Gynecology

Liens et agrandissements sur : images et texte en bleu. Links - Zoom: pictures and highlighted text.
 

Tumeur kystique ovarienne, femme de 27 ans.

 

Cystic ovarian mass, in a 27 yo female.

 
     
     
     
     
  Inhibine   Inhibin  
     
  CD99   CD99  
     
  Cytokeratine AE1-AE3   Cytokeratin AE1-AE3  
     
  MIB-1   MIB-1  
 

Diagnostic proposé

 

 

 

 

 

 

 

Tumeur de la granulosa de l'adulte, sarcomatoïde.

 

Proposed diagnosis

 

 

 

 

 

 

 

Sarcomatoïd, Granulosa cell tumour, adult type.

 
  Arguments   Clues  
     
         
 

Granulosa cell tumor (Rosai and Ackerman's Surgical Pathology, 10th Edition)

 
  Granulosa cell tumor is a sex cord–stromal ovarian neoplasm showing differentiation toward follicular granulosa cells. Whether it actually arises from granulosa cells in preexisting follicles or from the specialized ovarian stroma is debatable. Two distinct types exist, known respectively as adult and juvenile  
 

Adult granulosa cell tumor is usually diagnosed during child-bearing age, but it can occur after menopause and sometimes (despite its name) even before puberty. Three-fourths of cases are associated with hyperestrinism; the excessive production of estrogens can lead to isosexual precocious puberty in children and to metrorrhagia in adults, including postmenopausal patients. Some of the cases are hormonally inactive at the clinical level, and a very few are androgenic.

 
 

Grossly, adult granulosa cell tumors have a smooth, lobulated outline and a predominantly solid cut surface. The color is usually gray, but it may be yellow in areas of luteinization. Cysts filled with straw-colored or mucoid fluid may be present. Sometimes the cysts are so prominent as to simulate grossly the appearance of a cystadenoma. Interestingly, a disproportionate number of androgenic granulosa cell tumors are large and cystic, either unilocular or multilocular.

 
 

The microscopic appearance of granulosa cell tumors is extremely variable, even within the same neoplasm. Patterns of growth include microfollicular (with Call–Exner bodies), macrofollicular, trabecular, insular, watered-silk, solid, pseudopapillary, and diffuse (sarcomatoid). A theca cell component may also be present. Focal luteinization of either the granulosa or the theca cell component may occur; it is particularly prominent in those tumors associated with pregnancy, together with edema and disorderly arrangement. An important diagnostic feature is the presence of folds or grooves in the nuclei, resulting in a ‘coffee-bean’ appearance. Occasionally, bizarre nuclei and multinucleated giant cells (some of the ‘floret’ type) are seen; this change is not a sign of malignancy but rather of a degenerative nature. Cases of granulosa cell tumor have been reported exhibiting hepatocytic differentiation and others associated with mucinous cystadenoma.

 
  Traditionally, secretion of steroid hormones has been related to theca cells rather than granulosa cells, both in normal follicles and tumors; however, immunohistochemical studies have shown steroid production in both cell types, with a predominance of estradiol in the granulosa cells and progesterone in luteinized theca cells. Other consistent immunohistochemical markers of granulosa cell tumors include vimentin, desmoplakin (desmosomal plaque protein), inhibin, calretinin, follicle regulatory proteins, A103, and SF-1. Keratin is present in one-third to one-half of cases; it has a typical dot-like distribution and consists mainly of CK8 and CK18 types. Smooth muscle actin is seen in nearly all cases, but desmin less commonly so. Approximately 50% of cases are reactive for S-100 protein, whereas none is immunoreactive for EMA. Estrogen and progesterone receptors are frequently expressed. The peptide hormone inhibin and follicle regulatory proteins, two substances normally produced by ovarian granulosa cells, have been found to be elevated in the serum of patients with granulosa cell tumor. Curiously, granulosa cell tumors have also been found to be often immunoreactive for CD99 (O13; MIC2), a marker associated with Ewing sarcoma/PNET.  
 

Ultrastructurally, the neoplastic granulosa cells have abundant intermediate filaments and specialized cell junctions, some of the latter having the appearance of typical desmosomes. Cytogenetically, there is consistent trisomy for chromosome 12. Strangely, in some cases with bizarre nuclei, the only foci showing trisomy 12 by FISH are those in which the bizarre nuclei are present. Other recurrent karyotypic aberrations of this tumor are trisomy 14 and monosomy 22. Recently, it has been shown that almost all cases of adult granulosa cell tumor show somatic mutation in the FOXL2 gene (402C→G). Flow cytometry studies have shown that the large majority of adult granulosa cell tumors are diploid or near-diploid; evidence that DNA ploidy analysis has independent prognostic value remains controversial.

 
 

Juvenile granulosa cell tumor is diagnosed in nearly 80% of cases during the first two decades of life, most patients presenting with isosexual precocity. A few cases have been associated with enchondromatosis (Ollier disease) or Maffucci syndrome. Typical morphologic features of this subtype include diffuse or macrofollicular patterns of growth (the former predominating), mucin-positive intrafollicular secretion, larger tumor cells with extensive luteinization, paucity of nuclear grooves, presence of a thecal component, nuclear atypia, and variable but often high mitotic activity. Like their adult counterpart, they may exhibit pseudopapillary features. They also show consistent trisomy for chromosome 12.

 
 

DNA ploidy analysis has shown a greater percentage of aneuploidy in juvenile granulosa cell tumors than in the adult variety; however, the prognostic value of this determination still needs to be demonstrated.

 
  The differential diagnosis of granulosa cell tumor (particularly of the adult variety) includes poorly differentiated (predominantly solid) carcinoma of surface epithelial origin, carcinoid tumor, and the very rare tumors of endometrial stromal type. The nuclear features are of crucial importance in this regard. Some early series describing a poor prognosis for granulosa cell tumors are probably contaminated with solid ovarian carcinomas of surface origin. Strong and widespread positivity for keratin should point toward the direction of carcinoma in a controversial case, especially if this positivity is diffuse cytoplasmic rather than dot-like. The differential diagnosis also includes the ovarian granulosa cell proliferations of pregnancy; this change is usually microscopic, multiple, and associated with atretic follicles.  
 

The prognosis of granulosa cell tumors is largely dependent on the clinical staging. It also depends on size, tumor rupture, and presence of nuclear atypia. As a group, juvenile granulosa cell tumors behave more aggressively than their adult counterparts, and are more likely to produce distant metastases. The effect of the histologic pattern of the adult form on prognosis is not clearcut. Some authors have claimed that tumors with follicular or trabecular patterns have a better prognosis than those with a sarcomatoid pattern, but most studies have failed to demonstrate a convincing relationship. In the series of Norris and Taylor, 12 of 187 patients had persistent tumor after surgery, and 10 died as a result. Most deaths occurred more than 5 years after the original diagnosis and treatment, indicating that 5-year survival figures are not accurate predictors of permanent cure. The granulosa cell origin of a metastatic tumor should be suspected in the presence of a combination of microcystic and trabecular formations, especially if accompanied by Call–Exner bodies and grooved nuclei. Obviously, it is also essential to consider the possibility; otherwise one is likely to confuse it with a transitional cell carcinoma or something else.