ORIGINAL ARTICLE

Atypical Follicular Cyst of Pregnancy and Puerperium: A Case Report and Literature Review

Terrano D1, Hamele-Bena D1, Kim J2, Wright J2, Wright TC1 and Chen X1*
Department of Pathology and Cell Biology, Columbia University Medical Center, USA
Department of Obstetrics and Gynecology, Columbia University Medical Center, USA


*Corresponding author: Xiaowei Chen, Department of Pathology, Columbia University Medical Center, 630 West 168th Street, VC14-215, New York, NY, 10032, USA


Published: May 27, 2016 (see history)
DOI: 10.7759/cureus.625
Cite this article as: Mushtaq R, Pinto C, Tarfarosh S, et al. (May 27, 2016) A Comparison of the Behavioral and Psychological Symptoms of Dementia (BPSD) in Early-Onset and Late-Onset Alzheimer’s Disease - A Study from South East Asia (Kashmir, India). Cureus 8(5): e625. doi:10.7759/cureus.625

Abstract

Ovarian cysts in pregnancy are uncommon, and sometimes pose diagnostic challenges when there is rapid growth and unusual morphology. Herein, we report a case of a 20 year old pregnant woman who was found to have an ovarian cyst by first trimester screening ultrasound at 10 weeks gestational age. As the pregnancy progressed, the patient developed symptoms that prompted a cystectomy at 17 weeks of gestation. The cystectomy specimen showed a cyst of follicular origin with focal highly atypical nuclei and occasional mitoses. The patient had an uncomplicated spontaneous vaginal delivery at 38 weeks of gestation. Eight months after delivery, she underwent a salpingo-oophoretomy and tumor staging biopsies. Immunohistochemical studies were performed on both the cystectomy and oophorectomy specimens. Findings and the differential diagnosis are discussed.

Keywords

Atypical follicular cyst; Ovary; Pregnancy; Immunohistochemistry

Introduction

Ovarian tumors and tumor-like masses during pregnancy are uncommon, with a reported incidence of about 1% in one large study [1,2]. Most ovarian neoplasms occurring during pregnancy are benign. The overall reported incidence of ovarian cancer in pregnancy varies from 0.004 to 0.04% [3]. Although sonographic features may suggest a benign process, rapid growth may prompt clinical concern and surgical intervention. Some masses may represent diagnostic challenges pathologically, too, because luteinizing effects of pregnancy can result in cytological atypia, mitosis, and, occasionally, necrosis, sometimes even mimicking malignancy. Solitary luteinized follicular cyst of pregnancy and peurperium (SLFCPP) is the best example of this: it can display marked nuclear atypia but is a benign, non-neoplastic lesion. We report here a case of a large atypical ovarian cyst that represented a diagnostic challenge in a pregnant woman.

Case Presentation

The patient was a 20 year old woman, gravida 2 para 1 with one voluntary abortion, who presented initially at 6 weeks of gestation. Her past medical history included intermittent asthma and chronic migraines. Her surgical history was significant for an appendectomy. A first trimester screening ultrasound at 10 weeks gestational age showed a singleton pregnancy with no fetal abnormalities and a left ovarian cyst measuring 13.8 x 13.7 x 7.9 cm, with a smooth lining and containing mildly echogenic fluid. The patient was asymptomatic at that time. A “watchful waiting” approach was undertaken. An ultrasound at 12 weeks gestation showed minimal changes in the cyst size and normal fetal growth. However, the patient subsequently developed intermittent lower abdominal pain that was predominantly left-sided; one such episode of severe pain required intravenous pain medication. For symptomatic management and diagnostic purposes, a laparoscopic cystectomy was performed at 17 weeks of gestation.

Pathology

The cystectomy specimen was received fresh and consisted of an intact piece of tan-pink, cystic tissue with a smooth capsular surface and an overall measurement of 10.0 x 7.0 x 1.0 cm. Cut surface revealed a unilocular cyst filled with clear serous fluid. The inner cyst wall lining was smooth, with no excrescences or nodules. Histological sections showed thin-walled follicular cysts (Figure a) and a large cyst partially lined by single to multiple layers of small, round cells (Figure b), some of which appeared highly atypical, with enlarged, bizarre and hyperchromatic nuclei, nucleoli, and occasional mitoses (Figure c). Nests of luteinized theca cells were identified within the fibrous tissue of the cyst wall. The differential diagnosis included solitary luteinized follicle cyst of pregnancy and peurperium (SLFCPP), cystic granulosa cell tumor, and borderline serous cystic tumor. Immunohistochemical stains were performed with the following antibodies: inhibin (R1, Ventana, Tucson, AZ), calretinin (SP65, Ventana, Tucson, AZ), p53 (DO-7, Ventana, Tucson, AZ), CD99 (Leica, Buffalo Grove, IL), EMA (E29, Ventana, Tucson, AZ), and CK (Leica, Buffalo Grove, IL). The inner cyst lining cells were strongly positive for CD99 (Figure d) and p53 (Figure e) and focally positive for inhibin and calretinin, while the cells in the outer layer of the cyst were positive for inhibin (Figure f) and calretinin (Figure g) but negative for CD99 and p53. The cyst lining cells were negative for EMA and CK. Ki67 demonstrated a focally increased proliferative rate. A reticulin stain revealed very scanty reticulin fibers between the cyst lining cells (Figure h). The immunohistochemical staining profile and reticulin staining pattern suggested a cyst of follicular origin. Based on clinical information and morphology, a diagnosis of solitary luteinized follicle cyst of pregnancy and peurperium (SLFCPP) was made. However, because of the cytological atypia and mitotic activity, coupled with p53 and CD99 positivity, the case was sent out for consultation. An outside consultant render a diagnosis of an atypical follicular lesion, and a cystic juvenile granulosa cell tumor was favored.



