CASE REPORT
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A rare case of a concomitant ovarian fibroma and malignant steroid cell tumor: insights into pathogenesis and steroidogenesis
Chihiro Inoue1*, Yuto Yamazaki2, Hironobu Sasano1, Yayoi Aoyama1, Toyoharu Watanabe3 and Takashi Suzuki1,2
Abstract
Background Fibromas are common ovarian stromal tumors, while steroid cell tumors (SCTs) are rare, accounting for < 0.1% of ovarian neoplasms. Approximately, one-third of SCTs exhibit malignant behavior, but predicting malig- nancy remains challenging.
Case presentation A 73-year-old woman presented with nonspecific pelvic pain, and imaging revealed multiple pelvic masses. She underwent a simple hysterectomy and bilateral adnexectomy. Pathological examination revealed a unique colocalization of a fibroma and a SCT in the right ovary. One year later, the SCT recurred with lymph node metastasis. Morphological analysis and whole exome sequencing suggested a shared origin for the fibroma and SCT components. Notably, two missense mutations in MUC4 were identified in the SCT, with immunohistochemistry confirming MUC4 overexpression. Steroidogenesis patterns in the SCT resembled those of adrenocortical carcinoma, indicating disorganized steroidogenesis and potentially explaining the absence of clinical endocrine abnormalities.
Conclusion This case underscores the rarity and complexity of concomitant ovarian fibroma and malignant SCT. The identification of MUC4 mutations and disorganized steroidogenesis may provide insights into the pathogenesis of malignant SCTs. Further research is needed to understand the mechanisms and clinical implications of malignant SCT.
Keywords Ovary, Sex cord-stromal tumor, Steroidogenesis, Pathology, Immunohistochemistry, Whole exome sequencing
Background
Fibromas are the most common ovarian stromal tumors, accounting for 4% of all ovarian neoplasms. Steroid cell tumors (SCTs) are rare ovarian sex cord-stromal tumors, accounting for <0.1% of all ovarian neoplasms, which comprise tumor cells with steroid-secreting morphology
involving the ovarian parenchyma. Approximately, 50% of the patients with SCTs clinically present with androgenic symptoms, and 10% present with estrogenic symptoms; in rare cases, Cushing’s syndrome has been clinically reported. SCTs exhibit malignant behavior in approxi- mately one-third of cases [1]. Pathological features such as a size>7 cm, significant mitotic activity, necrosis, hemorrhage, and pronounced nuclear atypia have been reported to be associated with the malignant behavior of SCTs [2]. However, a recent report indicated that tumor necrosis, hemorrhage, and larger tumor size were signifi- cantly associated with International Federation of Gyne- cology and Obstetrics (FIGO) stage≥IB, reinforcing the conclusion that these features are not independent predictors of recurrence [3]. It is still difficult to predict
*Correspondence: Chihiro Inoue chihiro_inoue.med@tohoku.ac.jp
1 Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
2 Department of Pathology, Tohoku University Hospital, Sendai, Japan
3 Department of Gynecology and Obstetrics, Towada City Central Hospital, Towada, Japan
Springer Open
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malignant behavior based on pathological features, as the mechanisms by which SCTs acquire malignant charac- teristics remain unclear. Fibroma and SCTs are sex cord- stromal tumors, but there has been only one case report of an ovarian tumor comprising a fibroma and SCT, not otherwise specified (NOS) previously [4]. Here, we report the first case of an ovarian tumor comprising fibromas and a SCT, which was revealed to be malignant following metastasis 1 year after surgery.
Case presentation
A 73-year-old woman (gravida 2, para 2) presented with nonspecific pelvic pain. Ultrasonography revealed multiple pelvic masses, and she was referred to Tow- ada City Central Hospital for further evaluation. Pelvic T2-weighted magnetic resonance imaging (MRI) demon- strated two extrauterine tumors adjacent to the anterior aspect of the uterine fundus: one with low signal inten- sity measuring 14 cm in diameter and another with high signal intensity measuring 9 cm in diameter (Fig. 1a). The low signal intensity tumor was suspected to be a fibroma, fibrothecoma, or benign Brenner tumor. In contrast, the high signal intensity tumor was clinically considered malignant due to its increased size compared to findings from contrast-enhanced CT performed 1 year earlier during a pacemaker evaluation for atrioventricular block treatment. A simple hysterectomy and bilateral adnex- ectomy were subsequently performed for treatment and diagnosis.
