Hilus Cell Tumors Research Articles

A rare ovarian hilus cell tumour accompanying bilateral serous cystadenomas: report of a case

BackgroundHilus cell tumours is considered an uncommon branch of androgen producing neoplasms that accounts for < 5% of all ovarian tumours. They are mostly benign and have characteristic gross and microscopic features. Here we present the first case of a hilus cell tumour in association with bilateral serous cystadenomas.Case presentationA 65-year-old lady with no symptoms of virilization, presented with postmenopausal dysfunctional uterine bleeding and radiological investigations revealing bilateral ovarian cysts that required a total abdominal hysterectomy with bilateral salpingo-oophorectomy. Gross and microscopic evaluation confirmed the diagnosis of hilus cell tumour associated with bilateral serous cystadenomas.ConclusionsThis was the first case of hilus cell tumour in association with bilateral serous cystadenomas of the ovaries. Although, majority of hilus cell tumours that have been reported in the literature were benign, further studies are required to determine the behavior of the disease.

The Story of a Radiologically Undetectable, Testosterone Producing Leydig Cell Tumor

Introduction: Leydig stromal cell tumors are uncommon ovarian tumors that produce testosterone leading to hyperandrogenism. We present a case of a 63 year old lady with significantly elevated testosterone levels that did not have clear ovaries visualized on imaging, but was subsequently found to have a Leydig cell tumor on pathology after ovarian resection.Clinical Case: A 63 year old female with a past medical history of COPD, hypothyroidism, hyperlipidemia, hypertension and uterine fibroids status post hysterectomy and left oophorectomy in 1995 was referred to endocrinology for hirsutism. The patient reported first noticing abnormal hair growth approximately one year prior to presentation having developed increasingly coarse and thick facial hair, abdominal wall hair, and chest hair. On physical examination, she was noted to have coarse hair across her upper lip and chin continuous along the jawline along with fine, dark hair diffusely across her anterior abdomen. Initial laboratory cell evaluation revealed total testosterone 378 ng/dL, free testosterone 53ng/dL, DHEAS 64 ug/dL. Repeat labs drawn three months later confirmed the markedly elevated total testosterone of 362 ng/dL and free testosterone 44.2 ng/dL, concentrations normally seen in males. A CT scan of the abdomen and pelvis was done and did not reveal any masses. In addition, no ovaries were appreciated on imaging. A transvaginal ultrasound also did not reveal any clear ovaries. The patient ended up undergoing a right oophorectomy. Histological examination was consistent with a Leydig cell tumor. Following oophorectomy, her testosterone concentrations normalized (5ng/dL) and hirsutism began to regress.Clinical Lesson: Hyperandrogenism in women is typically classified into non-tumorous and tumorous. The differential for non-tumorous hyperandrogenism includes PCOS, congenital adrenal hyperplasia (CAH), and ovarian hyperthecosis. Tumorous causes include ovarian tumors such as Sertoli-Leydig cell tumors, hilus cell tumors, and theca cell tumors. Adrenal tumors secreting testosterone are extremely rare. Often with these tumors, there is significantly increased testosterone levels (> 140ng/dL) and rapid progression of symptoms. Sex cord stromal tumors account for only 5-8% of all ovarian tumors with Leydig stromal tumors a rare group that accounts for less than 0.1% of all ovarian tumors. The tumors are functional producing testosterone leading to marked hyperandrogenism and virilization. They are also usually benign and unilateral. This patient had hyperandrogenism manifested by hirsutism with markedly elevated testosterone concentrations. In addition, this case is unique in that a CT scan and transvaginal ultrasound did not clearly demonstrate her right ovary. Despite having a normal appearing right ovary during surgery, patient was found to have Leydig cell tumor following histological examination.

Utilisation of gonadotrophin-releasing hormone (GnRH) analogue to differentiate ovarian from adrenal hyperandrogenism in postmenopausal women.

