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Case report

  1. Top of page
  2. Case report
  3. Discussion
  4. References

A 29 year old woman attended at our clinic complaining of secondary amenorrhoea. She was found to have an androgenic adult granulosa cell tumour without androgenic manifestations. Signs of virilisation (increased facial or abdominal hair, hirsutism or clitoromegaly) were absent. Concentrations of luteinising hormone, follicle stimulating hormone, prolactin, dehydroepiandesterone sulphate, dehydroepiandesterone and cortisol were all within their reference ranges. The patient was initially treated with clomiphene citrate to induce menstruation; however, when she did not respond, she was treated with monophasic oral contraceptive pills. The amenorrhoea persisted for the next three months; a pelvic ultrasound scan revealed a right adnexal mass measuring 7.5 × 6.4 × 4.8 cm, with cystic and solid components. Her plasma testosterone was elevated to 192 ng/dL (normal range: 10–85 ng/dL); however, her plasma oestradiol was within normal limits at 41 pg/mL (normal range: 12–49 pg/mL). Her activated partial thromboplastin time (APTT) was 76.1 s (normal range: 29.7–47.4 s). Her prothrombin time, clotting factors VIII, IX, XI, XII, fibrinogen, lupus anticoagulant, glycoprotein 1 complex anti-cardiolipin β2 and tests of fibrinolysis were normal. Plasma factor VIII procoagulant activities and plasma factor IX procoagulant activities were normal. The mixing test using 25%, 50%, and 75% normal pooled plasma did not completely correct the elevated APTT (56, 45.5 and 37 s). The possibility of a mild coagulation factor inhibitor was considered; however, she did not exhibit thrombotic or haemorrhagic phenomena.

The woman underwent a wedge resection of the left ovary and right salpingo-oophorectomy. The right ovarian tumour measured 7.0 cm in its greatest diameter. No other gross evidence of disease was noted. Microscopic examination of the right ovarian tumour revealed the typical features of an adult granulosa cell tumour. It was composed of thin, fibrous septa separating sheets of small cells containing nuclei with prominent grooving. Occasional Call–Exner bodies were present (Fig. 1). The granulosa cells in the tumour were strongly positive for testosterone (Fig. 2). Peritoneal washings were negative for tumour cells. On the first post-operative day, the APTT was in the normal range. On the 12th post-operative day, her plasma testosterone was in the normal range. Six months post-operatively, normal menstruation resumed. There was no evidence of recurrent disease.

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Figure 1. Thin, fibrous septa separating sheets of small cells containing nuclei with (A) prominent grooving and (B) occasional tubular pattern is observed.

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image

Figure 2. Immunostaining of (A) tumour cells and (B) testis as a control for testosterone. Both the tumour and the testis showed positive immunostaining for testosterone within the cytoplasm of numerous cells. Immunostaining was performed with rabbit anti-testosterone antibody (5 μg/ml Nichirei, Tokyo, Japan) using the catalyzed signal amplification (CSA System, Dako).

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To our knowledge, this is the first case report of an androgenic adult granulosa cell tumour presenting with a coagulation factor inhibitor.

Discussion

  1. Top of page
  2. Case report
  3. Discussion
  4. References

Granulosa cell tumours typically produce oestrogen; however, in rare instances, they produce androgen. The clinical manifestations of excess androgen possibility of a granulosa cell tumours. Although our patient was not clinically virilised, the pre-operatively elevated plasma testosterone levels together with their return to normal following the removal of the ovarian tumour support the notion that the granulosa cell tumour produced high levels of testosterone. Furthermore, immunohistochemical examination of the granulosa cells revealed the presence of testosterone. Based on the two-cell hypothesis of oestradiol production, granulosa cells produce oestradiol if the precursor testosterone is secreted by adjacent theca cells. However, in androgenic granulosa cell tumours, few theca cells are present and it has been suggested that the granulosa cells lack aromatase activity to varying degrees. It has been reported that amenorrhoea is the result of suppression of gonadotrophins by the high levels of testosterone1. However, in our case, basal luteinising and follicle stimulating hormone concentrations were in the normal range. Therefore, it can be suggested that high plasma testosterone concentration induced atresia of the follicles in both ovaries and resulted in secondary amenorrhoea2.