Macroscopically, the right ovarian mass comprised two different components: one with a white cut surface and stiff appearance, measuring 13 cm in diameter, and the other with a yellow cut surface and soft, measuring 9.5 cm in diameter, associated with intra-tumoral necro- sis and hemorrhage (Fig. 1b). The two tumors were well circumscribed. A compressed nonneoplastic right ovary is detected on the surface of the white tumor. Addition- ally, multiple myomas were detected in the uterine body. No abnormalities were observed in the left adnexa.
Histologically, the white tumor comprised intersect- ing fascicles of spindle cells with bland spindle-to-ovoid nuclei and scant eosinophilic cytoplasm within a variably collagenous stroma and was subsequently diagnosed as a fibroma (Fig. 1c). The yellow tumor comprised diffuse proliferation of granular eosinophilic polygonal cells. The tumor cells showed significant nuclear atypia with large or multinucleated nuclei of irregular sizes and shapes (Fig. 1d). Some tumor cells with less atypia, small polyg- onal cells, and small round nuclei were predominantly observed in the peripheral area of the tumor (Fig. 1e). Mitotic activity was high (5 mitoses/10 high-power fields), with coagulative necrosis of tumor cells and intra- tumoral hemorrhage. No Reinke crystals were detected
in the tumor cells. The tumor cells were immunoposi- tive for inhibin alpha, calretinin, melan-A, and SF-1 and negative for pan-cytokeratin (AE1/AE3) and FOXL2 (Table 1). The tumor was diagnosed as a SCT-NOS based on morphology and immunohistochemistry results. The right ovarian mass comprised ovarian fibroma and SCT components. SCT cells with less atypia were observed, intermingling with fibroma cells in the boundary area between the two tumor components (Fig. 1f).
SCTs have all the factors that predict malignant behav- ior, including size>7 cm, significant mitotic activity, necrosis, hemorrhage, and significant nuclear atypia [2]. Therefore, the patient received six cycles of paclitaxel- carboplatin postoperatively; however, the SCT recurred with para-aortic lymph node metastasis 1 year postop- eratively. The recurrent tumor was surgically resected and found to comprise monotonous steroid cells with less nuclear atypia (Fig. 1g). No additional chemotherapy was administered because of recurrence. No other recur- rent lesions were detected on the follow-up CT 3 months after the second surgery.
The patient did not present with any clinical endo- crine manifestations, and the endometrium was atrophic; therefore, serum hormone levels were not examined. We immunostained 15 steroidogenic enzymes (StAR, SCC, 3BHSD, CYP11B1, CYP11B2, c17, c21, 5a1, 5a2, aro- matase, 17BHSD1, 17ßHSD2, EST, SDS, and DHEA-ST) to further explore the types of steroid hormones pro- duced in ovarian tumors. Steroidogenic enzymes besides CYP11B2, 17ßHSD2, 5x2, and STS were expressed, but their immunoreactivity status was markedly heteroge- neous, especially in steroid tumor cells with significant nuclear atypia (Fig. 2, Table 1). Fibroma cells showed weak and heterogeneous immunopositivity for ster- oidogenic enzymes, including 3BHSD, c17, 17BHSD1, 17BHSD2, aromatase, 5x1, and STS. SCT cells with less atypia exhibited immunostaining patterns similar to those of SCT cells with significant nuclear atypia, dem- onstrating immunopositivity for StAR, SCC, c17, and DHEA-ST, while being negative for CYP11B2 and 5x2. The immunoreactivity of 17BHSD2 and 5a1 in SCT cells with less atypia resembled that of fibroma cells, show- ing partial positivity for 17ßHSD2 and weak positivity for 5a1. SCT cells at the metastatic site demonstrated intra-tumoral heterogeneity of steroidogenic enzymes, as observed in primary tumors (Table 1). The SCT cells were immunohistochemically positive for glucocorticoid receptor (GR) and progesterone receptor (PgR), and the fibroma component was positive for GR, PgR, and andro- gen receptor (AR).
