Transformation in recurrent ovarian granulosa cell tumors: Ki67 (MIB-1) and p53 immunohistochemistry demonstrates a possible molecular basis for the poor histopathologic prediction of clinical behavior

doi:10.1016/S0046-8177(96)90069-6

Human Pathology

Volume 27, Issue 3, March 1996, Pages 274-281

https://doi.org/10.1016/S0046-8177(96)90069-6 Get rights and content

Abstract

Ovarian granulosa cell tumors (GCTs) behave unpredictably. Stage I patients suffer recurrences many years after treatment, and histopathologic evaluation of the primary GCT offers only a few clues. Grading, in particular, is largely ineffective. Ki67 (MIB-1) and p53 monoclonal antibodies (active on paraffin embedded tissues) provide insight into nuclear proliferation and control, respectively. In this study, the authors hypothesized that these molecular markers will help predict the clinical behavior of GCTs. Paraffin sections from 68 GCTs (arising in 56 patients: 53 primary and 15 recurrent) including 34 typical and 27 diffuse adult, and seven juvenile types were immunostained for Ki67 (MIB-1 clone; Immunotech, Westbrook, ME) and p53 (D07 clone; Novacastra Laboratories, UK). The Ki67 proliferation index (Ki67PI = percentage immunoreactive on a count of at least 400 nuclei) ranges from 1 to 50% (mean, = 12.2%; median, 9.3%). Nineteen percent of GCTs exhibited focal p53 immunoreactivity; the number of GCTs and proportion of nuclei decorated were as follows: four, <1%; seven, 1% to 10%; and one, 20%. Ki67PI was higher in recurrent tumors (P < .001) and correlated with mitotic rate (r = .75; P < .0001). p53 staining was associated with juvenile type GCTs (P < .001) and higher Ki67PI (P < .005). Other histopathologic features exhibited no association with p53 staining or Ki67PI. Follow-up was available for 54 of 56 patients: 18 suffered recurrences after 16 to 229 months (mean, 72.1 months; median, 59 months), and 36 were disease free 16 to 369 months (mean, 78.2 months; median, 70 months) after diagnosis. Curiously, high Ki67PI and mitotic rates of the primary GCT correlated weakly with a disease-free course (P = .03 and .07, respectively). Disease recurrence was associated with stage > I (P < .0005), vessel invasion in the capsule (P < .001), ruptured tumors (P < .005), and older patients (P < .02). p53 staining and size or subtype of GCT exhibited no prognostic value. For 12 patients, paired primary and first recurrence of GCT showed a striking increase in Ki67PI (P < .00005) and mitotic activity (P < .02) in the recurrence. p53 expression also appeared (de novo) in two recurrent GCTs. The interpretation of focal p53 staining (>10% nuclei decorated in only one GCT) is controversial. Some investigators suggest that this represents overexpression of wild type p53 rather than p53 gene mutation. Primary GCTs exhibit a wide spectrum of proliferative activity, and the seven juvenile GCTs (the most proliferative type) demonstrated no recurrences in this study. Recurrent GCTs displayed a transformation of molecular markers to increased proliferative activity and overexpression of p53, fundamentally, by these markers, a different GCT than the primary one. These findings suggest a molecular basis for the lack of histopathologic predictors for recurrence. Factors other than proliferation of the primary GCT (which relates most closely to grading) either extrinsic to the neoplasm (host dependent) or as yet undetectable must determine malignant behavior.

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Cited by (59)

