- Email: [email protected]
neu expressed in nonepithelial ovarian malignancies?
Research
www. AJOG.org
ONCOLOGY
Is Her-2/neu expressed in nonepithelial ovarian malignancies? Joseph Menczer, MD; Letizia Schreiber, MD; Bernard Czernobilsky, MD; Esther Berger, PhD; Abraham Golan, MD, FRCOG; Tally Levy, MD OBJECTIVE: The objective of this study was to assess the expression
CONCLUSION: Our limited sample size does not allow a gen-
of Her-2/neu in nonepithelial ovarian malignancies.
eralized conclusion concerning the lack of Her-2/neu expression in nonepithelial ovarian malignancies, but it adds information with regard to the expression of this oncogene in these rare neoplasms and seems to indicate that it is not a frequent occurrence.
STUDY DESIGN: Formalin-fixed paraffin-embedded archival tissue
blocks of 20 unselected nonepithelial ovarian malignancies (12 granulosa cell tumors and 8 germ cell tumors) diagnosed between 1993 and 2005 were immunohistochemically stained for Her-2/neu. RESULTS: Immunohistochemical staining for Her-2/neu was not
present in any of these nonepithelial malignancies examined.
Key words: germ cell tumor, granulosa cell tumor, Her-2/neu
Cite this article as: Menczer J, Schreiber L, Czernobilsky B, et al. Is Her-2/neu expressed in nonepithelial ovarian malignancies? Am J Obstet Gynecol 2007; 196:79.e1-79.e4
T
he human oncogene Her-2/neu (cerbB-2) is located on chromosome 17, q21. It specifies a transmembrane receptor-like phosphoglycoprotein that is closely related to the epidermal growth factor (EGFr ;c-erbB-1) and is a tyrosine kinase growth factor receptor. This oncogene is abnormally expressed and/or amplified in several malignancies and in some cases may contribute to transformation and tumorigenesis. In breast adenocarcinoma amplification and/or overexpression is frequently present, correlates with survival and is a treatment target for the
From the Gynecologic Oncology Unit, Department of Obstetrics and Gynecology (Dr Menczer, Dr Golan, and Dr Golan) and Department of Pathology (Dr Schreiber and Dr Berger), E. Wolfson Medical Center, Holon, Israel, Tel Aviv University, Faculty of Medicine, Tel Aviv, Israel; and Patho-Lab Laboratories (Dr Czernobilsky), Nes-Ziona, Israel. Received March 23, 2006; revised June 5, 2006; accepted July 6, 2006. Reprints not available from the authors. The contribution of both first authors was equal. 0002-9378/$32.00 © 2007 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2006.07.050
monoclonal anti-her-2/neu antibody of He-2/neu, trastuzumab.1 Expression of Her-2/neu in epithelial ovarian malignancies has been widely studied, and the level of Her-2/neu overexpression of these tumors has been variably reported to range between 0% and about 30%.2–11 In contrast to breast carcinoma, the Her-2/neu clinical and prognostic importance is controversial. According to several4,7,8,10 but not all5,6 studies, overexpression in ovarian carcinoma is associated with poor prognosis. Nonepithelial ovarian malignant tumors comprise less than 10% of ovarian malignancies. Studies of Her-2/neu expression in these neoplasms are scarce. Whereas a trastuzumab trial in persistent or recurrent epithelial ovarian or primary peritoneal carcinoma has been disappointing,11 such treatment has not been tried in advanced or recurrent or nonresponding nonepithelial malignancies. The presence of Her-2/neu overexpression in some of these tumors could indicate that such trials are warranted in them as well. Our aim was to assess the expression of Her-2/neu in nonepithelial ovarian malignancies.
M ATERIAL AND M ETHODS Twenty formalin-fixed paraffin-embedded archival tissue blocks of unselected
nonepithelial ovarian malignancies (12 granulosa cell tumors and 8 germ cell tumors) diagnosed between 1993 and 2005 were immunohistochemically stained for Her-2/neu after institutional review board approval. Formalin-fixed hematoxylin-eosin stained 6 slides from the same blocks were newly prepared and reviewed by a certified pathologist (L.S.) to reconfirm the diagnosis. Clinical data were abstracted from medical files.
