A 46-Year-Old Woman with Primary Infertility and a Diagnosis of Microcystic Stromal Tumor of the Ovary Confirmed by Histology and Gene Sequencing: A Case Report and Review of the Literature

Abstract

Patient: Female, 46-year-old

Final Diagnosis: Microcystic stromal tumor of the ovary

Symptoms: Abdominal pain • vaginal bleeding

Medication: —

Clinical Procedure: —

Specialty: Pathology

Objective:

Rare disease

Background:

Microcystic stromal tumor (MCST) of the ovary is a rare entity with distinct pathological and molecular features. However, a lack of awareness of ovarian MCST can lead to delayed diagnosis or misdiagnosis. We present a case of ovarian MCST and review all previously reported cases and discuss their clinical and pathological characteristics.

Case Report:

A 46-year-old woman with primary infertility due to polycystic ovary syndrome presented with bleeding and pain. Radiological images showed a complex solid and cystic adnexal mass. Microscopically, the tumor was lobulated with cellular regions separated by fibrous plaques and small anastomosing cysts, consistent with an ovarian MCST. The tumor cells showed positive staining for vimentin, CAM 5.2, CD10, β-Catenin, CD99, and cyclin D1. Genetic sequencing showed a point mutation in the CTNNB1 gene, with no mutations in the APC, BRCA1, and BRCA2 genes. The patient underwent surgery and was disease-free at 24 months after her initial diagnosis.

Conclusions:

The diagnosis of ovarian MCST should consider the differential diagnosis of cystic tumors of the ovary. Further research is encouraged to elucidate the various molecular pathways involved in the pathogenesis of this tumor and to determine its optimal treatment and long-term prognosis.

Background

Ovarian microcystic stromal tumor (MCST) was first reported in 2009 by Irving and Young [1] and was then included as a pure ovarian stromal tumor in the 2014 World Health Organization Classification of Tumors of the Female Reproductive Organs [2]. Ovarian MCSTs have distinctive morphological features, including microcysts and cellular lobules with an intervening fibrous, or sometimes hyalinized stroma. They lack the morphological features of other sex cord-stromal tumors and do not show any germ cell, teratomatous, or epithelial elements. They are also characterized by unique immunohistochemical and molecular profiles [1,3].

Fewer than 60 cases of ovarian MCSTs have been reported to date [1,4–27] all of which were in adults, had a mean size of <10 cm, and had benign outcomes, except for a case of pelvic recurrence [21]. We present a case of an ovarian MCST in a 46-year-old woman with primary infertility due to polycystic ovary syndrome. We also discuss the histopathological, radiological, immunophenotypical, and molecular features of this tumor and review all previously reported cases.

Case Report

A 46-year-old woman presented with intermittent vaginal bleeding and moderate abdominal pain for 3 days. She had a history of primary infertility and polycystic ovaries, for which she received various fertility regimens and underwent a series of ultrasound imaging for 3 years. She also underwent a myomectomy for a uterine fibroid 6 years before her presentation. She had no family history of malignant tumors. The patient had a body mass index of 36.85 kg/m² and a slightly tender abdomen with no palpable inguinal lymph nodes on physical examination. Her vital signs were stable upon admission, and all laboratory investigations were within normal limits, including a complete blood count, coagulation profile, urea and electrolyte panel, renal and liver function tests, and tumor markers (CA 125, CA 15-3, CA 19-9, CEA, AFP, and β-HCG).

Pelvic ultrasound showed a large complex left adnexal mass, measuring 15.3×12.3×10.6 cm, with cystic and solid components. Two small intramural fibroids were also noted. Magnetic resonance imaging (MRI) of the pelvis showed a complex multiloculated cystic mass with few enhancing solid areas, measuring 17×15×9 cm (Figure1A, 1B). The uterus was displaced with multiple intramural fibroids and showed diffuse adenomyosis. A large area of loculated fluid was also seen in the pouch of Douglas, measuring 7×6.5×7.5 cm, displacing the rectum posteriorly. Radiologically, these findings were likely to represent a malignant epithelial ovarian neoplasm. The patient was scheduled for surgery with an intraoperative consultation, which suggested at the time a sex cord-stromal tumor. The patient underwent an open left salpingo-oophorectomy, infra-colic omentectomy, bilateral peritoneal biopsies, left pelvic lymph nodes dissection, and an appendectomy. Fluid from the pouch of Douglas was taken for cytological examination and was negative for malignant cells.