Recurrence of adult granulosa cell tumor of the ovary: Experience at a tertiary care center
2014, Annals of Diagnostic Pathology
Citation Excerpt :
Since stage I tumors do not receive and higher stage tumors receive adjuvant therapy, which compensates the survival. Tumor capsule rupture has been associated with recurrence risk [8]. Two recurrent tumors in our series had capsule rupture at diagnosis, but the other six recurrent tumors had intact capsule.
Adult granulosa cell tumor (AGCT) is the most common ovarian sex cord stromal tumor with a favorable prognosis. However, a subset of patients develop recurrence. We retrieved and reviewed 156 cases of AGCT reported between 1992 and 2012. The ages ranged from 20 to 84 years (mean, 48 years). The size of the tumor ranged from 0.8 to 25 cm (mean, 10 cm). Histologically, all tumors were composed of round or polygonal cells with indented or grooved nuclei, eosinophilic cytoplasm, and well defined cell borders. A diffuse pattern was seen in the majority followed by microfollicular, trabecular and macrofollicular. The mitotic figures ranged from 2 to a maximum of 21/10 HPFs. Focal necrosis were seen in 17 cases. Associated simple hyperplasia of endometrium was seen in 9 cases, complex hyperplasia in 2, and endometrioid adenocarcinoma of the endometrium in 3 cases. Recurrence was seen in 8 cases with a follow-up of 2 to 19 years (mean, 6 years). The recurrent tumors were mostly >5 cm and sites included the same adnexal site and contralateral ovary, omentum, mesentery of small bowel, abdominal wall, uterine and fallopian tube serosa, lymph nodes, pelvis, and appendix. Histologically, recurrent tumors exhibited a diffuse histologic pattern and a mitotic count of 6.8 as compared to 3.3 in primary tumors. In conclusion, a tumor size of >5 cm and a diffuse histologic pattern were associated with increased recurrence risk. The recurrent tumors hadz increased mitotic figures compared with primary tumors. Appendix, a very rare site of recurrence was seen in one of our cases.
Surgical staging and adjuvant chemotherapy in the management of patients with adult granulosa cell tumors of the ovary
2012, Gynecologic Oncology
Citation Excerpt :
Of the nine patients with recurrence, eight had recurrence only in the peritoneal cavity. Although metastases to the liver, lungs, and bones can also occur [15], most recurrences are in the peritoneal cavity, suggesting that a majority of cases of recurrence in patients with stage I–II disease may be due to missed peritoneal disease during primary surgery. Upstaging due to microscopic extra-ovarian disease and recurrence due to occult disease has also been reported [16,17], with the spread pattern being primarily via the transperitoneal route, similar to findings in epithelial ovarian cancer [18].
To analyze the role of surgical staging and adjuvant chemotherapy in patients with adult type granulosa cell tumor (GCT) of the ovary.
Patients were divided into those with early-stage (stages I–II, n = 93) and advanced-stage (stages III–IV, n = 13) GCT and analyzed separately in this retrospective study.
Of the 93 patients with early-stage GCT, 30 were completely staged and 25 underwent lymph node dissection. After surgery, 17 patients received adjuvant chemotherapy with bleomycin/etoposide/cisplatin (BEP). None had lymph node metastasis. Completely staged patients had no recurrence or deaths. However, recurrences were observed in 9 of 63 patients (14.3%) who did not undergo complete staging, with four (6.3%) dying due to disease. The 5-year disease-free survival (DFS) rates of groups with and without complete staging were 100% and 84%, respectively (P = 0.037). Adjuvant chemotherapy was not significantly associated with DFS (P = 0.193). All patients with advanced-stage GCT underwent optimal cytoreduction and received adjuvant chemotherapy with BEP. None of the 6 patients who completed 6 cycles of BEP had recurrence, whereas 5 of the 7 patients (71.4%) who received fewer than 6 cycles of BEP had recurrences and 3 (42.9%) died due to disease. The 5-year DFS rates of these two groups were 100% and 50%, respectively (P = 0.022), with cycles of chemotherapy being the only significant factor for DFS in patients with advanced-stage GCT.
Complete surgical staging is recommended, but lymph node removal is not recommended for early-stage GCT. Optimal debulking followed by six cycles of BEP chemotherapy is recommended for advanced-stage GCT.
Juvenile granulosa-cell tumor: Clinical and molecular expression
2009, Gynecologie Obstetrique et Fertilite
Les tumeurs ovariennes des cordons sexuels sont des tumeurs rares qui se développent aux dépens des cellules non germinales de l’ovaire. Depuis deux décennies, l’individualisation des tumeurs juvéniles de la granulosa (TJG) a constitué une avancée majeure dans le traitement de ces tumeurs de l’enfant. Cependant, leur histoire naturelle n’est rapportée au sein de la littérature qu’à travers de courtes séries et des facteurs pronostiques fiables sont à établir. Nous rapportons ici une revue des aspects cliniques et génétiques des tumeurs de la granulosa de l’enfant, à travers une étude nationale de 40 observations réalisée en collaboration avec la Société française des cancers de l’enfant (SFCE) et huit centres d’endocrinologie pédiatrique français. Nous montrons notamment que la précocité du diagnostic devant des signes d’hyperestrogénie est un facteur pronostique important. De plus, la physiopathologie de ces tumeurs reste indéterminée et plusieurs altérations cellulaires et moléculaires pourraient être impliquées dans le développement des TJG. Le rôle des facteurs de croissance et d’oncogènes à travers la voie de signalisation de la MAP-kinase est discuté. En revanche, la prolifération des cellules de la granulosa pourrait être induite par la FSH ou une protéine, Gαs, constitutionnellement activée. Enfin, nous rapportons une anomalie d’expression des gènes de la détermination gonadique au sein de ces tumeurs, en particulier une diminution de l’expression de FOXL2 dans les tumeurs de mauvais pronostic.