Although menstrual irregularities are often associated with granulosa cell tumours, APTT prolongation has not been described with this condition. The elevated APTT suggests that there is an inhibitor to an APTT-based clotting factor, such as factor VIII, IX, XI and XII, in plasma. The mixing test is the best method to determine whether a clotting factor deficiency exists or whether there is an interfering substance in the plasma for which there is incomplete correction. If the mixing test shows incomplete, minimal, moderate or no correction of the clotting time, then an inhibitor to an APTT-based clotting factor must be present3. In our case, the mixing test resulted in partial correction; thus an inhibitor must have been present in the plasma.

Factor VIII inhibitors have been previously described in patients with lung cancer, liver cancer, prostate cancer and leukaemia4–7. Furthermore, factor IX, XI and XII inhibitors have been reported in colon cancer, chronic lymphocytic leukaemia, and gastric cancer, respectively8–10. However, in our case, factor VIII, IX, XI and XII activities were within the normal range. This finding raises the possibility of an unknown inhibitor affecting the APTT. The woman in our case report was not given any medication such as prednisolone pre- or post-operatively. This indicates that the APTT returned to normal because of the removal of the granulosa cell tumour, and that granulosa cell tumours might produce an APTT inhibitor.

Our patient did not exhibit thrombotic or haemorrhagic abnormalities; thus, patients with a coagulation factor inhibitor without thrombotic or haemorrhagic complications probably do not need any pre-operative correction of the APTT. Furthermore, women who have secondary amenorrhea and an ovarian tumour without virilisation should have plasma testosterone measured. In our case, surgical removal of the ovarian tumour led to rapid reversal of the abnormal APTT and the hormonal abnormality. We are unaware of any other cases with these findings.

References

  1. Top of page
  2. Case report
  3. Discussion
  4. References
  • 1
    Hatjis CG, Polon JI, Wheeler JE, Hayes JM. Amenorrhea–garactorrhea associated with a testosterone-producing, solid granulosa cell tumor. Am J Obstet Gynecol 1978;131: 226.
  • 2
    Louvet JP, Harman SM, Schreiber JR, Ross GT. Evidence for a role of androgens in follicular maturation. Endocrinology 1975;97: 366.
  • 3
    Sahud MA. Factor VIII inhibitor. Laboratory diagnosis of inhibitors. Semin Thromb Hemost 2000;26(2):195203.
  • 4
    Shwaiki A, Lara L, Ahmed F, Crock R, Rutecki GW, Whittier FC. Acquired inhibitor to factor VIII in small cell lung cancer: a case report and review of the literature. Ann Hematol 2001;80(2):124126 December 21.
  • 5
    Kiguchi T, Niiya K, Yamawaki Y, Shima M, Harada M. Development of factor VIII inhibitor in three non-hemophiliac patients. Rinsho Ketsueki 2000;41(11):11951200.
  • 6
    Orth T, Schnutgen M, Herr W, et al. Prostate carcinoma associated spontaneous factor VIII: C inhibitor hemophilia. Successful therapy of severe hemorrhagic complication with porcine factor VIII in a 75-year-old patient. Med Klin 1997;92(4):241245.
  • 7
    Mateo J, Martino R, Borrell M, Gari M, Casas F, Fontcuberta J. Acquired factor VIII inhibitor preceding chronic lymphocytic leukemia. Am Hematol 1993;67(6):309311.
  • 8
    Collins HW, Gonzales MF. Acquired factor IX inhibitor in a patient with adenocarcinoma of the colon. Acta Haematol 1984;71(1):4952.
  • 9
    Goodrick MJ, Prentice AG, Copplestone JA, Pamphilon DH, Boon RJ. Acquired factor XI inhibitor in chronic lymphocytic leukaemia. J Clin Pathol 1992;45(4):352353.
  • 10
    Chalkiadakis G, Kyriakou D, Oekonomaki E, et al. Acquired inhibitors to the coagulation factor XII associated with liver disease. Am J Gastroenterol 1999;94(9):25512553.
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