Rare case of steroid cell tumour presenting as resistant hypertension in early pregnancy

Abstract

A woman 12 weeks and 3 days pregnant was referred to the emergency department with significant hypertension which, despite aggressive medical management, remained uncontrolled. Markedly elevated levels of renin and aldosterone beyond what is typical in early pregnancy were present, which together with the finding of a right ovarian cyst pointed to the possible diagnosis of an extrarenal reninoma.and the decision was made to perform a right-sided oophorectomy at 16 weeks gestation. Histology demonstrated a staining pattern most consistent with a steroid cell tumour leading to the diagnosis of refractory hypertension secondary to an ovarian steroid cell tumour. Post oophorectomy blood biochemistry rapidly returned to normal, and our patient’s hypertension slowly resolved allowing for a large reduction in antihypertensive agent requirements and a successful pregnancy outcome.

Background

Steroid cell tumours of the ovary are an unusual type of sex cord-stromal tumour accounting for less than 0.1% of all ovarian tumours.¹ Typically, they present with symptoms of virilisation such as hirsutism, voice deepening, acne and oligomenorrhoea.^2–5 Atypical presentations are unusual⁶ and, though there are reports of steroid cell tumours during pregnancy, they are incredibly rare.⁷ We present an unusual case of steroid cell tumour presenting not with signs of virilisation but with medication-resistant hypertension in early pregnancy due to the excretion of abnormally high levels of renin and aldosterone as well as androstenedione and dehydroepiandrosterone sulfate (DHEA-S).

This case highlights the importance of considering a wide range of differentials when managing refractory hypertension in pregnancy. Atypical causes of hypertension should always be considered in patients exhibiting medication resistance and other unusual features. A multidisciplinary approach was invaluable in this case, allowing for swift diagnosis and treatment and a positive outcome for both mother and baby.

Case presentation

A G4P0+3 woman of 12+3 weeks gestation, with an own egg in vitro fertilisation (IVF) pregnancy, was referred to the emergency department of a regional acute hospital with uncontrolled hypertension by her primary care physician. On admission, she was found to have asymptomatic high blood pressure of 219/119 with no evidence of end organ damage. She had been commenced on 200 mg of labetalol two times per day at her initial booking assessment the week before for borderline high blood pressure. Her body mass index was 31 kg/m² at admission and she was noted to be taking oestradiol 1 mg daily and progesterone 400 mg two times per day as recommended by her IVF providers in addition to labetalol.

Background medical history of borderline high blood pressure prior to this pregnancy which had been managed with lifestyle modification was noted, as well as a family history of hypertension. Medical history also included a previous traumatic brain injury secondary to road traffic accident 7 years prior, Mobitz type 1 heart block and allergic rhinitis. Surgical history included an appendectomy at age 12 and mesh repair of a right-sided patella fracture. Gynaecological history included a large loop excision of the transformation zone (LLETZ) procedure 7 years prior to this pregnancy for cervical intraepithelial neoplasia grade 3. Of note, there were no symptoms suggestive of virtualisation prior to or during this pregnancy.

This was the patient’s fourth pregnancy; she had undergone a left salpingectomy for an ectopic pregnancy 3 years prior to this, and had experienced two early pregnancy miscarriages post two previous rounds of IVF. A right-sided salpingectomy for hydrosalpinx had been performed 1 year prior to aid fertility treatment, during which normal bilateral ovaries and uterus were noted.

Her hypertension proved resistant to medication with blood pressures ranging from 140 to 200 mm Hg systolic and from 80 to 110 mm Hg diastolic despite treatment with combinations of labetalol and nifedipine. She was transferred to our tertiary referral centre for further investigation and management of her blood pressure.

Investigations

Given the early stage of gestation, the asymptomatic and medication-resistant nature of her hypertension, the evidence that it potentially predated this pregnancy, and the fact that the patient had normal full blood count, renal function, liver function, prothrombin time/activated partial thromboplastin time (PT/APTT) and no evidence of proteinuria (table 1) investigations to identify non-pregnancy related causes of hypertension were initiated. Thyroid function tests and haemaglobin A1c (HbA1c) were both normal, and a thrombophilia screen showed no evidence of clotting disorder (table 1). However, morning serum cortisol proved to be mildly raised at 596 nmol/L (table 1) and an ultrasound abdomen to assess kidney structure demonstrated normal kidneys, but also noted the presence of a right-sided 6.03×6.43 cm ovarian cyst (figure 1).