Figure 1.

Magnetic resonance imaging of the pelvis with intravenous contrast showing a large complex multiloculated left adnexal mass. (A) A sagittal T2-weighted image and (B) an axial T2-weighted image.

Macroscopically, the ovarian mass weighed 935 g and measured 17.5×16×6.4 cm. It was firm with a smooth outer surface. Serial slicing showed a complex partially solid and partially cystic mass. The cystic areas were filled with a clear fluid, while the solid areas were pale tan and homogenous. No papillary projections were seen.

Microscopically, the tumor was lobulated with cellular regions separated by fibrous plaques (Figure 2A) and small anastomosing cysts (Figure 2B). The neoplastic cells were round with pale finely granular eosinophilic cytoplasm and round to oval nuclei (Figure 2C, 2D). Small nucleoli were occasionally noted, and mitoses were absent. The other specimens were histologically unremarkable.

Figure 2.

Microcystic stromal tumor. (A) A low-power photomicrograph showing the tumor’s lobular architecture with scattered fibrous plaques (hematoxylin and eosin stain, ×20). (B) The tumor shows a more cellular area in the center (star) surrounded by microcysts (arrows) (hematoxylin and eosin stain, ×100). (C) The distinctive anastomosing channels or microcysts (arrows) of this tumor are noted in this image (hematoxylin and eosin stain, ×100). (D) Tumor cells forming microcysts (arrows) and have a finely granular pale eosinophilic cytoplasm and round nuclei (hematoxylin and eosin stain, ×200).

The tumor cells showed positive staining for vimentin, CAM 5.2, CD10, β-Catenin, CD99 (paranuclear dot-like pattern), and cyclin D1 (Figure 3A–3F). Around 5% to 10% of cells showed weak nuclear positivity for progesterone receptors. All other markers were negative, including inhibin, calretinin, PLAP, EMA, cytokeratin 20, cytokeratin 7, melan A, chromogranin, synaptophysin, AFP, WT-1, and estrogen receptors. The microscopic findings and immunohistochemical results were in keeping with an MCST of the ovary. Genetic sequencing showed a point mutation in the CTNNB1 gene. There were no mutations detected in APC, BRCA1, and BRCA2 genes.

Figure 3.

A panel of immunohistochemical stains. (A) CD99 shows a paranuclear dot-like pattern of staining in tumor cells. Tumor cells are positive for (B) CAM 5.2, and (C) CD10. They also show positive nuclear staining for (D) β-Catenin, (E) cyclin D1, and focally for (F) progesterone receptors (immunohistochemical staining, ×200).

The patient was discharged in good health on the third day after surgery, and she was disease-free 24 months after her initial diagnosis. She is still following up with her gynecologist for primary infertility and general surgery for a future sleeve gastrectomy. A written informed consent for patient information and images to be published was obtained from the patient.

Discussion

The first detailed description of an ovarian MCST was published in 2009 by Irving and Young, based on 16 uncategorized tumors of the ovary [1]. In 2011, Maeda et al reported β-catenin nuclear expression and CTNNB1 point mutations in 2 cases of ovarian MCST, proposing that the Wnt/β-catenin pathway contributes to the pathogenesis of this tumor [4]. In 2014, ovarian MCST was added as a pure ovarian stromal tumor to the WHO Classification of Tumors of the Female Reproductive Organs [2]. Yang et al then described the ultrastructural features of these tumors and showed an aberrant nuclear expression of the p27 protein, suggesting a simultaneous dysregulation of the p27Kip1 tumor suppressor gene [5]. In 2015, Lee et al reported an ovarian MCST in a patient with familial adenomatous polyposis. The tumor displayed a somatic mutation in the APC gene (exon 11) and no mutations in the CTNNB1 gene [9]. The pure stromal origin of ovarian MCST was later supported by Meurgey et al, who reported the lack of FOXL2 and DICER1 mutations in 3 cases [18].