Immunohistochemical staining Additional 4 unstained slides were prepared from the formalin-fixed blocks of each case for Her-2/neu immunohistochemical staining. Immunohistochemical staining was performed using rabbit antihuman polyclonal antibody (Dako A/S, Glostrupe, Denmark) in a 1:150 dilution. Immunohistochemistry was performed by deparaffinization of slides in xylene and degraded alcohols. Immunoperoxidase stain was performed using the modified labeled streptavidin technique and run on an automated system (Ventana Autostainer Nexes, Tucson, AZ), using amino carbazole as chromogen. All sections were counterstained with Mayer’s hematoxylin. All the specimens were microscopically evaluated by counting 10 high-
JANUARY 2007 American Journal of Obstetrics & Gynecology
79.e1
Research
Oncology
www.AJOG.org
TABLE
Selected clinical data and the result of the immunohistochemical staining for Her-2/neu in patients with nonepithelial ovarian malignancies No.
Age
Presenting symptom
Marital status/P
Tumor type
Stage
Treatment
Status (mos)
Her-2/neu stain
Sex-cord tumors
................................................................................................................................................................................................................................................................................................................................................................................
1
59
Bleeding
M/1
GCT
I
TAH, BSO
NED (89)
Negative
2
50
Pain
W/1
GCT
I
BSO
LTFU
Negative
3
36
Bleeding
M/0
GCT primary
I
USO
AWD (63)
Negative
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
GCT recurrent
Negative
................................................................................................................................................................................................................................................................................................................................................................................
4
50
Bleeding
D/1
GCT
IA
TAH, BSO
NED (10)
Negative
5
10
Bleeding
S
GCT
I
USO
NED (8)
Negative
6
46
Pain
M/2
GCT
I
TAH, BSO
NED (138)
Negative
7
71
Incidental
W/3
GCT
I
Vag. Hyst, BSO
NED (8)
Negative
8
44
Pain
M/2
GCT
I
TAH, BSO
NED (129)
Negative
9
70
Bleeding
M/6
GCT
I
TAH, BSO
NED (191)
Negative
10
51
Bloating
M/3
GCT
I
LAH, BSO
NED (29)
Negative
11
41
Pain
S
GCT
IAG3
TAH, BSO
NED (17)
Negative
12
51
Bleeding
M/0
GCT
I
TAH, BSO
NED (4)
Negative
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
Germ cell tumors
................................................................................................................................................................................................................................................................................................................................................................................
13
15
Pain
S
Dysgerminoma
I
OSO,B EP
NED (6)
Negative
14
19
Unknown
S
Dysgerminoma
I
USO
LTFU
Negative
15
33
Bloating
M/0
Dysgerminoma
I
BSO, BEP
NED (94)
Negative
16
25
Incidental
S
Dysgerminoma
IC
USO, BEP
NED (26)
Negative
17
39
Pain
M/4
Mal. teratoma
I
TAH, BSO
NED (150)
Negative
18
25
Pain
S
Mal.teratoma
IAG1
USO
NED (36)
Negative
19
70
Pain
W/1
Mal.teratoma
III
TAH, BSO, BEP
DOD (11)
Negative
20
21
Pain
S
Mixed GT
I
USO, BEP
DOD (69)
Negative
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
AWD, alive with disease; BEP, bleomycin, etoposide, platin; BSO, bilateral salpingooophorectomy; DOD, died of disease; GCT, granulosa cell tumor; LAH, laparoscopic hysterectomy; LTFU, lost to follow-up; M, married; Mal., malignant; Mixed GT, mixed germ cell tumor; NED, no evidence of disease; P, parity; S, single; TAH, total abdominal hysterectomy; USO, unilateral salpingooophorectomy; Vag. Hyst, vaginal hysterectomy; W, widow.
power fields (⫻400) with a minimum of 1000 cells counted per slide. Sections of 2 archival breast carcinomas known to express Her-2/neu served as positive controls and showed a high staining score.