SummaryPostmenopausal hyperandrogenism is a relatively rare diagnosis resulting from excess androgen production from the adrenals or ovaries. The exclusion of malignant causes is a priority. Laboratory tests and imaging are utilised to help differentiate the source of excess androgens. We report two cases of postmenopausal hyperandrogenism in women aged 75 and 67 years. Both cases presented with clinical features suggestive of hyperandrogenism which had developed gradually over the previous 2 years. Laboratory investigations confirmed a significant elevation in their serum testosterone levels. In both cases, imaging did not reveal any abnormality of the adrenals or ovaries. To help differentiate an adrenal vs ovarian source a single-dose GnRH analogue was given with measurement of testosterone and gonadotrophin levels pre and post. The reduction in gonadotrophins achieved by the GnRH analogue resulted in suppression of testosterone levels which suggested an ovarian source. Both patients proceeded to bilateral oophorectomy. Histology revealed a benign hilus cell tumour in one case and a benign Leydig cell tumour in the other.Learning points:A key part of the work-up of postmenopausal hyperandrogenism is to differentiate between an adrenal or an ovarian source of excess androgens;Imaging may not identify small ovarian tumours or hyperthecosis and may also identify incidental adrenal masses which are non-functioning;Current guidelines suggest ovarian and adrenal venous sampling when imaging is inconclusive but this requires technical expertise and has a high failure rate;GnRH analogue use can successfully confirm ovarian source and should be considered as a diagnostic tool in this setting.

Use of F 18-fluoro-D-glucose–positron emission tomography–computed tomography to localize a hilar cell tumor of the ovary

To describe provocative testing and alternative imaging strategies used to localize an androgen-producing tumor in a 58-year-old woman with severe hirsutism. Case report. Clinical Research Center. A 58-year-old woman who was seen for evaluation of severe hirsutism. Serum androgen levels were measured at baseline, 4 hours after administration of 2000 IU of hCG, and 11 days after administration of 3.75 mg of leuprolide acetate (LA). Magnetic resonance imaging and F 18-fluoro-D-glucose-positron emission tomography-computed tomography (FDG-PET/CT) were performed. Description of preoperative provocative testing and imaging. In response to hCG, T rose from 243 to 288 ng/dL then decreased to 233 ng/dL after LA administration. The FDG-PET/CT scan demonstrated focal hypermetabolism in the right pelvis, corresponding to a soft-tissue density on the noncontrast CT scan. Magnetic resonance images were correlated with the PET/CT, and the right ovary was identified. Right salpingo-oophorectomy was performed, and final pathologic examination revealed a hilar cell tumor with ovarian cortical hyperplasia. This case demonstrates the utility of provocative testing in the evaluation of a patient with severe hirsutism and illustrates the value of FDG-PET/CT when traditional imaging is nondiagnostic.

Hilus Cell Tumor in the Ovary

Hilus Cell Tumor in the Ovary

Coincidental diagnosis of an occult hilar steroid cell tumor of the ovary and a cortisol-secreting adrenal adenoma in a 49-year-old woman with severe hyperandrogenism

Objective To report an exceptional association between an occult ovarian steroid cell tumor and a cortisol-secreting adrenal adenoma. Design Case report. Setting Endocrinology and nutrition unit at a general hospital in Spain. Patient(s) A 49-year-old woman who presented with persistence of severe hyperandrogenism after removal of a left adrenal adenoma. Intervention(s) An endocrine study evaluating serum androgens, adrenal function, and tumor markers was ordered. Transvaginal sonography was done to rule out an ovarian tumor. Finally, a selective catheterization of ovarian veins allowed the correct diagnosis. Main outcome measure(s) Clinical and endocrine description of the patient and preoperative localization of the source of T secretion. Result(s) After adrenal surgery, urinary free cortisol levels decreased to normal values, but serum T remained within the tumoral range (3.04 ng/mL). Selective catheterization of ovarian veins revealed a gradient of T concentration in the right ovary. After bilateral annexectomy, a microscopic steroid cell tumor of hilar type was found in the right ovary. Serum T fell within the normal range, and hirsutism progressively improved. Conclusion(s) This unusual association between an occult-virilizing ovarian steroid cell tumor and a cortisol-secreting adrenal adenoma illustrates the value of an accurate preoperative workup in women with severe hyperandrogenism.

