Cytologic Detection of Metastatic Immature Teratomas in Two Young Patients With Unique Presentations

ABSTRACT

Ovarian immature teratomas are rare malignant germ cell tumors composed of immature embryonal tissues, most commonly neuroepithelium, and account for less than 1% of all ovarian teratomas. Cytologic diagnosis is challenging because of overlapping morphologic features with other high‐grade malignant neoplasms and the limited utility of immunohistochemistry. Herein, we report two cases of high‐grade ovarian immature teratomas with metastatic immature neuroepithelial components in young women of childbearing age, emphasizing the cytologic findings, immunophenotypic features, histologic grading, and clinical course.

1. Introduction

Teratomas are the second most common germ cell malignancy, accounting for 1% of all ovarian cancers. They are mostly seen in adolescents and young adults and are composed of three germ cell layers: the ectoderm, endoderm, and mesoderm [1, 2]. Teratomas are classified into immature teratomas, mature teratomas, and monodermal highly specialized teratomas [3]. Among these, immature teratomas are considered malignant, whereas the latter two follow a benign clinical course. Immature teratomas contain immature embryonal neuroepithelium or other types of immature tissue elements, typically in the setting of peritoneal implants [1]. More than 99% of teratoma cases seen in everyday practice are typical mature cystic teratomas [3]. Pure immature teratomas are exceedingly rare, and cases in which immature neuroepithelial elements metastasize to other parts of the body are even less common [4]. Studies have reported that histologic grade is the best indicator of metastatic potential in these tumors [5]. Moreover, pure immature teratomas are considered to be very rare malignant tumors that are challenging to diagnose, especially in cytology specimens, since they can mimic other lesions, and essential morphologic criteria can be limited on cytology preparations [6]. Herein, we report two cases of immature teratomas with unique presentations, both in young patients of childbearing age.

2. Case Reports

The first case is that of a 27‐year‐old female who presented emergently with nausea, vomiting and abdominal pain for 2 weeks. The patient reported to have a positive urine pregnancy test but had a concerning low HCG result of 100 mIU/mL. Alpha feto protein (AFP), CA19‐9 and CA125 levels were elevated. Ultrasound examination during the first trimester revealed a pelvic mass with ascites, endometrial thickness of 0.8 cm, and absence of an intrauterine gestation. Follow up imaging showed a large heterogeneous mass measuring 12.8 cm, originating from the left ovary (Figure 1). Ascitic fluid cytology revealed scattered clusters of atypical cells with slightly enlarged nuclei, increased nuclear‐to‐cytoplasmic ratio, hyperchromasia with coarse chromatin and occasional prominent nucleoli (Figure 2). Immunohistochemistry was non‐specific, with tumor cells demonstrating positivity for cytokeratin AE1/AE3, calretinin, WT1 (patchy), vimentin and desmin, while being negative for Ber‐EP4, MOC 31, EMA, GFAP, S100, inhibin, c‐KIT, AFP, HCG, and p53. NSE showed scattered positive cells. PAX8 and synaptophysin showed focal weak nuclear reactivity. Additionally, the Ki‐67 demonstrated a very high proliferative index. The patient underwent an exploratory laparotomy, omentectomy and tumor debulking which demonstrated mature germ cell elements and immature neuroectodermal tissue involving the omentum and falciform ligament. Given the extensive amount of immature neuroepithelium and widespread disease, the tumor was graded as grade III, stage IIIc. She subsequently underwent chemotherapy, and follow‐up laparoscopy revealed residual peritoneal disease, for which, additional chemotherapy was administered. Unfortunately, 7 months later, follow‐up imaging showed extensive peritoneal disease.

FIGURE 1.

Case 1. CT abdomen and pelvis with contrast showing a large heterogeneous pelvic mass.

FIGURE 2.

Case 1. Cytologic and histologic findings. Top row: Papanicolaou smear of peritoneal fluid. Middle left: H&E‐stained cell block demonstrating atypical cells. Middle right: Omental metastases. Bottom left: Immunohistochemistry demonstrating OCT3/4 positivity. Bottom right: Immunohistochemistry demonstrating GFAP positivity.