R ESULTS Selected clinical characteristics of the patients and the results of Her-2/neu immunostaining are presented in the Table. The most common presenting symptoms were irregular bleeding and abdominal pain. In 1 patient a granulosa cell tumor was incidentally diagnosed after vaginal surgery because of prolapse (no. 8). In another single nulliparous patient with a dysgerminoma (no. 15), the 79.e2
tumor was detected during routine sonography prior to termination of pregnancy. In 1 case (no. 3), the primary granulose cell tumor and the recurrence were stained. One patient (no. 5) had a juvenile granulosa cell tumor. Full surgical staging was performed only in 3 patients (no. 4, 11, and 18). In the other patients with tumors grossly confined to the ovary (apparent stage I), surgical staging was not performed either because the diagnosis was obtained after the initial surgical procedure or because of young age or marital status and nulliparity. Two patients died, 1 with advanced malignant teratoma (no. 19) and the other (no. 20) with a repeatedly recurrent mixed germ cell tumor, consist-
American Journal of Obstetrics & Gynecology JANUARY 2007
ing of endodermal sinus tumor and malignant teratoma that did not respond to multiple chemotherapy regimens. None of the granulosa cell tumors and the germ cell tumors examined expressed Her-2/neu as assessed by immunohistochemical staining. In the mixed germ cell tumor, both its elements did not stain.
C OMMENT Granulosa cell tumors comprise about 70% of the ovarian sex-cord stromal neoplasms and are considered of low malignant potential. However, the clinical course of tumors confined to the ovary is unpredictable. They all have a potential for aggressive behavior, and re-
Oncology
www.AJOG.org currences may occur in about 20% or more. Advanced-stage disease and recurrences carry a poor prognosis.12–15 Contradictory results have been obtained in the few previous studies dealing with Her-2/neu expression in granulosa cell tumors. Kusamura et al16 found Her2/neu expression in none of their 18 granulosa cell tumors, and Leibl et al17 found none in their 40 granulosa cell tumors. In contrast, King et al18 reported its presence in 31 of their 32 cases (97%) and Furger et al19 in 6 of their 12 cases (50%). In the study by King et al,18 Her2/neu expression had no prognostic significance. The discrepancies between the studies have been previously explained16,17 and attributed partly to differences in methodology and to the broad variability in the sensitivity of immunochemistry, depending on the different anti-Her-2/neu clones and their loss because of antigenic alterations caused by fixation procedures. The results of our series, namely the lack of Her-2/neu expression in granulosa cell tumors, are in line with those of Kusamura et al16 and Leibl et al.17 Ovarian germ cell tumors are the most chemosensitive ovarian neoplasms, and the great majority are curable by surgery, usually followed by adjuvant combined platin-based chemotherapy. However, some patients with advanced or recurrent disease fail to respond to chemotherapy.20,21 To the best of our knowledge Her-2/ neu expression has not been assessed in ovarian germ cell tumors. None of our germ cell tumors expressed Her-2/neu. In this context it should be mentioned that Her-2/neu expression has been assessed in testicular germ cell tumors. Soul et al22 found no overexpression in any of 22 primary testicular tumors of unspecified histological type. The authors, therefore, concluded that a clinical trial with trastuzumab in testicular germ cell tumors is not warranted. On the other hand, Mandoky et al23 examined the Her-2/neu receptor status of 28 primary testicular nonseminomatous tumors (7 pure teratomas and 21 mixed germ cell tumors containing teratomatous components) and found that 7 (25%) showed positivity. They found
overexpression of Her-2/neu in the teratomatous components of 5 mixed germ cell tumors, in 3 choriocarcinoma components of mixed germ cell tumors, and in 1 case in both of these components. No Her-2/neu overexpression was detected in other, less differentiated histological subtypes. Interestingly, a case of partial remission achieved with trastuzumab in a heavily pretreated cisplatin refractory patient with testicular embryonal cell carcinoma who overexpressed Her-2/ neu has been reported.24 The great majority of our patients were diagnosed at an early stage, and this may in part account for the lack of Her-2 staining. Given our limited sample size, it is questionable whether the lack of Her-2/neu expression in our series of nonepithelial ovarian malignancies allows a generalized conclusion. The present investigation of nonepithelial ovarian tumors is also unable to clarify the conflicting results of Her-2/neu expression in granulosa cell tumors. We do, however, feel that in view of the rarity of nonepithelial ovarian tumors, it adds information with regard to the expression of Her-2/neu in these malignancies and seems to indicate that it is not a frequent occurrence. The assessment of Her-2/neu expression in a larger series of these tumors seems warranted. REFERENCES 1. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783-92. 2. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244:707-12. 3. Peethambaran PP, Clibee WA, Lubiniecki G, et al. Her-2/neu expression in ovarian cancer: pre- and postexposure to platinum chemotherapy. Gynecol Oncol 2003;89:99-104. 4. Berchuck A, Kamel A, Whitaker R, et al. Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer Res 1990;50:4087-91. 5. Rubin SC, Finstad CL, Wong GY, Almadrones L, Plante M, Lloyd KO. Prognostic significance of HER-2/neu expression in advanced epithelial ovarian cancer: a multivariate analysis. Am J Obstet Gynecol 1993;168:162-9.
