Ovary: Sex cord-stromal tumors

2003-11-01   Lisa Lee-Jones 

1.Tumour Molecular Genetics Group, Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK

Summary

Note

Sex cord-stromal tumours develop from the gonadal stroma, and are a type of ovarian tumour. They account for 5-10 % of all ovarian neoplasms.

Classification

Classification

Ovarian sex cord-stromal tumours are subdivided into the following clinicopathological entities:
  • Granulosa cell tumour
  • Theca cell tumour
  • Thecoma
  • Fibroma
  • Sertoli-Leydig cell tumour
  • Sex cord tumour with annular tubules
  • Lipid cell tumour
  • Gynandroblastoma.
  • Clinics and Pathology

    Etiology

    There appear to be several established clinical syndromes associated with several subtypes of sex cord-stromal tumours.

  • 30% of patients with sex cord tumours with annular tubules have Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterised by multiple gastrointestinal hamartomatous polyps, increased risk of various neoplasms, and melanocytic macules of the lips, buccal mucosa, and digits. Peutz-Jegher females are also susceptible to granulosa cell tumours. When associated with this syndrome, the tumour is usually small, benign and bilateral. Meanwhile in the absence of this syndrome, it is usually large and unilateral, and malignant in 20% of cases.

  • There have also been clinical reports of several other types of sex cord-stromal tumours being less frequently associated with PJS including: - oxyphilic Sertoli cell tumour; - Sertoli cell tumour (lipid-rich); - malignant Sertoli-Leydig cell tumour and - ovarian fibroma.

  • 10% of patients with lipid cell tumours have Cushing Syndrome.

  • Fibromas are associated with Meigs Syndrome. The phenotype of Meigs syndrome is a benign ovarian tumour (fibroma), with ascites and pleural effusion that resolve within several weeks to months following surgical resection without any recurrence. Thus it imitates a malignant tumour, but has a very good prognosis. Indeed, following resection, life expectancy is similar to the general population.

  • Ovarian fibromas occur in 75% of female patients with Gorlin syndrome (also known as Nevoid basal cell carcinoma syndrome). Gorlin syndrome is an autosomal dominant disorder that predisposes to basal cell carcinomas of the skin, ovarian fibroma and medulloblastoma.

    2 theories account for the aetiology of sex cord-stromal tumours hypothesising that they develop either from:(1) mesenchyme of the developing genital ridge, or(2) precursors of the mesonephric and coelmic epithelium.
    No definite aetiologies have been established for granulosa cell tumours, although chromosomal abnormalities and abnormal autocrine and endocrine signalling have been suggested.

  • Epidemiology

    The frequency of sex cord-stromal tumours is similar throughout the world. There does not appear to a racial predisposition, in contrast to epithelial ovarian cancers. Every year, 15-20,000 new cases of sex cord-stromal tumours are diagnosed in the USA. Sex cord-stromal tumours appear in any age group but usually in the 4th and 5th decades. Fibromas are usually detected in the fifth decade of life. The mean age of presentation of Leydig cell tumours is 50. The median age of diagnosis of adult granulosa cell tumours is 52, and is 53-years for theca cell tumours. Theca cell tumours account for 1 % of ovarian neoplasms, and are rarely diagnosed in women under 30-years of age, unless they have luteinized thecoma which is more apparent in younger women. However, Sertoli-Leydig cell tumours tend to present at a younger age, usually in the third decade of life.

    Clinics

    Granulosa cell tumours usually follow a nonaggressive clinical course. However, they may become malignant or recur (up to 30 years after the initial diagnosis). 65% of granulosa cell tumours occur in postmenopausal females. Juvenile and adult granulosa cell tumours, fibromas, and Sertoli-Leydig cell tumours are usually unilateral. Granulosa-theca cell tumours are usually large and benign, with cystic degeneration (

    Pathology

    All ovarian sex cord-stromal tumours are derived from the stroma of the developing ovary. The gonadal stoma is primitive, and consequently can develop in a testicular or ovarian differentiation pathway.