A total of 56 cases of ovarian MCST have been reported to date (Table 1). All cases were in adults, with a mean age of 44 years (range: 23–71 years) [1,4–27]. All cases were unilateral, with more on the left side, had a mean size of <10 cm, and lacked hormonal manifestations [1,4–27]. More than half of the patients presented with a mass (28/52, 53.85%), followed by pelviabdominal pain, discomfort, or fullness (14/52, 26.92%), or their tumors were discovered incidentally during routine checkups or while other unrelated symptoms were being investigated (10/52, 19.23%). More than half of the patients (24/51, 47%) had associated gynecological (12/24, 50%) or non-gynecological (12/24, 50%) disorders. The clinical features of familial adenomatous polyposis were present in 4 patients [9,15,21,22], and 5 patients had a history of malignancy (4 endometrioid endometrial adenocarcinomas, 1 contralateral ovarian endometrioid adenocarcinoma, and 1 colonic adenocarcinoma) [1,6,24]. Tumor markers were evaluated in 19 cases with limited data and undetermined clinical significance; however, an elevation in CA 125 was reported in 4 patients [5,11,14,17].

Table 1.

A summary of all previously published cases of an ovarian microcystic stromal tumor.

Case	Reference	Age	Molecular findings	Management	Follow-up (months)
1	Irving and Young, 2009 [1]a	62	NA	TAH, BSO, LND, OM	NA
2		45		TAH, BSO, peritoneal biopsies
3		51		TAH, BSO, OM, appendectomy, pelvic washings
4		29		LO
5		58		TAH, BSO, LND, peritoneal biopsy, pelvic washings
6		26		BSO
7		29		RO
8		45		LSO, endometrial curettage
9		63		RO
10		56		BSO
11		45		TAH, BSO
12		55		TAH, BSO
13		44		TAH, BSO
14		36		LSO
15		37		TAH, BSO
16		39		RSO, pelvic washings
17	Maeda et al, 2011 [4]	33	CTNNB1 mutation	1 GnRHa, RSO, enucleation of uterine masses, partial OM	NED (14)
18		41	CTNNB1 mutation	RSO, enucleation of uterine leiomyoma	NED (4)
19	Yang and Bhattacharjee, 2014 [5]	45	NA	Open ovarian tumor resection	NA
20	Niu and Peng, 2014 [6]	42	NA	NA	NA
21	Irving et al, 2015 [7] b,c	One of the cases was a 39-year-old patient with FAP	CTNNB1 mutation in 8/14 patientsb,c	NA	NA
22
23
24
25	Kang et al, 2015 [8]	41	CTNNB1 mutation	Laparoscopic LSO	NA
26	Lee et al, 2015 [9]	40	APC mutation	LSO, right ovarian wedge resection, total colectomy	NED (9)
27	Bi et al, 2015 [10]	69	CTNNB1 mutation	LSO	NED (60)
28		29	CTNNB1 wild-type	LO, right ovarian biopsy	NED (18)
29		40	CTNNB1 mutation	LO	NED (7)
30		65	CTNNB1 mutation	TAH, BSO	NA
31		57	CTNNB1 mutation	TAH, BSO	NED (59)
32		41	CTNNB1 wild-type	TAH, BSO, OM, appendectomy	NED (2)
33	Podduturi et al, 2015 [11]	50	CTNNB1 mutation	Hysterectomy, BSO, pelvic and para-aortic LND, OM, staging biopsies	NA
34	Chen et al, 2015 [12]	47	NA	LSO	NED (18)
35	Gunes et al, 2015 [13]	52	CTNNB1 mutation	TAH, BSO, OM	NED (3)
36	Lee et al, 2016 [14]	24	CTNNB1 mutation	Laparoscopic LSO	NED (8)
37		31	CTNNB1 mutation	Open LSO, para-aortic LND, peritonectomy	NED (3)
38	Liu, et al, 2016 [15]	23	APC mutation	Laparoscopic hysterectomy, RO, BS	NA
39	Murakami et al, 2017 [16]	26	CTNNB1 wild-type	4 GnRHa, LSO	NED (36)
40	Na et al, 2017 [17]	33	CTNNB1 mutation	Laparoscopic RSO, partial OM	NED (57)
41		31	CTNNB1 mutation	LSO, Para-aortic LND	NED (20)
42	Meurgey et al, 2017 [18]	46	FOXL2 and DICER1 wild-types	2 LSO, 1 RSO	NA
43		37
44		47
45	Qureshi et al, 2017 [19]	50	NA	LO	NA
46	Jeong et al, 2018 [20]	66	NA	BSO, bilateral pelvic and para-aortic LND, infra-colic OM, peritoneal biopsies	NED (18)
47	Zhang et al, 2018 [21]	33	APC mutation	Right laparoscopic cystectomy	Intraovarian and extraovarian recurrence (108)
48	Hasanzadeh et al, 2019 [23]	60	NA	TAH, BSO	NED (15)
49	McCluggage et al, 2019 [24]	61	CTNNB1 mutation	BSO	NA
50		56	CTNNB1 mutation	Hysterectomy, BSO
51		45	NA	Hysterectomy, BSO
52		71	CTNNB1 mutation	BSO and endometrial curettage
53	Liu et al, 2019 [25]	46	NA	Laparoscopic RSO	NED (54)
54		56	NA	Laparoscopic hysterectomy, BSO	NED (46)
55	Deng et al, 2020 [26]	25	NA	Laparoscopic resection of ovarian tumor	NED (4)
56	He et al, 2020 [27]	33	NA	Laparoscopic resection of ovarian tumor	NED (19)
57	Current case	46	CTNNB1 mutation	Open LSO, infra-colic OM, bilateral peritoneal biopsies, left pelvic LND, appendectomy	NED (24)