Research
6. Rubin SC, Finstad CL, Federici MG, Scheiner L, Lloyd KO, Hoskins WJ. Prevalence and significance of HER-2/neu expression in early epithelial ovarian cancer. Cancer 1994;73: 1456-9. 7. Hogdall EV, Christensen L, Kjaer SK, et al. Distribution of HER-2 overexpression in ovarian carcinoma tissue and its prognostic value in patients with ovarian carcinoma: from the Danish MALOVA Ovarian Cancer Study. Cancer 2003;98:66-73. 8. Camilleri-Broet S, Hardy-Bessard AC, Le Tourneau A, et al. GINECO Group. HER-2 overexpression is an independent marker of poor prognosis of advanced primary ovarian carcinoma: a multicenter study of the GINECO group. Ann Oncol 2004;15:104 –12. 9. Lee CH, Huntsman DG, Cheang MC, et al. Assessment of Her-1, Her-2, And Her-3 expression and Her-2 amplification in advanced stage ovarian carcinoma. Int J Gynecol Pathol 2005;24:147-52. 10. Verri E, Guglielmini P, Puntoni M, et al. HER2/neu oncoprotein overexpression in epithelial ovarian cancer: evaluation of its prevalence and prognostic significance. Clinical study. Oncology 2005;68:154-61. 11. Bookman MA, Darcy KM, Clarke-Pearson D, Boothby RA, Horowitz IR. Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group. J Clin Oncol 2003;21:283-90. 12. Stenwig JT, Hazekamp JT, Beecham JB. Granulosa cell tumors of the ovary. A clinicopathological study of 118 cases with longterm follow up. Gynecol Oncol 1979;7: 136-52. 13. Malmstrom H, Hogberg T, Risberg B, Simonsen E. Granulosa cell tumors of the ovary: prognostic factors and outcome. Gynecol Oncol 1994;52:50-5. 14. Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. J Clin Oncol 2003;21: 1180-9. 15. Stuart GC, Dawson LM. Update on granulosa cell tumours of the ovary. Curr Opin Obstet Gynecol.2003;15:33-7. 16. Kusamura S, Derchain S, Alvarenga M, Gomes CP, Syrjanen KJ, Andrade LA. Expression of p53, c-erbB-2, Ki-67, and CD34 in granulosa cell tumor of the ovary. Int J Gynecol Cancer 2003;13:450-7. 17. Leibl S, Bodo K, Gogg-Kammerer M, et al. Ovarian granulosa cell tumors frequently express EGFR (Her-1), Her-3, and Her-4: an immunohistochemical study. Gynecol Oncol 2006;101:18-23. 18. King LA, Okagaki T, Gallup DG, Twiggs LB, Messing MJ, Carson LF. Mitotic count, nuclear atypia, and immunohistochemical determination of Ki-67, c-myc, p21-ras,
JANUARY 2007 American Journal of Obstetrics & Gynecology
79.e3
Research
Oncology
c-erbB2, and p53 expression in granulosa cell tumors of the ovary: mitotic count and Ki-67 are indicators of poor prognosis. Gynecol Oncol 1996;61: 227-32. 19. Furger C, Fiddes RJ, Quinn DI, Bova RJ, Daly RJ, Sutherland RL. Granulosa cell tumors express erbB4 and are sensitive to the cytotoxic action of heregulin beta2/PE40. Cancer Res 1998;58:1773-8.
79.e4
www.AJOG.org 20. Gershenson DM. Management of early ovarian cancer: germ cell and sex cord stromal tumors. Gynecol Oncol 1994;55:S62-72. 21. Lu KH, Gershenson DM.Update on the management of ovarian germ cell tumors. J Reprod Med 2005;50:417–25. 22. Soule S, Baldridge L, Kirkpatrick K, Cheng L, Gilbert JL, Smith LR et al. HER-2/neu expression in germ cell tumours. J Clin Pathol 2002;55:656-8.