    Adult and Juvenile Granulosa cell tumour
    Adult granulosa cell tumours contain granulosa cells in the presence or absence of theca cells. Granulosa theca cell tumours are composed of at least 25% theca cells in addition to the granulosa cells. Varying histologies have been reported in adult granulosa cell tumours, including well-differentiated histologies such as microfollicular, macrofollicular, trabecular and insular, and less well diffentiated subtypes including diffuse and watered-silk (gyriform). Call-Exner bodies are pathognomonic of granulosa cell tumour,and are found in the microfollicular pattern, the most common histological subtype. Call-Exner bodies consist of small rings of granulosa cells surrounding eosinophilic fluid and basement membrane material (http://www.emedicine.com/med/topic928.htm#target1). Macrofollicular granulosa cell tumours contain one or more large cysts lined with granulosa cells. Granulosa cells are organised into nests and bands in the trabecular and insular histologies, with an intervening fibrothecomatous stroma present in the trabecular type. The diffuse subtype contains sheets of cells arranged in no pattern (http://www.emedicine.com/med/topic928.htm#target2 ), and the watered-silk entity contains cells arranged in single file in lines (http://www.emedicine.com/med/topic928.htm#target4). Both the well-differentiated and the less well-differentiated adult granulosa cell tumours contain large, pale, ovoid or angular nuclei with nuclear grooves.Few mitotic figures, mild nuclear atypia and little cytoplasm are usually found, however luteinization can sometimes be evident.

    The gross appearance of juvenile granulosa cell tumours is similar to the adult counterparts-both comprise a mixture of solid and cystic components with many haemorrhagic areas. However the similarity ceases at the gross level, as morphologically both types differ greatly. Juvenile granulosa cell tumours contain round hyperchromatic nuclei, nuclear grooves are usually absent, severe nuclear atypia, contain more mitotic figures, more cytoplasm (which is dense).

    Gross image of granulosa cell tumour can be viewed at:
    http://www-medlib.med.utah.edu/WebPath/FEMHTML/FEM057.html

    Microscopic images at varying magnification powers can be viewed at:
    http://www-medlib.med.utah.edu/WebPath/FEMHTML/FEM058.html
    http://www-medlib.med.utah.edu/WebPath/FEMHTML/FEM063.html
    http://pathweb.uchc.edu/eAtlas/GYN/1953.htm
    http://pathweb.uchc.edu/eAtlas/GYN/1954.htm
    http://pathweb.uchc.edu/eAtlas/GYN/1955.htm

    Fibromas
    Fibromas are benign and are classified as such if they contain 4 mitoses per high-power field. Less than 5% of fibromas are malignant.

    Gross appearance of an ovarian fibroma can be viewed at:
    http://www-medlib.med.utah.edu/WebPath/FEMHTML/FEM049.html
    http://pathweb.uchc.edu/eAtlas/GYN/469.htm
    http://pathweb.uchc.edu/eAtlas/GYN/470.htm
    http://pathweb.uchc.edu/eAtlas/GYN/471.htm

    Histological images of fibromas can be viewed at:
    http://pathweb.uchc.edu/eAtlas/GYN/1956.htm
    http://pathweb.uchc.edu/eAtlas/GYN/1957.htm
    http://pathweb.uchc.edu/eAtlas/GYN/1958.htm

    Thecomas
    Thecomas or theca cell tumours contain exclusively theca cells. Thecomas are solid, tan or yellow-orange tumours. They are highly similar to fibromas, except that thecomas secrete excess oestrogen. Thecomas are usually benign, and are characterised by 3 mitoses per field. Microscopic analysis reveals round or ovoid cells with pale nuclei and a lipid-rich cytoplasm. Hyaline bands frequently intersperse cells (http://www.emedicine.com/med/topic928.htm#target5). Luteinized thecomas contain lipid rich cytoplasmic cells and a more fibromatous stroma (http://www.emedicine.com/med/topic928.htm#target6). Less than 5% of thecomas are malignant.
    http://pathy.med.nagoya-u.ac.jp/atlas/misc/thecoma.html

    Sertoli cell tumours
    Sertoli cell tumours contain Sertoli cells in a tubular arrangement.

    Sertoli-Leydig cell tumours
    As the name suggests, Sertoli-Leydig cells contain both Sertoli and Leydig cells. They are subclassified in accordance with the WHO as follows:
    1. well-differentiation (predominant tubular pattern) 2. intermediate differentiation (sheets of immature Sertoli cells with some stroma) 3. poor differentiation (immature Sertoli cells with little or no stroma) 4. containing heterologous elements with retiform pattern.
    Less than 5% of Sertoli-Leydig tumours are malignant.

    Leydig cell tumours
    Leydig cell tumours contain Leydig cells, and are usually benign. When located in the hilus they are described as hilus cell tumours. Leydig cell tumours contain Reinke crystals.