Melan-A (A103) and inhibin expression in ovarian neoplasms.

A103 is a melanocyte-associated monoclonal antibody that recognizes the Melan-A/MART-1 antigen in melanomas. The Melan-A/MART-1 antigen is also expressed in Leydig cells, adrenal tissue, and steroid-secreting tumors. A103 immunoreactivity in ovarian neoplasms, specifically sex cord stromal tumors (SCSTs), has not been well studied. Inhibin is known to be expressed in SCSTs but is also expressed in some carcinomas and other tumors. We sought to explore the usefulness of both antibodies in the diagnosis of ovarian neoplasms. Using conventional tissue sections and a tissue microarray, we studied the immunoreactivities of 131 ovarian tumors for A103 and inhibin: 30 SCSTs, including fibrothecoma, luteoma, hilus cell tumor, granulosa cell tumor, Sertoli-Leydig cell tumor, and sex cord tumor with annular tubules, and a control group of 96 surface epithelial tumors. A few other rare ovarian tumors including 1 small cell carcinoma, 1 adenocarcinoid tumor, 1 ovarian tumor of probable wolffian origin, 1 Krukenberg tumor, and 1 desmoplastic small round cell tumor were also studied. Inhibin staining was generally strong and diffuse in the majority of SCSTs (83%) and at least focally positive in the small cell carcinoma, ovarian tumor of probable wolffian origin, Krukenberg tumor, and desmoplastic small round cell tumor. Variable immunoreactivities were also present in 7 of 96 (7.3%) surface epithelial tumors. In comparison, A103 expression was usually weaker and more focal than that of inhibin and was present in a smaller proportion of SCSTs (37%) and negative in all the surface epithelial tumors. A103 was typically positive in the lipid-containing cells (both neoplastic and normal components) of these tumors (fibrothecomas, luteomas, Sertoli-Leydig cell tumors, hilus cell tumors, and granulosa cell tumors), and in some cases, moderate positivity was noted in these cells. Weak A103 positivity was identified in the single case of ovarian tumor of probable wolffian origin. A103 is relatively less sensitive than inhibin for recognizing SCSTs but does not appear to be expressed by ovarian surface epithelial tumors. It is therefore more specific than inhibin for SCSTs and is a useful marker for specifically identifying lipid-containing cells in tumors. Thus, adding A103 to a panel of markers including inhibin may be a valuable adjunct in the differential diagnoses of SCSTs and their distinction from other ovarian neoplasms.

Expression of calretinin in human ovary, testis, and ovarian sex cord-stromal tumors.

Calretinin, a calcium-binding protein, is primarily expressed in certain subtypes of neurons. It has also been found to be present in mesothelial cells and mesotheliomas but not in many types of carcinomas. Using a polyclonal anti-calretinin antibody, we investigated the expression of calretinin immunohistochemically in nonneoplastic human ovaries and testes and ovarian sex cord-stromal tumors (SCSTs). In ovaries, calretinin was expressed in theca interna cells, hilus cells, and scattered individual stromal cells. Oocytes, granulosa cells, theca externa cells, rete ovarii, and most stromal cells were negative. Expression of calretinin was also seen in the ovarian surface epithelium and in collapsed and flat epithelial inclusion glands (EIGs), but not in round, columnar, and ciliated EIGs. In some glands, a transition from calretinin-positive to calretinin-negative epithelium was observed. In postpubertal testes, calretinin was expressed in Leydig cells, but not in germ cells or most rete testes and Sertoli cells. In ovarian SCSTs, strong calretinin staining was seen in all hilus cell tumors (4/4) and the Leydig cell component of Sertoli-Leydig cell tumors (10/10). The Sertoli cell component showed focal weak positivity in 5/10. Fibrothecomas were completely negative (0/8). In granulosa cell tumors, the tumor cells were either completely negative (8/14) or weakly positive at the periphery of the tumor (6/14) while scattered stromal cell staining was seen in 9/14 cases. The expression of calretinin in normal Leydig cells, theca interna cells, the Leydig cell component of Sertoli-Leydig cell tumors, and hilus cell tumors suggests its functional relationship with androgen production. Its pattern of expression in ovarian SCSTs is useful in the differential diagnosis of these tumors. The presence of a transition from calretinin-positive, flat, nonciliated epithelium to calretinin-negative, columnar, ciliated epithelium in the same glands provides strong evidence for mullerian metaplasia.