Table 1.

Full blood count, renal function, liver function, PT/APTT, protein creatinine ratio, thrombophilia screen, HbA1c and thyroid function tests at presentation. ↑↓ indicates results that are higher or lower than the normal reference range respectively.

		Normal range
WBC	11	4.4–11.3×109/L
HB	12.7	11.7–15.9 g/dL
Platlets	212	140–440 ×109/L
Neutrophils	9.28 ↑	1.4–6.6×109/L
PT	10.9	9.7–11.3 s
INR	1	0.9–1.1
APTT	24	22–30 s
Albumin	40	35–52 g/L
ALT	22	1–34 U/L
Alkaline phosphatase	74	30–120 µmol/L
Total bilirubin	19	2–20 µmol/L
Sodium	136	132–144 (mmol/L)
Potassium	3.7	3.5–5.1 (mmol/L)
Chloride	106	95–107 (mmol/L)
Urea	1.6	2.8–8.4 (mmol/L)
Creatinine (serum)	46	49–90 (umol/L)
Protein creatinine ratio (urinary)	22.7	0–30 mg/mmol
Fibrinogen	4.4 ↑	1.7–4.1 g/L
Antithrombin	96	80%–120%
Protein C	79	70%–120%
APC ratio	Negative
Protein S (free)	57 ↓	60%–114%
Anti-cardiolipin IgG	3.1	0–10 GPL/mL
Anti-cardiolipin IgM	1.1	0–7 MPL/mL
Lupus anticoagulant	Weakly positive
Anti-beta 2 glycoprotein 1	1.4	<5 U/mL
HBA1c	26	20–42 mmol/L
T4	9.6	9.0–19.1 pmol/L
TSH	1.47	0.35–4.94 mlU/L
Cortisol (AM)	596	101–536 nmol/L

ALT, Alanine aminotransferase; HB, Haemoglobin; HbA1C, Haemoglobin A1C; INR, International normalised ratio; PT/APTT, Prothrombin time/activated partial thromboplastin time ; TSH, Thyroid stimulating hormone; WBC, White blood cells.

Figure 1.

Ultrasound image of right-sided ovarian cyst measuring 6.03×6.43 cm. The label LOGIQ E9 in the image indicates that it was taken using a General Electric logiq E9 ultrasound machine.

Differential diagnosis

Further investigation revealed unusual blood chemistry, renin levels and aldosterone levels were unusually high, at levels that could not be accounted for by pregnancy alone, at 4665.8 pg/mL and 1157 pg/mL, respectively (table 2). MRI of the pelvis, adrenal glands and brain demonstrated no pituitary or adrenal abnormalities. Instead, a right-sided ovarian mass measuring 6.4×6.2×6.7 cm was identified (figure 2). This was accompanied by spontaneous development of hypokalaemia (table 2) suggesting a working diagnosis of a renin-secreting ovarian tumour.

Table 2.

Table showing abnormally high levels of renin, aldosterone, androstenedione and DHEA-S (highlighted in bold) which returned to normal post laparoscopic cystectomy. Abnormal biochemical results are indicated in bold. ↑↓ indicates results that are higher or lower than the normal reference range respectively.

	Preoperative	Postoperative	Normal range
Sodium (mmol/L)	138	136	132–144 (mmol/L)
Potassium (mmol/L)	3.4 ↓	3.5	3.5–5.1 (mmol/L)
Chloride (mmol/L)	107	108	95–107 (mmol/L)
Urea (mmol/L)	1.7	2.3	2.8–8.4 (mmol/L)
Creatinine (serum) (µmol/L)	52	47	49–90 (µmol/L)
Renin (pg/mL)	4665.8 ↑	9.4	<20 pg/mL resting 5–40 pg/mL ambulatory
Aldosterone (pg/mL)	1157 ↑	150	42–209 pg/mL resting 67–335 pg/mL ambulatory
Aldosterone/renin ratio	0.25	15.96	<24 (>90 indicated a diagnosis of primary hyperaldosteronism)
Androstenedione (nmol/L)	>50.0 ↑	2.4	1.1–5.7 nmol/L
DHEA-S (µmol/L)	13 ↑	4	1.3–8.5 (µmol/L)
Plasma metanephrine (pmol/L)	243	224	0–510 pmol/L
Plasma normetanephrine (pmol/L)	<300	<300	0–1180 pmol/L
Plasma 3 methoxytyramine (pmol/L)	<100	---	0–180 pmol/L

DHEA-S, dehydroepiandrosterone sulfate.