Ovarian sex cord-stromal tumors are rare tumors that originate from the nongerminal cells of ovary. Two decades ago, the identification of juvenile granulosa-cell tumors (GCT), as a specific entity inside this group, allowed a better treatment of these tumors in children. However, little data have been reported on the natural course of the disease and reliable prognostic factors have not been yet defined. We here review the clinical and genetics aspects of granulosa tumors, based on a series of 40 children. This national collaborative study involved the French Society of Children Cancer and eight clinical departments of pediatric endocrinology. We found that early diagnosis of a tumor, revealed by clinical signs of hyperoestrogeny, is an important prognostic factor. The pathophysiology of these tumors is still debatable and several cellular- and molecular-abnormal signals could be implicated in their development. The role of growth factors and oncogenes through the signaling pathway of MAP kinase is still discussed. According to our data, FSH signaling-transduction pathway, such as a constitutionally activated Gαs, could also be implicated in the induction of granulosa cell proliferation and seems to modulate the invasiveness of the tumor. Last, we have described a low-expression pattern or an extinction of an ovarian-determination gene, FOXL2, which is related to a worse prognosis of this tumor.
Granulosa cell tumor of the ovary
2008, Cancer Treatment Reviews
Citation Excerpt :
Management of recurrence should involve aggressive debulking surgery followed by combination chemotherapy. Most recurrences are present in the peritoneal cavity, although liver, lung and skeletal metastases can occur.2,73 Given the long natural history of GCTs, repeated surgical debulking, depending on age, performance status and resectability of the disease, as a useful method of both symptom control and prolonging survival has been used.1,16,19,73
Ovarian granulosa cell tumors (GCTs) are uncommon neoplasms that arise from the sex-cord stromal cells of the ovary. GCTs are characterized by long natural history and their tendency to recur years after the initial diagnosis. They present with symptoms and signs due to estradiol secretion, including vaginal bleeding and precocious puberty. Occasionally, tumor rupture causes abdominal pain and hemoperitoneum. GCT is usually associated with a mass on pelvic examination which is subsequently confirmed with imagine techniques. Surgery is the mainstay of initial management for histological diagnosis, appropriate staging and debulking surgery. In patients with stage I disease and those in reproductive age a more conservative unilateral salpingo-oophorectomy is indicated. In postmenopausal women and those with more advanced disease a total abdominal hysterectomy with bilateral salpingo-oophorectomy is the appropriate surgical treatment. The most important prognostic factor associated with a higher risk of relapse is the stage of disease. The role of post-operative chemo- or radiotherapy in stage I disease and those with completely resected tumor has not been defined. Nevertheless, the use of adjuvant chemotherapy or radiotherapy has sometimes been associated with prolonged disease-free survival and possibly overall survival. Chemotherapy should be considered for patients with advanced, recurrent or metastatic disease and the BEP (bleomycin, etoposide, cisplatin) is the currently preferable regimen. Although overall response rate (RR) is high, the impact on disease-free or overall survival is unknown. Due to their tendency to recur years after the initial diagnosis, prolonged surveillance is essential.
Immunohistochemical markers of prognosis in adult granulosa cell tumors of the ovary – a review
2023, Journal of Ovarian Research
Can adjuvant chemotherapy improve the prognosis of adult ovarian granulosa cell tumors? A narrative review
2022, Medicine (United States)

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^☆: Presented in abstract form at the fall meeting of the American Society of Clinical Pathologists in New Orleans, LA, September 16–22, 1995.

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Original contributionTransformation in recurrent ovarian granulosa cell tumors: Ki67 (MIB-1) and p53 immunohistochemistry demonstrates a possible molecular basis for the poor histopathologic prediction of clinical behavior☆

Abstract

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Hum Pathol

Cell

Hum Pathol

Hum Pathol

Hum Pathol

Hum Pathol

Hum Pathol

Sex cord-stromal tumors of the ovary

J Pathol

Ovarian sex cord-stromal tumors: Recent progress

Int J Gynecol Pathol

Ovarian sex cord-stromal tumors: Problems in differential diagnosis

Pathol Annu

A clinicopathologic study of 92 cases of granulosa cell tumor or the ovary with special reference to the factors influencing prognosis

Cancer

Granulosa tumors of the ovary in children: A clinical and pathologic study of 32 cases

Am J Surg Pathol

Original contribution
Transformation in recurrent ovarian granulosa cell tumors: Ki67 (MIB-1) and p53 immunohistochemistry demonstrates a possible molecular basis for the poor histopathologic prediction of clinical behavior☆