Vaginal bleeding imitated rape in a 6-year old girl, a case report about granulosa cell tumor as a reason of peripheral precocious puberty

Abstract

Introduction

Although female victims of sexual child abuse present with symptoms such as local pain and vaginal bleeding, however, before any definitive diagnosis a comprehensive physical examination along with a detailed history related to vaginal bleeding should be taken from the patient. Undoubtedly, we must not forget that only one of the causes of vaginal bleeding is rape. Therefore, before making a final diagnosis, other causes of this symptom must be carefully examined.

Case presentation

The patient was a 6-years-old female who was hospitalized for notable generalized abdominal distention, acute lower abdomen pain associated with nausea and mild fever lasting 5 days progressively worsening, thelarche and vaginal bleeding. Ultrasound examination showed that multilocular–solid masses located in right side of abdomen which led to surgery and mass excision. Histopathology diagnosis was a juvenile granulosa cell tumor of the ovary.

Discussion

Among the various causes of peripheral premature puberty, granulosa cell tumor (GCT) is rare but very important. Since in the two age groups – prepuberty and menopause - we don't expect to see vaginal bleeding, the occurrence of this disorder especially in association with breast enlargement in prepubertal group, need to appropriate imaging including pelvic ultrasound and bone age determination also laboratory data such as level of sex hormones and tumor markers to avoid misdiagnosis.

Conclusion

We report the case of a granulosa cell tumor patient with vaginal bleeding that a complete history and examination provides the right path to a diagnosis.

Highlights

• •Granulosa cell tumor (GCT) is a type of ovarian cancer that is particularly rare.
• •Due to nonspecific clinical presentations, granulosa cell tumor (GCT) is difficult to diagnose.
• •Surgical intervention is necessary for treatment.

1. Introduction

Peripheral precocious puberty (PPP) is the term used to designate forms of pathologic precocious puberty at an age younger than the accepted lower limits for age of onset of puberty namely, before age 8 years in girls and 9 years in boys and is independent of the hypothalamus-pituitary-gonadal axis [1,2]. In girls one of the most common etiologies of PPP is ovarian follicular cysts and hormone-producing malignancies [2]. These malignancies are rare in children or adolescent patients. Granulosa cell tumor accounts for about 2–5 % of ovarian solid neoplasms, the most common type of sex cord stromal tumor [3] and may be classified into 2 subtypes, juvenile and adult, according to histopathological presentation but the age of onset and clinical symptoms cannot completely distinguish AGCT from JGCT [4]. Although GCT of the ovary affects women of all ages and the median age of the patients is 50 years (range, 17–71 years) however only 0.1 % of all ovarian tumors and 4–5 % of GCTs occur in the sexually non-active ages (prepubertal) and also the occurrence of adult type granulosa cell tumor is extremely rare in childhood [[5], [6], [7]]. Meanwhile the mean age at the diagnosis of JGCT has been reported as 8–9 years and 13–17 years in series consisting of girls under 16 years of age. The youngest reported patient has been 6 years old [8]. The median duration of symptoms was 5 months (range, 4–24). Although the juvenile form of a GCT is rare but fortunately due to the hormonal activity the tumor gives signs usually leading to the correct diagnosis at an early stage of the disease because nearly all GCTs are hormonally active to some extent and up to 80–90 % of patients under 8 years of age have signs of isosexual precocious pseudopuberty (the most common clinical manifestation is isosexual precocious puberty) [9].

One of the common presenting symptoms is abdominal pain and vaginal bleeding even in pre- pubertal and postmenopausal ages (50 %) [7]. Therefore, the probability of delay in the diagnosis of this tumor at a young and prepubertal age will be much lower than the delay in the diagnosis at reproductive age [8]. The clinical manifestation as acute abdomen due to ovarian torsion, is very rare in children while the most torsions of ovarian tumor described in the literature are caused by germ cell tumors [5].

For these tumors, complete resection via unilateral oophorectomy or salpingo-oophorectomy appears to be curative, regardless of tumor size and histopathologic features. Hormone levels, most commonly serum inhibin concentration, should return to normal postoperatively and can be used to assess response to treatment and monitor for recurrence and spread. Recurrence is rare and related to the stage at diagnosis. Cases of recurrence have been reported up to 3 years after the initial surgery [10].

In this study, we report a case of a girl with cystic GCT, managed surgically at our hospital. This study is reported in line with the SCARE 2023 criteria [11].