The second case is that of a 28‐year‐old female who presented with abdominal distention. She had a history of bilateral abdominal ovarian cystectomies performed 6 months earlier, with pathology reported as mature cystic teratomas. Her AFP and CA‐125 levels were elevated. Imaging revealed a 13.0 cm left adnexal mass in the abdomen, along with ascites and omental caking (Figure 3). Fine needle aspiration cytology of the retroperitoneal lesion identified malignant cells with high nuclear‐to‐cytoplasmic ratio and scant cytoplasm (Figure 4). The tumor cells were positive for GFAP, weakly positive for SALL4 and showed focal scattered reactivity for AE1/AE3, CAM5.2 and NSE. BerEP4, MOC31, OCT3/4, Glypican 3, p40, p63, LCA, synaptophysin, chromogranin, and S100 were all negative. Ki‐67 demonstrated a very high proliferation index of 65%. The prior surgical specimen slides from bilateral ovaries were reviewed and did not show any immature teratomatous elements. Subsequently, the patient underwent a diagnostic laparoscopy which showed high‐grade immature teratoma involving the omentum, peritoneum and rectosigmoid colon. She received two rounds of bleomycin sulfate, etoposide phosphate and cisplatin.

FIGURE 3.

Case 2. CT abdomen showing a large amount of dense fluid in the abdomen and pelvis and mild thickening of the peritoneum.

FIGURE 4.

Case 2. Cytologic and histologic findings. Top row: Papanicolaou smear of peritonealfluid. Middle left: H&E‐stained cell block demonstrating atypical cells. Middle right: Immunohistochemistry demonstrating GFAP positivity. Bottom row: H&E‐stained block of rectosigmoid metastases.

3. Discussion

The word “teratoma” is derived from the ancient Greek word “teraton” meaning “monster”. Immature teratomas of the ovary constitute less than 1% of all teratomas of the ovary and are usually seen in women less than 30 years of age [1, 7]. While these tumors are rare, they make up about one third of all malignant germ cell tumors [8]. These tumors are usually unilateral, tend to grow rapidly, and have a high metastatic potential [1]. Given their propensity for rapid growth, immature teratomas are often associated with acute abdominal distention and ovarian torsion.

The World Health Organization (WHO) criteria for immature teratoma necessitate the presence of a germ cell tumor containing immature neuroectodermal tissue, intermingled with ectodermal and endodermal tissues of varying maturation [1]. Cytologically, immature teratomas exhibit cells in clusters, sheets, or as individual cells and at times may form rosette‐like structures. Immature neuroepithelial cells may look like neuroblasts with large nuclei and prominent nucleoli. Other cytologic features include hyperchromasia, increased nuclear‐to‐cytoplasmic ratio with or without vesicular nuclei, and increased mitotic figures. Rarely, other immature elements such as immature cartilage and primitive muscle cells may be present. It is important to note that there may be components of other neoplastic germ cell elements making it a malignant mixed germ cell tumor [1, 8]. Immunohistochemistry has limited diagnostic utility in immature teratomas; however, stains such as S100 and GFAP may be useful in staining neuroepithelium although they can stain both mature and immature neural elements [1], while OCT4 may help in differentiating between mature and immature components [1]. Additional immunostains such as SOX2 and FOXG1 have shown efficacy in highlighting immature neuroepithelial components [9]. Distant metastasis of the immature teratomatous elements is extremely rare with only a handful of cases reported in the literature.

Histologic evaluation is essential to grade immature teratomas, which is based on the number of low power fields in one slide that display aggregates of immature neuroepithelium [1]. Grade 1 tumors have aggregate amounts of immature neuroepithelium present in less than or equal to one low power field; grade 2 tumors demonstrate this morphology in more than one but less than or equal to three low power fields in a given slide, and grade 3 tumors have immature neuroepithelium in more than 3 low power fields (diameter = 4.5 mm) [1]. To decrease intra and inter observer disagreement with regards to grading, O'Connor and Norris proposed that immature teratomas be divided into two groups: low grade tumors with grade 1 morphology demonstrating a slight amount of immaturity and high‐grade tumors encompassing grades 2 and 3 tumors with a higher degree of immaturity [5]. The same criteria are utilized to grade metastatic sites demonstrating immature teratomas. Histologic grading is considered to be the most important prognostic indicator [1, 5].

Diagnosing immature teratomas can be challenging, especially on cytology specimens as their morphologic features mimic other malignant entities. Given the rarity of these tumors, ovarian torsion in pediatric and young adult patients warrants a broad differential diagnosis. When radiologic evidence suggests involvement of surrounding anatomic structures, immature teratoma should be placed higher on the differential [8]. While the differential diagnosis varies case by case, some entities to consider are listed below in Table 1:

TABLE 1.