Whole exome sequencing (WES) of these two tumor components, fibroma and SCTs, using FFPE specimens was performed to examine whether they were composite
(a)
(b)
MRI (T2WI)
Steroid cell tumor
Fibroma
V
Fibroma
Steroid cell tumor
Leiomyoma
: 108 of 173
M9
5 cm
(c)
(d)
e
100 pm
100 um
100 jam
(f)
(g)
tumors derived from the same progenitor cell or colli- sion tumors derived from different progenitor cells. No clinically significant or known pathogenic mutations known to be associated with malignancy were identified after filtering for potential single-nucleotide polymor- phisms (SNPs). For example, both tumor components harbor a heterozygous missense mutation in DICER1 (c.2033C>T); however, the pathogenic significance of
this mutation remains unknown. Mutations in several genes, such as ATRX, BAP1, BRCA2, CASP10, CDK4, CTNNB1, DCM1, FH, FOXO4, HIF1A, HOXA13, IDH2, LHCGR, MDM2, NPM1, SDHB, SRC, SS18, TP53, and VHL, have been reported in SCT, NOS, and malig- nant cases [6-8]. However, no mutations in any of these genes were detected in our case. Immunohistochemical expressions of MLH1, MSH2, MSH6, and PMS2 were
| Antibody | SCT cells with significant atypia | Primary site SCT cells with less atypia | Fibroma cells | Metastatic site SCT cells |
|---|---|---|---|---|
| pan-CK (AE1/AE3) | - | - | - | (Not examined) |
| a-Inhibin | + | + | - | + |
| Melan-A | +>weak+>- | +>- | - | +/weak+/- |
| Calretinin | + | + | ->>weak+ | + |
| FOXL2 | - | - | + | - |
| SF-1 | + | + | +>>- | + |
| StAR | +>- | + | - | + |
| SCC | Weak+>>- | +>weak+ | - | + |
| 3ßHSD | Weak+>- | +>weak+ | Weak+ | Very weak+ |
| c17 | +/weak+/- | + | ->>very weak+ | + |
| c21 | ->>+ | - | - | - |
| CYP11B1 | Weak+>+ | ->>weak+ | - | ->weak+>>+ |
| CYP11B2 | - | - | - | - |
| 17HSD1 | Weak+>+ | +>weak+ | + | Weak+>>+ |
| 17ßHSD2 | - | ->weak+ | Weak+>- | - |
| Aromatase | Weak+>->+ | +>->weak+ | ->very weak+ | Weak+>+ |
| 5a1 | +>>- | +>weak+ | Weak+ | Weak+>+>- |
| 5a2 | - | - | - | - |
| EST | ->>>weak+ | Very weak+ | - | - |
| STS | - | Weak+>+ | ->>weak+ | ->weak+ |
| DHEA-ST | +>weak+>- | + | - | +>weak+>- |
Immunohistochemical expression was evaluated using the PRIME notation method [5]
retained, and microsatellite instability was not demon- strated. Interestingly, six and four mutations in exon 2 of MUC4 were identified in the SCT and fibroma compo- nents, respectively. Each tumor component harbored two missense variants, one of which was a common variant while the others were distinct (Table 2). Immunohisto- chemically, mucin 4 (MUC4) expression was observed in SCT cells, particularly in tumor cells with less atypia, including those at the metastatic site, whereas fibroma cells were immunonegative for MUC4 (Fig. 3). This may represent overexpression, as normal ovarian and adrenal gland cells showed weak positivity or were negative for MUC4 (Supplemental Fig. 1).