2. Case presentation

A 6-years-old patient was admitted in our Children Hospital due to notable generalized distention and acute lower abdomen pain associated with nausea and mild fever lasting 5 days progressively worsening. She had no history of considerable fever, constipation and vomiting.

The first physical examination was performed by an emergency physician. The abdomen was distended and tender to deep and even light palpation, with no palpable masses. In addition to the abdominal tenderness and the child's complaints of annoying pain, the doctor's attention was drawn to the presence of fresh and old blood stains in the child's panties and for this reason, while hemodynamic was stable, consultation with the surgeon and the forensic specialist was also requested at the same time.

While denying any rape of the child by the family and those around the child, the presence of thelarche drew the attentions to endocrinopathies and consultation was done with an endocrinologist (Fig. 1). With the priority to diagnose the cause of acute abdomen, ultrasound was requested and it was decided to perform the necessary examinations on the cause of the onset of precocious puberty as soon as possible after the treatment of acute abdomen.

Fig. 1.

Anterior (a) and lateral (b) views of breast enlargement.

The ultrasound report was surprising and unexpected for almost everyone; Ultrasound examination showed that multilocular–solid masses with heterogeneous echogenicity approximately measuring 63 × 40 mm located in right side of abdomen. Therefore, in addition to fluid therapy and antibiotic administration, pelvic and abdominal CT scan and hormonal assessment confirming premature puberty was requested whose results are shown in the Fig. 2 and Table 1 respectively.

Fig. 2.

Cross-sectional views (a, b and c) of the patient's pelvic CT scan with and without contrast showing a122 × 106 mm solid-cystic mass.

Table 1.

Hormonal assessment.

Test	Value	Normal range
Follicle Stimulating Hormone	<0.55	1.2–12.5 IU/L
Luteinizing Hormone	<0.10	0.3–2.5 IU/L
Estradiol	115	<9 pg/mL
Androstenedione	5.8	0.0–3.0 nmol/L
Dehydroepiandrostenedione–sulfate (DHEAS)	0.57	0.090–3.350 μmol/L
Testosterone	1.01	0.0–2.2 nmol/L
Anti-Mullerian Hormone (AMH)	1322	0.1–38.6 pmol/L
Alpha Fetoprotein	12	1–33 kIU/L
Beta human Chorionic Gonadotropin	0.11	0.0–5.0 IU/L
Serum inhibin A	291	<4.7 pg/mL
Serum inhibin B	956	<111 pg/mL

In lower abdominal cavity a thin wall cyst contains multiple enhancing septa approximately measuring 70 × 48 mm is found located posterior to anterior abdominal wall. Subsequently, computed tomography (CT) showed a mass and other low mixed density lesion in the pelvic cavity with the maximum cross-sectional area about 122 mm × 106 mm; the boundary was clear, part of it was close to the uterus, and the pelvic space was occupied. It was considered that the mass may be attached at some point (as shown in Fig. 2).

Before the above test results were available, surgery was performed and the mass was removed due to the most likely diagnosis by right salpingo-oophorectomy. Although young females need for fertility-sparing surgery, this method was considered from the beginning, but it was not possible to preserve any part of the ovary with the widespread involvement, and due to early diagnosis, the opposite ovary and uterus remained intact (Fig. 3).

Fig. 3.

Intra-operative and intact gross images (a and b) and cut sections macroscopic view (c) of the mass. Multilocular ovarian cystic mass with intracystic thin septation without any solid component.

The specimen received in formalin consists of the right salpingo-oophorectomy, totally M: 11.5 × 8 × 2 cm with intact fallopian tube attached to the large cystic ovary. External surface of the ovary appeared cystically enlarged but the capsule was intact without any ruptures. On sections, multilocular cystic spaces filled with clear pale yellowish fluid with thin septation was seen, almost entirely replacing ovarian tissue.

Granulosa cell tumor can rarely be completely cystic, creating diagnostic difficulty, because of overlapping gross features with cystic solitary/multiple follicle cysts, cystic stroma ovarii and serous cysts. Based on these findings, the most important differential diagnosis are follicular cyst and serous cyst adenoma, although it may rarely be seen in granulosa cell tumors. From the pathological point of view there are no overwhelming data that could clearly differentiate them from each other.