American Journal of Obstetrics & Gynecology JANUARY 2007
23. Mandoky L, Geczi L, Bodrogi I, Toth J, Bak M. Expression of HER-2/neu in testicular tumors. Anticancer Res 2003;23:3447-51. 24. Kollmannsberger C, Pressler H, Mayer F, Kanz L, Bokemeyer C. Cisplatin refractory, HER2/neu-expressing germ-cell cancer: induction of remission by the monoclonal antibody Trastuzumab. Ann Oncol 1999;10: 1393-4.
www. AJOG.org
ONCOLOGY
Is Her-2/neu expressed in nonepithelial ovarian malignancies? Joseph Menczer, MD; Letizia Schreiber, MD; Bernard Czernobilsky, MD; Esther Berger, PhD; Abraham Golan, MD, FRCOG; Tally Levy, MD OBJECTIVE: The objective of this study was to assess the expression
CONCLUSION: Our limited sample size does not allow a gen-
of Her-2/neu in nonepithelial ovarian malignancies.
eralized conclusion concerning the lack of Her-2/neu expression in nonepithelial ovarian malignancies, but it adds information with regard to the expression of this oncogene in these rare neoplasms and seems to indicate that it is not a frequent occurrence.
STUDY DESIGN: Formalin-fixed paraffin-embedded archival tissue
blocks of 20 unselected nonepithelial ovarian malignancies (12 granulosa cell tumors and 8 germ cell tumors) diagnosed between 1993 and 2005 were immunohistochemically stained for Her-2/neu. RESULTS: Immunohistochemical staining for Her-2/neu was not
present in any of these nonepithelial malignancies examined.
Key words: germ cell tumor, granulosa cell tumor, Her-2/neu
Cite this article as: Menczer J, Schreiber L, Czernobilsky B, et al. Is Her-2/neu expressed in nonepithelial ovarian malignancies? Am J Obstet Gynecol 2007; 196:79.e1-79.e4
T
he human oncogene Her-2/neu (cerbB-2) is located on chromosome 17, q21. It specifies a transmembrane receptor-like phosphoglycoprotein that is closely related to the epidermal growth factor (EGFr ;c-erbB-1) and is a tyrosine kinase growth factor receptor. This oncogene is abnormally expressed and/or amplified in several malignancies and in some cases may contribute to transformation and tumorigenesis. In breast adenocarcinoma amplification and/or overexpression is frequently present, correlates with survival and is a treatment target for the
From the Gynecologic Oncology Unit, Department of Obstetrics and Gynecology (Dr Menczer, Dr Golan, and Dr Golan) and Department of Pathology (Dr Schreiber and Dr Berger), E. Wolfson Medical Center, Holon, Israel, Tel Aviv University, Faculty of Medicine, Tel Aviv, Israel; and Patho-Lab Laboratories (Dr Czernobilsky), Nes-Ziona, Israel. Received March 23, 2006; revised June 5, 2006; accepted July 6, 2006. Reprints not available from the authors. The contribution of both first authors was equal. 0002-9378/$32.00 © 2007 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2006.07.050
monoclonal anti-her-2/neu antibody of He-2/neu, trastuzumab.1 Expression of Her-2/neu in epithelial ovarian malignancies has been widely studied, and the level of Her-2/neu overexpression of these tumors has been variably reported to range between 0% and about 30%.2–11 In contrast to breast carcinoma, the Her-2/neu clinical and prognostic importance is controversial. According to several4,7,8,10 but not all5,6 studies, overexpression in ovarian carcinoma is associated with poor prognosis. Nonepithelial ovarian malignant tumors comprise less than 10% of ovarian malignancies. Studies of Her-2/neu expression in these neoplasms are scarce. Whereas a trastuzumab trial in persistent or recurrent epithelial ovarian or primary peritoneal carcinoma has been disappointing,11 such treatment has not been tried in advanced or recurrent or nonresponding nonepithelial malignancies. The presence of Her-2/neu overexpression in some of these tumors could indicate that such trials are warranted in them as well. Our aim was to assess the expression of Her-2/neu in nonepithelial ovarian malignancies.
M ATERIAL AND M ETHODS Twenty formalin-fixed paraffin-embedded archival tissue blocks of unselected
nonepithelial ovarian malignancies (12 granulosa cell tumors and 8 germ cell tumors) diagnosed between 1993 and 2005 were immunohistochemically stained for Her-2/neu after institutional review board approval. Formalin-fixed hematoxylin-eosin stained 6 slides from the same blocks were newly prepared and reviewed by a certified pathologist (L.S.) to reconfirm the diagnosis. Clinical data were abstracted from medical files.