^aFollow-up data were available for 7 patients with no evidence of disease after a mean period of 51 months.

^bThe study evaluated 15 patients; 11 were included in Irving et al, 2009 and 4 were additional cases.

^cIn 2017, the cases were re-examined by McCluggage et al for APC mutations. Two cases were initially reported to have CTNNB1 wild-type showed CTNNB1 mutations and 3 cases showed APC mutations including the patient with FAP.

BEMP – benign endometrial polyp; BS – bilateral salpingectomy; BSO – bilateral salpingo-oophorectomy; EEA – endometrioid endometrial adenocarcinoma; FAP – familial adenomatous polyposis; GnRHa – gonadotropic releasing hormone analog; LND – lymph nodes dissection; LO – left oophorectomy; LSO – left salpingo-oophorectomy; NA – not available; NED – no evidence of disease; OM – omentectomy; RO – right oophorectomy; RSO – right salpingo-oophorectomy; TAH – total abdominal hysterectomy.

Ovarian MCSTs are well-circumscribed lesions, and they are usually solid and cystic (29/50, 58%) on macroscopic and/or radiologic examinations. Sonographically, ovarian MCST appears as a hypovascular complex or anechoic cystic mass [14,20]. It is seen as a heterogeneous mass with hyperattenuating and hypoattenuating components on computed tomography scans. Positron emission tomography shows FDG uptake within the solid areas [20]. On MRI, the cystic areas show high-signal intensity on T2-weighted MRI images and iso-signal intensity on T1-weighted images [16].

Microscopically, MCST is a cellular lobulated neoplasm with intervening fibrous, sometimes hyalinized, plaques or bands and, as the name indicates, anastomosing microcysts. The cells are usually monotonous with round to oval nuclei, small nucleoli, and a finely granular pale eosinophilic cytoplasm. Occasionally, the neoplastic cells are spindle-shaped or show a diffuse corded and nested growth pattern either focally, predominantly, or exclusively [24]. Multinucleated cells and cells with bizarre pleomorphic degenerative (symplastic-like) nuclei can infrequently occur, and the latter can account for up to 50% of the tumor [10,12,18,27]. Mitoses are rare in most cases (0–2 in 10 high-power fields), with no reported atypical forms [10,18]. The stromal nature of ovarian MCST was supported by ultrastructural findings, including the lake of Reinke crystals, true lumina, cilia, microvilli, desmosomes, and cellular junctions [5].

The use of immunohistochemical staining helps differentiate ovarian MCST from its mimickers. The neoplastic cells in MCST show an aberrant nuclear expression for β-catenin and cyclin D1 [1,4–27]. They are usually positive for vimentin, CD10, WT-1, FOXL2, and SF-1 [1,4–27]. Similar to our case, Bi et al reported paranuclear dot-like staining for CD99 in 3 of the 5 cases examined in their series and progesterone-receptor expression in around 5% of cells in 2 cases [10]. CD56 was reported as positive in 10% of tumor cells in 1 case of ovarian MSCT [10]. However, a more diffuse, stronger progesterone-receptor and CD56 staining was displayed in another study [12]. Deng et al reported patchy positive staining for synaptophysin and diffuse positive staining for androgen receptors in 2 cases [24,26]. Reports showed that ovarian MCST is negative for inhibin, calretinin, EMA, E-cadherin, CD117, PLAP, SALL-4, desmin, and melan A [1,4-27].