Figure A

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Figure A
Cystectomy specimen with small cystic follicles lined by small round and uniform granulosa cellsand surrounded by a fibrotic wall. There was no cytological atypia. (H&E, x40)

The patient had an uncomplicated spontaneous vaginal delivery at 38 weeks of gestation. At eight months post-partum, she underwent a left salpingo-oophorectomy with staging biopsies. Grossly, the ovary was enlarged, measuring 10.2 x 4.1 x 1.8 cm, with a benign 1.1 x 1.0 x 0.9 cm para-tubal cyst. The cut surface of the ovary revealed numerous small red-brown cysts, ranging from 0.1 cm to 2.0 cm. Microscopically, these cysts were lined by multilayered follicular cells (Figure i and j). Normal atretic follicles and prominent cortical fibrosis (Figure k) also were noted. Immunohistochemical stains were performed for the purpose of comparison to the prior cystectomy specimen. The cells in the inner granular cells were strongly positive for CD99 (Figure l); however, the majority of the cells were negative for p53 (Figure m), and cells in the outer layer of theca cells were positive for inhibin (Figure n) and calretinin (Figure o), and Ki67 demonstrated a low proliferative index. A reticulin stain showed a normal reticulum network within the theca interna layer and an absence of reticulin fibers within the granulosa layer (Figure p). Neoplasia was not identified in the ovary and staging biopsies (omentum, pelvic side walls, cul-de-sacs, and peri colic gutters). The final diagnosis of the salpingo-oophorectomy specimen was multicystic follicles and atretic follicles of the ovary, and multicystic ovarian disease could not be excluded. This combination of multiple cystic and atretic follicles and prominent cortical fibrosis can be seen in polycystic ovarian syndrome (PCOS); however, the patient did not have clinical features of PCOS. She is being followed with routine gynecologic care.

Discussion

The detection of ovarian masses during pregnancy has become increasingly common due to the use of routine obstetrical ultrasound. The majority of adnexal masses are discovered incidentally, in approximately 1% of pregnancies.1The majority of ovarian tumors in pregnancy are benign. Most common are functional cysts, followed by benign cystic teratomas, serous cystadenomas, paraovarian cysts, mucinous cystadenomas, and endometriomas [4]. Since most functional cysts resolve spontaneously, surgical intervention is not recommended during the first trimester, especially for asymptomatic patients or small cysts, because of a low likelihood of malignancy and an increased potential for pregnancy loss. However, surgical management may be considered in symptomatic patients or if there is a rapid increase in the size of the lesion. Pathologically, some of the lesions pose diagnostic challenges because stimulation by human chorionic gonadotropin (hCG) and/or increased tissue sensitivity to hCG during pregnancy may cause atypical pathologic features [5], as in our case.

SLFCPP is an uncommon, benign, non-neoplastic ovarian lesion associated with pregnancy and the puerperium. It was first described by Clement and Scully [6] as a unilocular cyst lined by single to multiple layers of large cells with abundant eosinophilic cytoplasm. A striking feature of SLFCPP is the focal presence of cells with enlarged hyperchromatic nuclei with bizarre shapes. The outer walls of the cysts are composed of fibrous tissues within which are small nests of luteinized cells, similar to those seen in our case. Although not common, occasional mitoses may be present in SLFCPP [7].

Cystic granulosa cell tumor (CGCT) in pregnancy is very rare and may present as a giant unilocular or multilocular thin-walled cyst. Within the cyst wall, there may be nodules of cells with characteristics of granulosa cell tumor, including nuclear grooves and Call-Exnerbodies. However, juvenilecystic granulosa cell tumor (JCGCT) lacks nuclear grooves and Call-Exner bodies [8]. Although CGCT usually lacks luteinization and characteristic nuclear pleomorphism of SLFCPP, based on our patient’s age, JCGCT was in the differential. JGCTs reportedly usually are associated with elevated serum estradiol and inhibin levels and, less frequently, increased testosterone levels, while serum follicle-stimulating hormone, luteinizing hormone, and gonadotropin-releasing hormone levels usually are low [9]. However, our patient did not have a clinical presentation consistent with JGCT.

The immunohistochemical findings in our case posed a diagnostic problem. P53 and CD99 were positive in the cyst lining cells and negative in the luteinized theca cells. Both specimens had similar staining patterns. The significance of this staining pattern is unclear. CD99 has been reported to be positive in mature granulosa cells and granulosa cell tumors [10]. Piana [11] reported CD99 positivity in pregnancy luteoma, a non-neoplastic lesion. Therefore, CD99 positivity alone is not diagnostic of a granulosa cell tumor. The p53 tumor suppressor gene has been extensively studied in various human tumors, including ovarian cancer. There are very few reports regarding the relationship between p53 expression and granulosa cell tumors. Liu et al. [12] reported that alteration of the p53 tumor suppressor gene is not a common finding in ovarian granulosa cell tumors. Experimental research in an animal model [13] demonstrated atemporal expression of p53 in the ovary during a gonadotropin/human chorionic gonadotropin (PMSG/hCG) artificially induced ovulatory cycle, suggesting a role for p53 in the differentiation of granulosa cells into luteal cells. This might explain the finding of p53 positivity in the cyst of the cystectomy specimen and negative p53 staining in the cyst of the oophorectomy specimen in our patient. Atypical follicular cysts in pregnancy should be managed conservatively. Cytological atypia and positive immunostaining for CD99 and p53 in these lesions do not necessarily indicate an ovarian neoplasm. Awareness of pregnancy-associated atypia may avert unnecessary surgery in young patients.

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