Discussions
Knowingly, this is the first reported case of an ovarian tumor with malignant SCT and fibroma components. A previously reported case of an ovarian tumor with SCT, NOS, and fibroma components demonstrated features similar to those in our case. The two components were macroscopically well demarcated, and the SCT com- ponent showed high mitotic activity and focal necrosis, which were reported to predict malignant behavior [4]. However, follow-up data of the patient were not reported
in their study; therefore, whether any malignant behav- ior, such as recurrence or metastasis, was detected post- operatively remains unknown. The authors reported that the fibroma component contained aggregates of lute- inized cells, which were not detected in our case, and postulated that the tumor was composite because the SCT component could have arisen from the neoplastic transformation of luteinized cells within the fibroma- tous component. However, there have been a few reports of fibromas with minor sex cord components [9] whose origin remains unclear. A tumor with two types of com- ponents is classified as either a composite or collision. Composite tumors typically share the same progenitor cells, whereas collision tumors arise from different pro- genitor cells. Morphologically, composite tumors have two distinct components that coexist, intermingled or with one predominant and a focal minority component [10]. Collision tumors comprise two well-circumscribed components. In our case, the fibroma and SCT compo- nents were macroscopically well-circumscribed, suggest- ing a collision tumor. However, microscopically, cuboidal steroid cells with fewer nuclear atypia were intermin- gled with fibroma cells at the boundary. Other sex cord components and potential progenitors of SCTs were not
(a)
(b)
(c)
Cholesterol
(+>-)
StAR Scc (weak+>>-)
36HSD (weak+>-)
c21(→>+)
CYP11B2 (-)
aldosterone
Pregnenolone
progesterone
Deoxy- corticosterone
corticosterone
c17
(+/weak+/-)
17aOH- pregnenolon
17aOH- progesterone
11-Deoxycortisol
cortisol
(+/weak+/-)
c17
CYP11B1 (weak+>+)
(+>weak+>-) DHEA-ST
DHEA
Androstenedione
Estrone
DHEA-S
(-)
17@HSD2
17@HSD5
(-)
17@HSD1 (weak+>+)
(-)
17@HSD2
17@HSD2
Androstenediol
Testosterone
(→>>weak+)
Estradiol
EST
5a1(+>>-) 5a2 (-)
Aromatase (weak+>>>+)
Estradiol -sulfate
STS(-)
5a-DHT
| Steroid cell tumor | Fibroma | ||
|---|---|---|---|
| p.Ser3221_Thr3268del | (Conservative inframe deletion) | p.Ala2425Gly | (Missense variant) |
| p.His2765His | (Synonymous variant) | p.Thr2255Thr | (Synonymous variant) |
| p.Ser2055Phe | (Missense variant) | p.Ser2055Phe | (Missense variant) |
| p.Ser1783Ser | (Synonymous variant) | p.Val1702Val | (Synonymous variant) |
| p.Ala1558Thr | (Missense variant) | ||
| p.Thr1951_Pro1952insSerLeuProValThrAspAlaSerSerValSerThrGly- HisAlaThrSerLeuProValThrlleProSerSerAlaSerSerGlyHisThrThr | (Conservative inframe insertion) | ||
found in the fibroma. SCT cells with less atypia showed intermediate immunohistochemical features between those of fibromas and SCTs with marked nuclear atypia. Fibroma and SCTs harbored 621 and 779 single-nucle- otide variants (SNVs) and indels, respectively. These
two tumors shared 477 mutations, supporting a com- posite tumor diagnosis. However, a definitive differen- tial diagnosis between collision or composite tumors could present diagnostic challenges because no previ- ously reported driver mutations were detected by WES
Fibroma
Steroid cell tumor, the component with less atypia
Steroid cell tumor, the component with significant atypia
Steroid cell tumor in the metastatic site
analysis. Missense variants of MUC4 gene detected in SCT could contribute to the stabilization of the MUC4 protein or enhance its translation efficiency, although function of these variants is still unknown. MUC4 has been reported to be overexpressed in various tumors and to interact with ERBB2, promoting proliferation and contributing to malignancy [11]. MUC4 could also be associated with the development of malignant SCTs. The detailed pathogenesis of these tumors remains unclear. Therefore, investigations using animal models or in vitro models with stem cells, such as induced pluripotent stem cells, are warranted.
In this case, SCT exhibited disorganized expression patterns of steroidogenic enzymes, which are charac- teristic of adrenocortical cancers [12]. These tumors produce various hormones and precursors at different levels, leading to inefficient hormone receptor activa- tion and a tendency to be non-functional. Here, the SCT shared features with adrenocortical carcinoma, includ- ing compact cells with diffuse growth, variable cytologi- cal atypia, mitosis, necrosis, and disorganized enzyme patterns. A comparative analysis not only between SCTs and other ovarian tumors but also with adrenal tumors may help elucidate the characteristics of malignant SCTs, warranting further investigation in the future. In addi- tion, the fibroma and steroid cell components express the hormone receptors PgR, GR, and AR. Although a few efficient hormones may have been produced, these ligands may have only weakly enhanced the growth of both components. The impact of steroid hormones on tumor development and growth should also be taken into consideration.