Figure 2.

Transverse (A) and coronal (B) sections of a pelvic MRI showing a right-sided ovarian mass as indicated by the white arrows measuring 6.4×6.2×6.7 cm.

Treatment and definitive diagnosis

To maintain safe blood pressure levels, our patient now requires a combination of oral labetalol 500 mg four times per day, nifedipine 40 mg two times per day and methyldopa 500 mg three times per day. The decision was made to perform a right oophorectomy to remove a 5 cm solid but soft and friable ovarian mass laparoscopically. Histological examination of the right mass revealed tissue comprising plump cells with round nuclei, small inconspicuous nucleoli and abundant pale to eosinophilic cytoplasm (figure 3). Mild nuclear atypia was present with a mitotic count of ~1 per 10 high-power field. Immunohistochemical staining was positive for inhibin and calretinin with a patchy expression of synaptophysin and Melan-A and negative staining for AE1/3, CD 56 and chromogranin; a staining pattern most consistent with steroid cell tumour (figure 3).⁸

Figure 3.

Immunohistochemical features of the right ovarian mass (A) H&E at ×10 and (B) H&E at ×400 showing plump cells with round nuclei, small inconspicuous nucleoli and abundant pale to eosinophilic cytoplasm. (C) Immunohistochemical staining positive for calretinin and (D) for inhibin.

Urine steroid analyses showed an increase in androstenedione metabolites relative to those of cortisol. Specifically, urine biochemical analyses showed increased 17-hydroxyprogesterone metabolites, pregnanetriol and 17-hydroxypregnanolone which are ovarian androstenedione metabolites and no increase in the adrenal androstenedione metabolite marker 11-oxopregnanetriol, supporting the diagnosis of ovarian steroid cell tumour. Blood biochemistry demonstrated that the androgens androstenedione and DHEA-S were both abnormally raised preoperatively (table 2). Only 2 days after having the oophorectomy, the patient’s blood test results showed a dramatic reduction in the levels of renin, aldosterone, DHEA-S and androstenedione, all of which returned to normal confirming the ovarian mass as the culprit for her abnormal biochemical results.

Outcome and follow-up

Only 3 days after undergoing the oophorectomy, the patient’s blood pressure had improved to the point where she was now requiring only labetalol 600 mg four times per day to control her blood pressure. This was a significant reduction from the triple combination of medications she required prior to the procedure. Her blood pressure would continue to fall throughout the pregnancy allowing for her medications to be titrated down to labetalol 200 mg two times per day only at the time of delivery. Her antinatal course remained uneventful, apart from a diagnosis of diet controlled gestational diabetes, and she delivered a healthy 3.57 kg baby boy via elective caesarean section at 38+6 weeks.

Discussion

To our knowledge, this is the first case of a renin-secreting steroid cell ovarian tumour in pregnancy that has been reported. Most renin-secreting tumours arise from the juxtaglomerular apparatus from which renin is excreted, rare cases of extrarenal renin-secreting tumours, including renin-secreting ovarian cell tumours, have been documented.⁹ Steroid cell tumours of the ovary are a rare type of sex cord-stromal tumour accounting for less than 0.1% of all ovarian tumours. They can be divided into three subtypes according to their cells of origin. These are stromal luteoma tumours, Leydig (or hilus) cell tumours and steroid cell tumours not otherwise specified (NOS).¹

Steroid cell tumours NOS account for approximately 56% of all steroid cell ovarian tumours, the majority of which are unilateral and well circumscribed^{1 3} and can occur at any age, but mostly in women in the fourth and fifth decade of life. Androgenic manifestations due to the secretion of hormones such as androstenedione, testosterone and 17-alpha-hydroxyprogesterone often lead to symptoms of virilisation such as oligomenorrhoea and eventual amenorrhoea, hirsutism, voice deepening, acne and temporal baldness.^2–5 Atypical presentations of these tumours without signs of virilisation have been reported⁶ and, though rare, several case reports of steroid cell tumours in pregnancy have been reported.⁷

This case is unique, it is one of only a few documented cases of steroid cell ovarian tumour in pregnancy and presentation did not include symptoms of virilisation. Instead, the presenting symptom was medication-resistant high blood pressure and biochemical findings of abnormally high renin and aldosterone.