Immunohistochemical staining Additional 4 unstained slides were prepared from the formalin-fixed blocks of each case for Her-2/neu immunohistochemical staining. Immunohistochemical staining was performed using rabbit antihuman polyclonal antibody (Dako A/S, Glostrupe, Denmark) in a 1:150 dilution. Immunohistochemistry was performed by deparaffinization of slides in xylene and degraded alcohols. Immunoperoxidase stain was performed using the modified labeled streptavidin technique and run on an automated system (Ventana Autostainer Nexes, Tucson, AZ), using amino carbazole as chromogen. All sections were counterstained with Mayer’s hematoxylin. All the specimens were microscopically evaluated by counting 10 high-
JANUARY 2007 American Journal of Obstetrics & Gynecology
79.e1
Research
Oncology
www.AJOG.org
TABLE
Selected clinical data and the result of the immunohistochemical staining for Her-2/neu in patients with nonepithelial ovarian malignancies No.
Age
Presenting symptom
Marital status/P
Tumor type
Stage
Treatment
Status (mos)
Her-2/neu stain
Sex-cord tumors
................................................................................................................................................................................................................................................................................................................................................................................
1
59
Bleeding
M/1
GCT
I
TAH, BSO
NED (89)
Negative
2
50
Pain
W/1
GCT
I
BSO
LTFU
Negative
3
36
Bleeding
M/0
GCT primary
I
USO
AWD (63)
Negative
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
GCT recurrent
Negative
................................................................................................................................................................................................................................................................................................................................................................................
4
50
Bleeding
D/1
GCT
IA
TAH, BSO
NED (10)
Negative
5
10
Bleeding
S
GCT
I
USO
NED (8)
Negative
6
46
Pain
M/2
GCT
I
TAH, BSO
NED (138)
Negative
7
71
Incidental
W/3
GCT
I
Vag. Hyst, BSO
NED (8)
Negative
8
44
Pain
M/2
GCT
I
TAH, BSO
NED (129)
Negative
9
70
Bleeding
M/6
GCT
I
TAH, BSO
NED (191)
Negative
10
51
Bloating
M/3
GCT
I
LAH, BSO
NED (29)
Negative
11
41
Pain
S
GCT
IAG3
TAH, BSO
NED (17)
Negative
12
51
Bleeding
M/0
GCT
I
TAH, BSO
NED (4)
Negative
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
Germ cell tumors
................................................................................................................................................................................................................................................................................................................................................................................
13
15
Pain
S
Dysgerminoma
I
OSO,B EP
NED (6)
Negative
14
19
Unknown
S
Dysgerminoma
I
USO
LTFU
Negative
15
33
Bloating
M/0
Dysgerminoma
I
BSO, BEP
NED (94)
Negative
16
25
Incidental
S
Dysgerminoma
IC
USO, BEP
NED (26)
Negative
17
39
Pain
M/4
Mal. teratoma
I
TAH, BSO
NED (150)
Negative
18
25
Pain
S
Mal.teratoma
IAG1
USO
NED (36)
Negative
19
70
Pain
W/1
Mal.teratoma
III
TAH, BSO, BEP
DOD (11)
Negative
20
21
Pain
S
Mixed GT
I
USO, BEP
DOD (69)
Negative
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
AWD, alive with disease; BEP, bleomycin, etoposide, platin; BSO, bilateral salpingooophorectomy; DOD, died of disease; GCT, granulosa cell tumor; LAH, laparoscopic hysterectomy; LTFU, lost to follow-up; M, married; Mal., malignant; Mixed GT, mixed germ cell tumor; NED, no evidence of disease; P, parity; S, single; TAH, total abdominal hysterectomy; USO, unilateral salpingooophorectomy; Vag. Hyst, vaginal hysterectomy; W, widow.
power fields (⫻400) with a minimum of 1000 cells counted per slide. Sections of 2 archival breast carcinomas known to express Her-2/neu served as positive controls and showed a high staining score.