Conclusion
This case of an ovarian tumor comprising fibromas and malignant SCT components highlights the complexity of sex cord-stromal tumors, particularly the mechanisms
underlying the development and malignant transfor- mation of SCTs. Although immunohistochemistry and genetic analyses were performed in this case, these mech- anisms remain unclear. Further case studies are required to advance our understanding of these tumors.
Abbreviations
| SCT | Steroid cell tumor |
| FIGO | International Federation of Gynecology and Obstetrics |
| NOS | Not otherwise specified |
| MRI | Magnetic resonance imaging |
| StAR | Steroidogenic acute regulatory protein |
| SCC | Side-chain cleavage enzyme |
| 3ßHSD | 3ß-Hydroxysteroid dehydrogenase |
| CYP11B1 | Cytochrome P450 family 11 subfamily B member 1 |
| CYP11B2 | Cytochrome P450 family 11 subfamily B member 2 |
| C17 | 17a-Hydroxylase |
| C21 | 21-Hydroxylase |
| 5a1 | 5a-Reductase type 1 |
| 5a2 | 5a-Reductase type 2 |
| Aromatase | Cytochrome P450 family 19 subfamily A member 1 |
| 17ßHSD1 | 17ß-Hydroxysteroid dehydrogenase type 1 |
| 17ßHSD2 | 17ß-Hydroxysteroid dehydrogenase type 2 |
| EST | Estrone sulfotransferase |
| SDS | Steroid sulfatase |
| DHEA-ST | Dehydroepiandrosterone sulfotransferase |
| GR | Glucocorticoid receptor |
| PgR | Progesterone receptor |
| AR | Androgen receptor |
| WES | Whole exome sequencing |
| SNP | Single-nucleotide polymorphisms |
| MUC4 | Mucin 4 |
| SNV | Single-nucleotide variants |
Supplementary Information
The online version contains supplementary material available at https://doi. org/10.1186/s43046-025-00281-3.
Supplementary Material 1: Supplemental Figure 1. Normal ovarian granu- losa and stromal cell, and adrenal gland cells showed weak positivity or negativity for MUC4. Bar = 100 um.
Supplementary Material 2. Supplement: materials and methods of whole- exome sequencing (WES). DNA was extracted from the fibroma and steroid cell tumor tissues using the QIAamp DNA FFPE Tissue Kit (Qiagen, Valencia, CA, USA) according to the manufacturer’s protocol. Extracted
genomic DNA was subjected to WES. WES was outsourced to Macrogen Japan Company and performed using the SureSelect V6-Post and Illumina platforms. Paired-end sequences produced by the NovaSeq Instrument were mapped to the human reference gene GRCh38 using the mapping program BWA, and variant calling was performed using GATK. Mutations with variant allele frequency < 0.1, depth < 30, or those registered in 1000 Genomes with AF > 0.05 (possible SNPs) were excluded for filtering germline mutations.
Acknowledgements
We would like to thank the staff of the Pathology Department at Towada City Central Hospital for their technical support and Editage (www.editage.jp) for English language editing.
Authors’ contributions
Conceptualization, C.I .; Data curation, C.I., Y.Y., Y.A., and T.W .; Formal analysis, C.I., Y.Y., and S.H .; Resources, T.W .; Supervision, H.S., and T.S .; Writing-original draft, C.I .; Writing-review and editing, Y.Y., S.H., and T.S. All authors read and approved the final manuscript.
Funding
The authors received no specific funding for this work.
Data availability
The data supporting the findings of this case report are not publicly available due to sensitivity concerns but can be obtained from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
This study was conducted in accordance with the Declaration of Helsinki. The Ethics Committee of Tohoku University waived the requirement for review, given the nature of a case report. Written informed consent was obtained from the participants for genetic analysis and publication of this case report.
Consent for publication
Written informed consent was obtained from the participants for genetic analysis and publication of this case report.
Competing interests
The authors declare no competing interests.
Received: 3 February 2025 Accepted: 22 March 2025 Published online: 19 May 2025
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