Recurrent ovarian Sertoli-Leydig cell tumor in a child with Peutz-Jeghers syndrome.

We present a female child with Peutz-Jeghers syndrome (PJS) with a recurrent ovarian Sertoli-Leydig cell tumor (SLCT). SLCTs are relatively rare sex cord neoplasms that can occur in PJS. The patient was an African-American female who first presented at the age of 3 years with precocious puberty, and then at the age of 17 years with abdominal pain and irregular menses. In each case, she had resection of the mass, which included oophorectomy. To our knowledge, this is the first reported case in a child with PJS to have a recurrent ovarian SLCT.

INTRODUCTION

Peutz–Jeghers syndrome (PJS) is an autosomal dominant condition characterized primarily by mucocutaneous pigmentation and intestinal polyposis [1]. Sertoli–Leydig cell tumors (SLCTs) are sex cord neoplasms that can occur in patients with PJS. However, SLCTs are rare, making up to 1% of all ovarian tumors [2]. Recurrent ovarian SLCT in a pediatric-aged patient has yet to be documented.

CASE REPORT

A 3-year-old African-American female with a strong paternal history of PJS and associated polyposis presented with gonadotropin-independent isosexual precocious puberty and vaginal bleeding. Her laboratory studies revealed undetectable serum luteinizing hormone (LH) and follicle stimulating hormone (FSH), elevated testosterone 78 ng/dl (0–9.9) and estradiol 210 pg/ml (0–55)—consistent with peripheral etiology of her pubertal signs. Oncologic workup included CA-125 54 U/ml (0–35), often elevated in ovarian neoplasm, but with negative alpha-fetoprotein and beta-human chorionic gonadotropin (β-HCG) tumor markers. Abdominal computed tomography demonstrated a large pelvic mass involving the right ovary and a prominent thick-walled uterus. She underwent mass resection with right salpingo-oophorectomy. Pathology results demonstrated an SLCT limited to the ovary with confirmatory positive cytokeratin, vimentin and inhibin staining. Uterine bleeding ceased 6 days after the surgery, with decrease in breast size and pubic hair over the following months. Her bone age was 8 years at the chronological age of 4 years at follow-up. She underwent menarche at the age of 11.5 years with a bone age concordant with her chronological age at that time.

Although she had been followed until the age of 13 years without tumor recurrence, she was lost to follow-up until the age of 17 years when she presented with 1-year history of intermittent stabbing abdominal pain, daytime fatigue and irregular menses. She had no clinical signs of hyperandrogenemia and no palpable mass on abdominal examination. Laboratory studies revealed appropriately post-pubertal serum FSH 1.9 IU/l (3.4–10), testosterone 53 ng/dl (11–62) and estradiol 201 pg/ml (2–259). However, she demonstrated an unusually elevated serum LH 48 IU/l (2.1–10.9), concerning for impending ovarian failure, which prompted further workup.

Abdominal magnetic resonance imaging (MRI) demonstrated a left adnexal complex cystic mass extending to the midline (Fig. 1). An extremely high inhibin B level suggested a likely recurrence of SLCT. It also explained why in the presence of ovarian failure, FSH was decreased, as inhibin provides negative feedback on FSH secretion. She underwent mass excision with left salpingo-oophorectomy and cervical biopsy. Pathology results again demonstrated an SLCT limited to the ovary (Fig. 2). Immunohistochemical stains were positive for vimentin, inhibin (Fig. 3), as well as WT1, calretinin, CAM 5.2 and estrogen receptors. Additionally, 30% of the lesion demonstrated heterologous annular features, known as sex cord tumor with annular tubules (SCTATs) (Fig. 4). Lab results are summarized in Table 1.

Figure 1:

T2-weighted MRI. Midline complex, cystic mass demonstrating thick internal septations and mass effect on surrounding organs, characteristic of SLCTs. Measures 9.5 × 8.0 × 9.5 cm. (A) Axial view and (B) sagittal view.

Figure 2:

Ovarian lesion with Sertoli cell nests and intervening Leydig cells (6×, H&E).

Figure 3:

Positive staining can be found with SLCTs (3×, inhibin staining).

Figure 4:

Ovarian lesion with annular tubules adjacent to Sertoli–Leydig component (3×, H&E).

Table 1:

Summary of laboratory workup.