Hilus Cell Tumour of the Ovary in a Virilized, Premenopausal Woman. Case Report and Review of Hyperandrogenism of Ovarian Origin

A 35 year-old woman presented with virilization and was found to have elevated serum testosterone levels. Investigation revealed an 11 mm hilus cell tumour in the left ovary. After unilateral oophorectomy, serum testosterone levels rapidly returned to normal levels. The various ovarian tumours and conditions causing virilization are described and a clinical approach to the investigation of virilization is outlined.

Total testosterone and DHEAS levels as predictors of androgen-secreting neoplasms: A populational study

Androgen excess affects between 2% and 10% of women. While the majority of these patients suffer from polycystic ovary syndrome, a few present with an androgen-secreting neoplasm. An elevated circulating total testosterone level and dehydroepiandiosterone sulfate (DHEAS) level have been proposed as screening methods for detecting ovarian and adrenal androgen-secreting neoplasms, respectively. To determine the predictive value of these tests for androgen-secreting tumors in a population of consecutive hyperandrogenic patients, we studied 478 consecutive untreated hyperandrogenic patients presenting over a ten-year period (1987-97). All had at least two of the following features: (1) oligomenorrhea (i.e. cycles > 35 days or < 8 cycles/year), (2) hyperandrogenemia (i.e. a total or free testosterone, or DHEAS > 95th percentile of controls), or (3) hirsutism (i.e. a modified Ferriman—Gallwey score ≥ 6). None of these patients had a prior diagnosis of an androgen-secreting neoplasm. Basal levels of testosterone and DHEAS were determined in all patients, with transvaginal sonography and an adrenal computed tomography scan in select individuals. Of the 478 patients included, 65% had hirsutism and oligomenorrhea; 20% had hyperandrogenic oligomenorrhea; and 15%) had hirsutism and hyperandrogenemia, without overt oligomenorrhea. Overall, 11 (2.3%>) patients had a total testosterone > 8.7 nmol/l (250 ng/dl), of which one actually had an androgen-secreting neoplasm (i.e. true-positive). This postmenopausal patient presented with rapidly progressive virilization, and demonstrated an ovarian hilar cell tumor at surgery. The calculated sensitivity of an elevated testosterone level (> 8.67 nmol/l) for a neoplasm was 100% (1/1), the specificity was 98% (467/477), and the negative predictive value was 100% (467/467), but the positive predictive value was only 9% (1/11). Ten subjects had DHEAS levels > 16.3 μmol/l (6000 ng/ml), and none was diagnosed with an adrenocortical tumor. Although the sensitivity and positive predictive value of a high DHEAS for a neoplasm could not be calculated due to the absence of a test case, the specificity was 98% (468/478) and the negative predictive value was 100% (468/468).These data suggest that the measurement of testosterone and DHEAS is not a cost-effective method of screening for these tumors, due to the low frequency of the disorder and the fact that clinical evaluation alone is often sufficient screening.

Laparoscopic removal of virilizing hilar cell tumor in a postmenopausal patient

A postmenopausal woman experienced rapidly progressing hirsutism and signs of virilization. Hormone evaluations showed markedly elevated serum testosterone levels and no evidence of excess cortisol or dehydroepiandrosterone sulfate production. A computerized tomographic scan of the adrenals and ovaries was normal, and transvaginal ultrasound revealed a left ovary with a maximum diameter of 3.2 cm. At outpatient laparoscopic bilateral oophorectomy, the left ovary had a benign, 2.5-cm Leydig cell tumor, hilar cell variant. Laparoscopy may be useful in the diagnosis and treatment of select cases of virilizing tumors of the ovary.