On microscopic examination, the cyst was lined by multi-layered relatively uniform cells with angulated nuclei: granulosa cells (Fig. 4a, b and c). Some of the tumor cells surrounded small, rounded spaces filled with eosinophilic material, which is called microfollicular pattern or Call-Exner bodies (Fig. 4c).

Fig. 4.

Lining granulosa cells of the cyst wall with sheet and microfollicles formation (a and b). Microfollicles formation (resembling Call-Exner bodies of the Graafian follicles: small follicle-like structures filled with eosinophilic material) (c).

On immunohistochemical study inhibin and calretinin, were positive, supported the final diagnosis of cystic granulosa cell tumor. Laboratory investigations after two weeks showed complete return of all hormones to normal prepubertal levels. Its normalization occurred 2 weeks after surgery and provided us its value as a good biomarker for tumor monitoring.

3. Discussion

Since serum estradiol and AMH as a controlling factor of follicle formation in GCT are nearly always elevated, it comes as no surprise that up to 80–90 % of patients under 8 years of age have signs of isosexual precocious pseudopuberty. Therefore, we expect that patients with this tumor come with symptoms related to premature puberty, such as breast development, increased pubic hair, vaginal bleeding, or advanced growth and bone age at an early age [7,12].

On the other hand, although according to reports, a total of 37 % and 19 % of the patients presented with intermenstrual bleeding and postmenopausal bleeding respectively at diagnosis, we must be aware that due to most literatures the common causes of prepubertal vaginal bleeding include vaginal foreign bodies, vulvovaginitis and trauma [8,13,14]. Although it seems that the prevalence of the above causes is similar for children, however, we consider that there are not any clear reports of vaginal bleeding at before 8 years old until now. Therefore, we believe that the doctor in the emergency department should not have focused only on the rape, and of course, he should also have been taken into consideration the possibility of other causes with a careful examination related to signs of puberty such as thelarche. However, paying attention to a complete examination with all the details will definitely help in an accurate diagnosis.

All guidelines suggest that diagnostic work should include both imaging tests (at least ultrasound of abdomen and pelvis) and the measurement of a basic panel of serum tumor markers, while there is debate around the necessity of MRI, molecular biology and immunohistochemistry and the diagnostic value of PET scan [15]. Considering basic therapeutic principles and treatment strategies, recommendations from existing guidelines are mostly identical, suggesting that a combination of fertility-preserving surgery (when it is oncologically safe) and adjuvant therapy is effective in most cases of ovarian cancer in adolescents. The differences in the reviewed guidelines, although they are limited, highlight the need for the adoption of an international consensus in order to further improve the management of ovarian malignant tumors in the adolescent population [15].

As a result, 80–90 % of GCTs are detected at an early stage, with surgery being curative in the majority of cases when tumor remains confined to the ovary. Also, GCT recurrence remains largely unpredictable, although this risk may be increased by factors such as patient's age, tumor size >10 to >15 cm, intraoperative tumor rupture and genetic [[16], [17], [18]]. Recurrences after therapy have typically occurred within 5 to 10 years [19]. Therefore, we suggest following up every 3 months in endocrine clinic about regression of puberty signs and symptoms and at least every 6 months laboratory tests and pelvic ultrasound be done.

In our patient, complete removal of the tumor with unilateral salpingo-oophorectomy was performed with complete return of all hormones to normal prepubertal levels. It should be noted that due to the low prevalence of this tumor in adolescents, assigning a specific type of pathology to an age range is not true. Microscopic characteristics of tumor in this patient were too compatible with adult GCT. Considering that this tumor may occur in connection with associated with various congenital anomalies including Ollier disease, Maffucci syndrome, leprechaunism, Potter syndrome, hypercalcemia, Peutz-Jeghers syndrome, and cytogenetic aberrations [10], our patient did not have any of the characteristics of the mentioned syndromes.

4. Conclusion

Always careful examination of the patient, before the final diagnosis, along with laboratory evaluations and imaging, facilitates the diagnosis of this tumor in children and, in addition to timely treatment, prevents the occurrence of psychological complications for the child and the family.

CRediT authorship contribution statement

Samayeh Dadakhani and Daavoud Amirkashani contributed to patient management. Seyyed Javad Nasiri and Mina Khoshkbarforoushan performed the surgery. Nafiseh Mortazavi diagnosed the pathological findings. Samayeh Dadakhani and Daavoud Amirkashani wrote the initial draft of the manuscript. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work.

Declaration of competing interest

The authors declare that they have no competing interests.