Differential diagnosis for high N:C lesions of the ovary on cytology specimen.

Entity	Average age	Cytomorphology in brief	IHC profile	Molecular findings
Immature teratoma	~20 years	Variety of neoplastic cells, including immature neuroepithelial cells forming rosette‐like structures, keratinized squamous cells, squamoid metaplastic cells, and immature glial‐appearing cells [10]	GFAP S100 NSE SOX2 FOXG1	None. Gain of 12p or isochromosome 12p if part of a mixed germ cell tumor [11]
Small cell carcinoma	~25 years	Monomorphic round, ovoid cells arranged in sheets, nets or cords	Neuroendocrine markers, keratins (e.g., EMA), variable claudin‐4 Loss of SMARCA4 expression [12]	May harbor SMARCA4 mutations [12]
Lymphoma	Varies	Abnormal lymphoid cells, monomorphic cell population, with clumped chromatin [13]	T cell– CD3, CD4, CD8, CD7, TCR B cell—CD19, CD20, CD22 [13]	Varies
Desmoplastic small round blue cell tumor	First to fifth decade of life [14]	Cells with a high N:C ratio, having granular chromatin, nuclear molding, variable nuclear membranes and pseudorosettes	Cytokeratins, EMA, Desmin, WT1	EWSR1‐WT1 gene fusion [15]
Ewing/PNET	Usually less than 20 years old	Uniform small round cells with fine chromatin, scant cytoplasm and rare rosette‐like formation [16]	CD99, NKX2.2, Vimentin, FLI, ERG	t(11;22)(q24;q12) resulting in EWSR1‐FLI1 fusion [16]
Neuroblastoma	~2 years	Small, blue cells containing hyperchromatic to vesicular chromatin and scant, fibrillary cytoplasm, and rare Homer‐Wright rosettes [17]	NSE, CD56, ALK, FOX2B, GFAP [17]	MYCN and MYC overexpression [18]
Rhabdomyosarcoma (RMS)	0–4 years	Small round cells with rare intranuclear cytoplasmic inclusions	Desmin, MyoD1 Myogenin	DICER1, PIK3CA and TP53, PAX3::FOXO1 [19]
Blastemic component of Wilm's tumor	37 months (male) and 43 months (female)	Typically not performed	WT1, PAX8, Vimentin (blastemic components) [20]	Mutations in WT1, CTNNB1, IGF2 or TP53 [20]

A high nuclear‐to‐cytoplasm ratio with scant cytoplasm is a characteristic cytomorphologic feature shared by the entities listed above. However, when immunohistochemistry cannot provide sufficient diagnostic evidence, additional molecular testing, including fluorescence in situ hybridization (FISH) and RNA sequencing, may be required. FISH can identify chromosomal translocations seen in tumors such as Ewing sarcoma and Neuroblastoma, while RNA sequencing can detect fusion gene products, including those found in Alveolar Rhabdomyosarcoma.

Histologic grading and staging play a major role in guiding therapy for patients with immature teratomas [21]. Low‐stage and low‐grade tumors generally have a favorable prognosis, with recurrence being extremely rare in both pediatric and adult patients [21]. The primary treatment is surgical resection, with adjuvant chemotherapy considered for high‐grade tumors [1]. Management may also be tailored to individual circumstances, particularly when fertility preservation is desired. For patients with early‐stage disease, fertility‐sparing surgery followed by chemotherapy has become the standard of care [22]. Although the necessity of adjuvant chemotherapy has not been fully established, likely due to the rarity of this disease, studies suggest it is effective in preventing recurrence [23]. In the two cases reported here, post‐surgical chemotherapy did not achieve complete remission. The poor initial response may be related to the advanced stage at presentation, as prognosis and survival decline with increasing tumor grade and metastatic spread of immature elements [23].

4. Conclusion

In a young patient presenting with ascites, it is crucial to consider all potential diagnoses. Given the rarity of these tumors and the limited discussion in the literature and educational resources, we hope these cases contribute to the existing body of knowledge on the cytologic features of immature teratomas. Documentation of grade with presence or absence of metastasis and other germ cell tumors is essential in the appropriate management of these rare lesions.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.