    Lipid cell tumours
    Lipid cell tumours are characterised by round Leydig-like cells, luteinized stroma, adrenocortical cells and the absence of Reinke crystals. 30% of lipid cell tumours are malignant.

    Gynandroblastoma
    These are rare ovarian tumours which contain granulosa stromal cells and Sertoli stromal cells. 100% of gynandroblastomas are malignant.

    Sex cord tumour with annular tubules (SCTAT)
    Histologically SCTAT is intermediate between granulosa cell tumour and the Sertoli cell tumour. It is characterised by sex cord cells in the form of a ring with nuclei orientated around a central hyalonized body.

    Treatment

  • Surgery may be the only treatment necessary. Surgical intervention of patients with sex cord-stromal tumours is age dependent. Trans abdominal hysterectomy or bilateral salpingo-oophorectomy is appropriate for women beyond childbearing age, whereas unilateral oophorectomy is appropriate for younger women. There is a paucity of data on treatment of advanced or recurrent stromal tumours due to their rarity, varied histology and indolence.
  • Combination chemotherapies have yielded some responses in each subtype of sex cord-stromal tumour.
  • Pelvic radiation has also been used for localised tumours.
    No effective treatment is available for metastatic lipid cell tumours.
  • Evolution

    20% of lipid cell tumours metastasise. In the low percentage of granulosa cell tumours showing aggressive behaviour, any organ can be affected by metastatic disease, although it is usually confined to the pelvis and abdomen.

    Prognosis

    The prognosis of sex-cord-stromal tumours is good, as these tumours usually present when confined to a single ovary, and are responsive to chemotherapy.

    Cytogenetics

    Cytogenetics morphological

    Trisomy 12 is a recurrent finding, often as the sole anomaly in benign sex cord-stromal tumours including fibromas, fibrothecomas, thecomas, granulosa cell tumours. The consistent occurrence of trisomy 12 in different subtypes of sex cord-stromal tumours suggests a common mechanism of oncogenesis within this diverse group of neoplasms. Numerical abnormalities of chromosome 12 can readily be demonstrated by interphase cytogenetics.

    Trisomy 12 and 14, and monosomy 22 are the characteristic recurrent cytogenetic aberrations in granulosa cell tumours. There has been a single case of a Sertoli cell tumour in which cytogenetics was performed. Supernumerary i(1q) was present as the sole abnormality. Monosomy 22 was identified as the sole anomaly in a mixed germ cell-sex cord-stromal tumour in the ovary, by both karyotyping and CGH, which may suggest a common pathogenetic mechanism for both tumour types. Monosomy 22 was also identified as the sole abnormality in a fibrothecoma. Monosomy 22 and trisomy 14 may be early events in the pathogenesis of adult granulosa cell tumour, and particularly adult granulosa-thecoma cell tumours.

    Other abnormalities found include:

  • 44,XX,dup(p13p31),del(3)(p14),add(10p),-16,-22 in one case of fibrothecoma,
  • 57,XX,+4,+5,+6,+10,+12,+12,+14,+17,+18,+19,+20 in another fibrothecoma case,
  • +4,+9,+12 in fibrothecoma,
  • trisomy 12 and 4 as only cytogenetic aberrations in a thecoma.
  • Cytogenetics molecular

    CGH and FISH analysis of an ovarian metastasising Sertoli-Leydig cell tumour demonstrated trisomy 8 as the sole anomaly, suggesting that the molecular pathogenesis of Sertoli-Leydig cell tumours differs from the other subtypes of sex cord-stromal tumours.
    In a study, FISH using DNA-specific probes for chromosome 12, 17, 22 and X on granulosa cell tumours revealed monosomy 22 in 6/20; trisomy 12 in 5/20; monosomy X in 2/20 and monosomy 17 in 1/20. They also analysed this series of tumours by CGH and identified gains of chromosome 12 (6/20) and 14 (6/20) and losses of chromosome 22 (7/20) and X (1/20) as the predominant findings. These findings corroborate previous reports of the prevalence of trisomy 12 and 14 and monosomy 22 in granulosa cell tumours.

    Genes Involved and Proteins

    Note

    Involvement of the follicle stimulating hormone receptor,

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    External Links

    Citation

    Lisa Lee-Jones

    Ovary: Sex cord-stromal tumors

    Atlas Genet Cytogenet Oncol Haematol. 2003-11-01

    Online version: http://atlasgeneticsoncology.org/solid-tumor/5223/ovary-sex-cord-stromal-tumors