Androgen suppressive effect of GnRH agonist in ovarian hyperthecosis and virilizing tumours.

Recent studies have suggested that androgen secretion by ovarian virilizing tumours may be gonadotrophin dependent. The aim of this study was to investigate the suppressive effect of GnRH agonist administration on androgen secretion in women with such tumours. A single i.m. injection of D-Trp-6-GnRH (GnRHa), 3.75 mg, was given to five unrelated patients referred for clinical symptoms of virilization with plasma testosterone (T) levels greater than 7 nmol/l but with normal dehydroepiandrosterone sulphate (DHEAS) levels. Diagnoses of adrenal tumour or a non-classical 21-hydroxylase deficiency were screened for by the dexamethasone suppression test, ACTH stimulation test and adrenal CT scanning, and were ruled out in all patients. The one premenopausal patient received cyproterone acetate in a dose of 50 mg twice daily for 3 weeks, starting 1 week before GnRHa administration. Testosterone, androstenedione (A), DHEAS, 17-hydroxyprogesterone (OHP), LH and FSH plasma concentrations were measured by radioimmunoassay of blood samples taken before and 3 weeks after GnRHa. In each patient, GnRHa suppressed gonadotrophin levels and reduced T and A to the range for normal control women. With these results, and because accurate localization of an ovarian androgen secreting tumour could not be achieved by pelvic ultrasonography and CT scanning, exploratory laparotomy was undertaken. A Sertoli-Leydig cell tumour was found in the premenopausal patient, and granulosa cell tumour, hilus cell tumour and two hyperthecoses in the four post-menopausal patients. After bilateral ovariectomy and hysterectomy in the post-menopausal woman and after unilateral ovariectomy in the premenopausal women, androgen levels were normalized. In virilized women, the findings of increased serum testosterone with normal gonadotrophin levels and GnRHa suppression of gonadotrophins leading to normalization of testosterone levels, suggest that various ovarian androgen-secreting tumours, as well as hyperthecosis, are not autonomous but apparently depend upon continuous gonadotrophin stimulation.

A CASE OF OVARIAN HILUS CELL TUMOR WITH VIRILIZATION

A 75-year-old postmenopausal woman with virilization, as demonstrated by temporal baldness, hirsuism, and mustache is presented.Laboratory data on admission revealed polycythemia, markedly elevated plasma testosterone level (29 ng/ml), and normal 17-KS value. Abdominal echography and CT-scan revealed a solid mass of the left ovary. The presumptive diagnosis was a virilizing ovarian tumor. The patient underwent bilateral salpingo-oophorectomy. The resected left ovary measured 3×3×2 cm, and weighted 13 grams.Microscopically, both ovaries were composed of hilar cells. Postoperatively, the plasma testosterone level was recovered to the normal level. The patient has remained asymptomatic.Hilus cell tumors of the ovary are very rare. In Japan, only 4 cases have been reported on the litrature, and besides, bilateral hilus cell tumors are so rare that the case is the 3rd in the world.

Hilus Cell Pathology and Hirsutism

SUMMARY Hilus cell abnormalities are uncommon causes of hirsutism with virilization. Although hilus cell tumours have been well described, hilus cell hyperplasia is rare and is poorly defined clinically. We describe three cases of hilus cell hyperplasia and compare them with a case of hilus cell tumour. Both pathologies were associated with increased testosterone and oestradiol secretion. Suppression of testosterone to the ‘normal range’in response to exogenous oestrogen was seen only in the cases with hyperplasia; only partial responsiveness was seen in the case with hilus cell tumour. Bilateral oophorectomy offers the potential for cure for both hilus cell hyperplasia and tumour.

HILUS CELL PATHOLOGY AND HIRSUTISM

Hilus cell abnormalities are uncommon causes of hirsutism with virilization. Although hilus cell tumours have been well described, hilus cell hyperplasia is rare and is poorly defined clinically. We describe three cases of hilus cell hyperplasia and compare them with a case of hilus cell tumour. Both pathologies were associated with increased testosterone and oestradiol secretion. Suppression of testosterone to the 'normal range' in response to exogenous oestrogen was seen only in the cases with hyperplasia; only partial responsiveness was seen in the case with hilus cell tumour. Bilateral oophorectomy offers the potential for cure for both hilus cell hyperplasia and tumour.