R ESULTS Selected clinical characteristics of the patients and the results of Her-2/neu immunostaining are presented in the Table. The most common presenting symptoms were irregular bleeding and abdominal pain. In 1 patient a granulosa cell tumor was incidentally diagnosed after vaginal surgery because of prolapse (no. 8). In another single nulliparous patient with a dysgerminoma (no. 15), the 79.e2
tumor was detected during routine sonography prior to termination of pregnancy. In 1 case (no. 3), the primary granulose cell tumor and the recurrence were stained. One patient (no. 5) had a juvenile granulosa cell tumor. Full surgical staging was performed only in 3 patients (no. 4, 11, and 18). In the other patients with tumors grossly confined to the ovary (apparent stage I), surgical staging was not performed either because the diagnosis was obtained after the initial surgical procedure or because of young age or marital status and nulliparity. Two patients died, 1 with advanced malignant teratoma (no. 19) and the other (no. 20) with a repeatedly recurrent mixed germ cell tumor, consist-
American Journal of Obstetrics & Gynecology JANUARY 2007
ing of endodermal sinus tumor and malignant teratoma that did not respond to multiple chemotherapy regimens. None of the granulosa cell tumors and the germ cell tumors examined expressed Her-2/neu as assessed by immunohistochemical staining. In the mixed germ cell tumor, both its elements did not stain.
C OMMENT Granulosa cell tumors comprise about 70% of the ovarian sex-cord stromal neoplasms and are considered of low malignant potential. However, the clinical course of tumors confined to the ovary is unpredictable. They all have a potential for aggressive behavior, and re-
Oncology
www.AJOG.org currences may occur in about 20% or more. Advanced-stage disease and recurrences carry a poor prognosis.12–15 Contradictory results have been obtained in the few previous studies dealing with Her-2/neu expression in granulosa cell tumors. Kusamura et al16 found Her2/neu expression in none of their 18 granulosa cell tumors, and Leibl et al17 found none in their 40 granulosa cell tumors. In contrast, King et al18 reported its presence in 31 of their 32 cases (97%) and Furger et al19 in 6 of their 12 cases (50%). In the study by King et al,18 Her2/neu expression had no prognostic significance. The discrepancies between the studies have been previously explained16,17 and attributed partly to differences in methodology and to the broad variability in the sensitivity of immunochemistry, depending on the different anti-Her-2/neu clones and their loss because of antigenic alterations caused by fixation procedures. The results of our series, namely the lack of Her-2/neu expression in granulosa cell tumors, are in line with those of Kusamura et al16 and Leibl et al.17 Ovarian germ cell tumors are the most chemosensitive ovarian neoplasms, and the great majority are curable by surgery, usually followed by adjuvant combined platin-based chemotherapy. However, some patients with advanced or recurrent disease fail to respond to chemotherapy.20,21 To the best of our knowledge Her-2/ neu expression has not been assessed in ovarian germ cell tumors. None of our germ cell tumors expressed Her-2/neu. In this context it should be mentioned that Her-2/neu expression has been assessed in testicular germ cell tumors. Soul et al22 found no overexpression in any of 22 primary testicular tumors of unspecified histological type. The authors, therefore, concluded that a clinical trial with trastuzumab in testicular germ cell tumors is not warranted. On the other hand, Mandoky et al23 examined the Her-2/neu receptor status of 28 primary testicular nonseminomatous tumors (7 pure teratomas and 21 mixed germ cell tumors containing teratomatous components) and found that 7 (25%) showed positivity. They found
overexpression of Her-2/neu in the teratomatous components of 5 mixed germ cell tumors, in 3 choriocarcinoma components of mixed germ cell tumors, and in 1 case in both of these components. No Her-2/neu overexpression was detected in other, less differentiated histological subtypes. Interestingly, a case of partial remission achieved with trastuzumab in a heavily pretreated cisplatin refractory patient with testicular embryonal cell carcinoma who overexpressed Her-2/ neu has been reported.24 The great majority of our patients were diagnosed at an early stage, and this may in part account for the lack of Her-2 staining. Given our limited sample size, it is questionable whether the lack of Her-2/neu expression in our series of nonepithelial ovarian malignancies allows a generalized conclusion. The present investigation of nonepithelial ovarian tumors is also unable to clarify the conflicting results of Her-2/neu expression in granulosa cell tumors. We do, however, feel that in view of the rarity of nonepithelial ovarian tumors, it adds information with regard to the expression of Her-2/neu in these malignancies and seems to indicate that it is not a frequent occurrence. The assessment of Her-2/neu expression in a larger series of these tumors seems warranted. REFERENCES 1. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783-92. 2. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244:707-12. 3. Peethambaran PP, Clibee WA, Lubiniecki G, et al. Her-2/neu expression in ovarian cancer: pre- and postexposure to platinum chemotherapy. Gynecol Oncol 2003;89:99-104. 4. Berchuck A, Kamel A, Whitaker R, et al. Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer Res 1990;50:4087-91. 5. Rubin SC, Finstad CL, Wong GY, Almadrones L, Plante M, Lloyd KO. Prognostic significance of HER-2/neu expression in advanced epithelial ovarian cancer: a multivariate analysis. Am J Obstet Gynecol 1993;168:162-9.