	2002 (3 years) Pre-resection 1	2014 (17 years) Pre-resection 2	2015 (6 months post-resection)
LH (IU/l)	<0.2	48 (2.1–10.9)	33
FSH (IU/l)	<0.2	1.9 (3.4–10)	65
Testosterone (ng/dl)	78 (0–9.9)	53 (11–62)	14
Estradiol (pg/ml)	210 (0–55)	201 (2–259)	3.0
CA-125 (U/ml)	54 (0–35)	18 (0–35)	–
Inhibin B (pg/ml)	–	>5000 (0–360)	<10
ΑFP	Negative	Negative	–
β-HCG	Negative	Negative	–

At the age of 3 years, the patient's estradiol and testosterone were elevated with undetectable gonadotropins, consistent with peripheral precocious puberty. At the age of 17 years, there was an elevated LH likely due to ovarian failure secondary to tumor infiltration. Elevated inhibin from the Sertoli cell tumor component explains the FSH suppression. At 6 months post-resection, the biochemical profile is consistent with a bilateral oophorectomy.

Six months after her surgery, she developed hot flashes, at which point she was started on low-dose estrogen replacement. She continues to be followed by gynecology and gastrointestinal (GI) services for cancer surveillance. The recurrent mass was very likely a new primary lesion due to its differences in histological, biochemical and clinical properties when compared with the original neoplasm.

DISCUSSION

PJS is an autosomal dominant condition that has a clinical diagnosis that includes two or more histologically confirmed PJ polyps, any number of PJ polyps in someone with a family history of PJS, mucocutaneous pigmentation in someone with a family history of PJS or any number of PJ polyps in an individual who also has characteristic mucocutaneous pigmentation [1]. Additionally, it is associated with other malignancies of the GI tract, pancreas, lung, breasts and cervix [3]. In fact, the cumulative risk of a patient diagnosed with PJS developing a malignancy between the ages of 15 and 64 years is 93% [3]. The genetic etiology in more than 90% of those meeting the clinical criteria is a germline mutation in STK11, a serine–threonine kinase gene within a region on chromosome 19p13.3, whose product functions as a tumor suppressor [4].

Sertoli–Leydig cell tumors are a type of sex cord stromal tumors (SCSTs), which make up to <7% of ovarian tumors but with a cumulatively increased risk of up to 20% in PJS [2, 5]. SCSTs may present with symptoms similar to those of other ovarian tumors such as abdominal pain and distention, isosexual precocity, primary or secondary amenorrhea and/or virilization [2]. Histopathologic diagnosis is based on characteristic stains, which include inhibin, cytokeratin and vimentin [2].

The patient's recurrent mass included heterologous elements, known as SCTATs. This type of neoplasm, first described in patients with PJS, is a rare subtype of SLCT [6]. SCTAT is considered a variant of either pure Sertoli or Granulosa cell tumor and observed in ∼20% of SLCTs [7]. Microscopically, the neoplasm differs in its ring arrangement of tubules and frequent presence of calcification. When occurring in patients with PJS, SCTAT is typically bilateral, multifocal, <3 cm and benign [8]. It has also been known to secrete estrogen and/or progesterone, which can present clinically as precocious puberty and menstrual irregularities [8]. However, in our patient, estrogen was not elevated. It is possible that either the small focus of the SCTAT or the interaction of the surrounding SLCT prevented sufficient differentiation for secretion of sex steroid hormones. It remains unclear the prognostic implication of a neoplasm with both SLCT and SCTAT features. Owing to the neoplasm's focality in both instances, surgical resection with oophorectomy and ipsilateral pelvic lymphadenectomy were performed. Metastatic SCTAT, however, can be treated via resection with adjuvant radiation therapy [9].

This case demonstrates two vastly different presentations of the same neoplasm due to its presence at different time points in the child's age and development. Guidelines recommend cancer surveillance to begin at the age of 8 years [1]. However, this case emphasizes the importance of screening at any age when there is suspicion of malignancy in a patient with PJS or family history of PJS. Furthermore, due to the high risk of malignancy recurrence in patients with PJS, regular cancer surveillance is critical to minimize morbidity and mortality. A patient who is lost to follow-up presents a dangerous risk for cancer progression; thus, extra care must be taken to maintain continuity of care.