Normal pregnancy is associated with a striking alteration in the renin–angiotensin–aldosterone (RAAS) system. It involves volume expansion and vasodilation which is carefully coordinated by several hormones.^{10 11} Renin is released from extrarenal sites including the ovaries and decidua, while the placenta releases oestrogen triggering angiotensinogen synthesis by the liver and an increase in angiotensin II (ANG II). Despite this, blood pressure falls in early pregnancy as the vasoconstrictive effects of the RAAS system are offset by the increased levels of relaxin, oestrogens, and progesterone and ANG II insensitivity.^{10 11} Typically, aldosterone levels increase from the 8th week of pregnancy and peaks at 3–6 times the upper limit of normal in the third trimester.^{10 12} In our case, aldosterone was already more thanseven times higher than normal (table 2) in the early second trimester, this along with highly elevated levels of renin, androstenedione and DHEA-S pointed to a pathological process. As our patient’s blood pressure dramatically increased once pregnant, it is reasonable to speculate that the natural upregulation of the RAAS may have driven an abnormal increase in the level of these hormones from the ovarian tumour, vastly overwhelming the ameliorating effects of the increased levels of relaxin, oestrogens and progesterone which manifested as treatment resistant hypertension.

As in this case steroid cell tumours and other malignant adnexal masses identified at the time of pregnancy are typically managed surgically by explorative laparotomies with unilateral salpingo-oophorectomy to preserve fertility and the fetus.^{7 13 14} Previous studies suggest that pregnancy outcomes are better when surgery is performed before 23 weeks gestation.¹⁴ In cases that occur in women who have completed their families a total abdominal hysterectomy and bilateral salpingo-oophorectomy and complete surgical staging is the typical recommended standard of care.¹³ The presence of malignant features as determined by Hayes and Scully⁶ which are a diameter >7 cm, >2 mitotic figures per 10 high-power fields, grades 2–3 atypia, necrosis and haemorrhage is the most important factor to be determined in steroid tumours as this determine the need for adjuvant therapy. Fortunately, this case had no features of malignant disease.

Though rare, malignant ovarian steroid cells tumours do present in pregnancy and, as in this case, may present with atypical clinical features. In this case of refractory hypertension maintaining an open mind and the consideration of more unusual differentials lead to the identification of a renin-secreting steroid cell tumours NOS. Swift diagnosis and a multidisciplinary approach led to the successful treatment and a positive outcome for both mother and baby.

Patient’s perspective.

The most challenging aspect of my IVF journey and my pregnancy was even though I knew it was probably my last chance for a successful pregnancy, I was being so careful with everything, so I could not fathom how I had such high blood pressure (BP). I was being so careful; I was constantly being checked for BP; I had no symptoms whatsoever except for pains in my thighs. It became a mystery that could have terminated my hard fought for pregnancy. On a number of occasions, I got very anxious and concerned when I was initially admitted to hospital. When I was transferred to CUMH, the investigation went up an entire notch, it became more intense and eventually, after a lot of hard work, showed positive promise. When eventually my condition was diagnosed, the terrific CUMH team pulled out all the stops to address the various issues to a successful conclusion. We now have a very healthy and beautiful baby boy, our only child, who, by any stretch of the imagination, is an absolute miracle baby. Our heartfelt thanks and admiration goes out to the ENTIRE CUMH TEAM for their inspirational dedication to task, their persistence and their patience.

Learning points.

• Atypical presentation of steroid cell tumours can include refractory hypertension in early pregnancy.

• A wide range of differentials should always be considered when managing refractory hypertension in pregnancy.

• Early investigation and a multidisciplinary approach was key to a successful pregnancy outcome in this case.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).