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6. Rubin SC, Finstad CL, Federici MG, Scheiner L, Lloyd KO, Hoskins WJ. Prevalence and significance of HER-2/neu expression in early epithelial ovarian cancer. Cancer 1994;73: 1456-9. 7. Hogdall EV, Christensen L, Kjaer SK, et al. Distribution of HER-2 overexpression in ovarian carcinoma tissue and its prognostic value in patients with ovarian carcinoma: from the Danish MALOVA Ovarian Cancer Study. Cancer 2003;98:66-73. 8. Camilleri-Broet S, Hardy-Bessard AC, Le Tourneau A, et al. GINECO Group. HER-2 overexpression is an independent marker of poor prognosis of advanced primary ovarian carcinoma: a multicenter study of the GINECO group. Ann Oncol 2004;15:104 –12. 9. Lee CH, Huntsman DG, Cheang MC, et al. Assessment of Her-1, Her-2, And Her-3 expression and Her-2 amplification in advanced stage ovarian carcinoma. Int J Gynecol Pathol 2005;24:147-52. 10. Verri E, Guglielmini P, Puntoni M, et al. HER2/neu oncoprotein overexpression in epithelial ovarian cancer: evaluation of its prevalence and prognostic significance. Clinical study. Oncology 2005;68:154-61. 11. Bookman MA, Darcy KM, Clarke-Pearson D, Boothby RA, Horowitz IR. Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group. J Clin Oncol 2003;21:283-90. 12. Stenwig JT, Hazekamp JT, Beecham JB. Granulosa cell tumors of the ovary. A clinicopathological study of 118 cases with longterm follow up. Gynecol Oncol 1979;7: 136-52. 13. Malmstrom H, Hogberg T, Risberg B, Simonsen E. Granulosa cell tumors of the ovary: prognostic factors and outcome. Gynecol Oncol 1994;52:50-5. 14. Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. J Clin Oncol 2003;21: 1180-9. 15. Stuart GC, Dawson LM. Update on granulosa cell tumours of the ovary. Curr Opin Obstet Gynecol.2003;15:33-7. 16. Kusamura S, Derchain S, Alvarenga M, Gomes CP, Syrjanen KJ, Andrade LA. Expression of p53, c-erbB-2, Ki-67, and CD34 in granulosa cell tumor of the ovary. Int J Gynecol Cancer 2003;13:450-7. 17. Leibl S, Bodo K, Gogg-Kammerer M, et al. Ovarian granulosa cell tumors frequently express EGFR (Her-1), Her-3, and Her-4: an immunohistochemical study. Gynecol Oncol 2006;101:18-23. 18. King LA, Okagaki T, Gallup DG, Twiggs LB, Messing MJ, Carson LF. Mitotic count, nuclear atypia, and immunohistochemical determination of Ki-67, c-myc, p21-ras,
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www.AJOG.org 20. Gershenson DM. Management of early ovarian cancer: germ cell and sex cord stromal tumors. Gynecol Oncol 1994;55:S62-72. 21. Lu KH, Gershenson DM.Update on the management of ovarian germ cell tumors. J Reprod Med 2005;50:417–25. 22. Soule S, Baldridge L, Kirkpatrick K, Cheng L, Gilbert JL, Smith LR et al. HER-2/neu expression in germ cell tumours. J Clin Pathol 2002;55:656-8.
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23. Mandoky L, Geczi L, Bodrogi I, Toth J, Bak M. Expression of HER-2/neu in testicular tumors. Anticancer Res 2003;23:3447-51. 24. Kollmannsberger C, Pressler H, Mayer F, Kanz L, Bokemeyer C. Cisplatin refractory, HER2/neu-expressing germ-cell cancer: induction of remission by the monoclonal antibody Trastuzumab. Ann Oncol 1999;10: 1393-4.