synaptophysin & CD 99 positive in the immature neuroepithelium & Vimentin and Desmin positive in the sarcomatoid component with rhabdomyoblastic differentiation while CK 7, ER, PgR, CD 30, PLAP, and AFP was negative. The standard treatment approach includes surgery with adjuvant chemotherapy, like ovarian GCTs, although the prognosis for uterine GCTs remains uncertain due to limited cases. Adjunct chemotherapy after surgery, which demonstrated an efficacious clinical outcome, is also reported as a promising approach for the treatment of the disease. Immature teratomas, in uterus are noted for aggressive behavior and poor outcomes. Considering the limited cases of uterine GCT seen in literature, their suspicion during clinical examination and subsequent comprehensive detailed histopathological examination becomes imperative for differential diagnosis from other malignancies of uterine origin.

Conclusion

This case underlines the diagnostic and therapeutic complexities associated with rare extragonadal germ cell tumors of the uterus. Given the aggressive potential of uterine immature teratomas, prompt and accurate histopathological evaluation is crucial for guiding effective treatment. Clinicians should remain vigilant about atypical tumor presentations and consider comprehensive communication with pathologists to ensure appropriate diagnostic clarification and optimal management strategies. This case illustrates the diagnostic and clinical challenges in managing a rare uterine malignant mixed germ cell tumor, highlighting the role of thorough histopathological and immunohistochemical analyses for diagnosis and guiding onward treatment strategies.

Conflict of Interest

No conflict of interest.

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