Hilus Cell Tumor of the Ovary

The clinical and pathological features of 12 Reinke crystal-positive and nine probable (crystal-negative) hilus cell tumors of the ovary were reviewed. The patients' ages ranged from 32 to 82 years. The initial manifestation was androgenic in 62% of the cases. The levels of testosterone were high (200-2,400 ng/dl) even though the tumors had a mean diameter of only 2.1 cm. All the tumors were centered in the hilus of the ovary, extending for varying distances into the ovarian stroma. They were composed of polyhedral to rounded cells with generally abundant eosinophilic cytoplasm and often showed a perivascular aggregation of nuclei with avascular pooling of cytoplasm or hyalinization of stroma. Fibrinoid changes in the vessels of the tumors were frequently noted. None of the 10 patients for whom follow-up data of 1-17 years were available died of tumor; virilizing symptoms regressed but did not completely disappear in five of the 10 patients after the removal of the tumor.

Androgen-Producing Hilus Cell Tumor of the Ovary

IN 1942 Berger¹reported the first clinical case of a hilar cell tumor of the ovary in a 50-year-old woman with signs of virilization. Since then approximately 50 cases have been reported in the literature.^2,3This is a case of a hilar cell tumor in a postmenopausal woman detected by ultrasound and duplex Doppler scanning. The<i>hilar cell tumor</i>is a neoplastic growth of mature hilar cells with a closely packed uniform appearance. The tumors are often brown, small (&lt;6 cm), unilateral, and benign. The hallmark feature of the hilus cell tumor is virilization in a perimenopausal or postmenopausal woman. This virilization is usually insidious in onset, having been present in some cases for more than ten years. There has also been an unusually high frequency of endometrial hyperplasia found in these patients.^2,3 The possibility of using pulsed Doppler flow signals for the early detection of physiologically

Androgen-producing hilus cell tumor of the ovary. Detection in a postmenopausal woman by duplex Doppler scanning

Androgen-producing hilus cell tumor of the ovary. Detection in a postmenopausal woman by duplex Doppler scanning

Steroid secretion and testosterone binding in a woman with an ovarian hilus cell tumor and thyrotoxicosis

Presented is the case of a 21-year-old woman with an ovarian hilus cell tumor and thyrotoxicosis. Despite massivley elevated of serum testosterone, virilization was lacking and cyctic ovulatory menses were maintained. Hypersecretion of thyroxine and an increased circutating testosterone-estradiol binding globulin (TeBG) resulted In a level of free testosterone lower than expected, thereby perhaps accounting for the negligible androgen effect. Determinations of peripheral and ovarian venous steroids provided the first In vivo evidence for the preferred synthesis of testosterone via the AΔ5 pathway in a hilus cell tumor. (Am. J. Osstet. Gynecol. 141:535,1981.)

Ovarian hilar cell tumor with coexistent polycystic ovary syndrome and myometrial hypertrophy

Ovarian hilar cell tumor with coexistent polycystic ovaries and diffuse myometrial hypertrophy have been found in a 34-year-old virilized woman with a markedly elevated plasma level of testosterone. Following total abdominal hysterectomy and bilateral salpingo-oophorectomy, the plasma level of testosterone returned to normal. Light microscopic examination of the tumor showed polygonal cells with abundant eosinophilic cytoplasm. A few cells contained intracytoplasmic crystals of Reinke. Electron microscopy revealed abundant endoplasmic reticulum forming vesicles and whorls and numerous pleomorphic mitochondria with peripherally located tubular cristae: ultrastructural features of cells engaged in synthesis of hormones. Immunoperoxidase studies of formalin-fixed, paraffin-embedded tissue demonstrated the presence of testosterone within ovarian tumor, ovarian stroma, and granulosa cells lining the follicular cysts.