The differential diagnosis encompasses a wide range of ovarian tumors. Thecomas usually occur in older women and present with estrogenic effects. They do not show the microcystic pattern of ovarian MCSTs and are positive for calretinin and inhibin [1,11]. Although an ovarian solid pseudopapillary neoplasm (SPN) shows an aberrant β-catenin nuclear expression and CTNNB1 mutations, ovarian MCSTs lack the pseudopapillary pattern and the nuclear grooves that are characteristic of ovarian SPNs. Furthermore, SPN is usually negative for WT-1, diffusely positive for CD56, and can stain for CD117 [28,29]. Ovarian MSCT lacks the grooved nuclei and Call-Exner bodies seen in adult granulosa cell tumors. In addition, ovarian MSCTs are negative for calretinin and inhibin and they do not harbor FOXL2 gene mutations [11,18]. Ovarian MCSTs can mimic germ cell tumors, especially yolk sac tumors or metastatic carcinomas, but positive staining for FOXL2 and negative staining for germ cells and epithelial markers exclude these entities.

On a molecular level, essentially all ovarian MCSTs are thought to have heterozygous point mutations in the CTNNB1 gene, or less frequently in the APC gene (Table 1). All reported CTNNB1 mutations were missense mutations [4,7,8,10,11,13,14,17,24] except for 1 case, which was a deletion mutation [17]. APC mutations were present in 5 cases [9,15,21,22]. CTNNB1 gene encodes the multifunctional β-catenin protein, an adherence junction protein and a transcription regulator, in the Wnt signaling pathway. In the absence of Wnt stimulation, β-catenin remains in the cytoplasm and undergoes phosphorylation and destruction via the axin-APC complex [15,30]. When Wnt binds to its receptor, the axin-APC complex is inactivated, and βcatenin accumulates in the cytoplasm and eventually translocates to the nucleus to initiate DNA transcription [15,30]. Thus, mutations in the Wnt/β-catenin pathway genes (eg, CTNNB1 or APC) result in an aberrant nuclear immunoreactivity for βcatenin protein, although this expression does not always correlate with β-catenin mutations [10].

Ovarian MCST was treated surgically in a total of 36 patients (66.67%) undergoing oophorectomy (with or without salpingectomy) or cystectomy and 18 patients undergoing hysterectomy (including bilateral or unilateral salpingo-oophorectomy) with or without omentectomy, lymph node dissection, or appendectomy (33.33%) (Table 1). Two patients received gonadotropin-releasing hormone analog injections but showed tumor size progression and eventually underwent unilateral salpingo-oophorectomy [4,16].

Lymph node dissection is not mandatory in cases of sex cord-stromal tumors and germ cell tumors. The lymph nodes in our patient were not palpable bilaterally, and they were not suspicious radiologically; however, since the diagnosis was not confirmed during the surgery, an ipsilateral lymph node dissection was performed. If lymph nodes are involved with a sex cord-stromal tumor or germ cell tumor, chemotherapy would be indicated, regardless of the status of the contralateral lymph nodes. An appendectomy, although it may not have been necessary, was performed in our patient because an epithelial mucinous tumor was still among the radiological differential diagnoses.

Regardless of the chosen surgical management, all reported cases of ovarian MCST showed a good prognosis and uneventful outcomes (mean follow-up of 26.45 months), except for 1 patient who presented with a recurrence 9 years after her initial diagnosis [21]. The literature is limited regarding the optimal follow-up approach for these patients; however, we recommend annual pelvic ultrasound screening, followed by MRI if indicated.

Conclusions

We described a case of ovarian MCST and outlined the clinical, radiological, and pathological features of this tumor in view of all the reported cases in the literature. This tumor should be considered when there is presentation of cystic ovarian tumors. Furthermore, the present data provide insight into this tumor and encourage further research into its pathogenesis, behavior, treatment, and long-term prognosis.