Center for Reconstructive Pelvic Endosurgery, Reproductive Medicine Unit, S.Orsola Hospital, University of Bologna, Massarenti 13, 40138 Bologna, Italy
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Abstract |
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Key words: Gorlin syndrome/ovarian fibromas/recurrence/surgical treatment
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Introduction |
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Recent studies have demonstrated that NBCC is caused by mutation in the human homologue of Drosophila patched (PTC) gene (Hahn et al., 1996), which is a strong candidate as a gatekeeper (tumour suppressor) gene. PTC contains 6.5 kb of transcribed sequence dispersed over 35 kb of genomic DNA. Of the mutations that have been identified in NBCC patients, the great majority are premature stop mutations of frameshift mutations scattered throughout the coding sequence.
Diagnostic studies can be performed by an indirect method, linkage analysis, if a family contains more that one affected individual. If there is only one affected family member or the diagnosis is in doubt, direct mutation detection can be done. This technique includes PCR amplification of 22 exons encompassing the coding region with flaking regions containing intronexon junctions. The PCR products are screened for mutations by SSCP analysis and SSCP variants are directly sequenced. If no variants are detected, the entire coding sequence with intronexon junctions is directly sequenced.
Where there is a family history of Gorlin syndrome it is possible to carry out genetic analysis of individual family members to see who is carrying the defective gene and who is not. It is also possible to perform this test prenatally by choriocentesis, but only after 1012 weeks gestation.
Unlike the DNA studies, prenatal ultrasonography today provides both diagnostic and prognostic information. Indeed a prenatal ultrasound scan can identify at 19 weeks gestation CNS malformations, rib anomalies, vertebral anomalies and intracardiac tumours; these manifestations determine the severity of the condition better than DNA analysis (Petrikovsky et al., 1996).
The syndrome is associated with a spectrum of developmental anomalies and a predisposition to a range of neoplasms (Gorlin, 1987). The main manifestations are basal cell carcinomas, keratocistis of the jaw, palmar/piantar pits, calcified dural folds, spine and rib anomalies, characteristic facie (Gorlin and Goltz, 1960
), and an increased frequency of tumours, particularly medulloblastomas (Hertzberg and Wiskemann, 1963), other CNS tumours such as meningiomas (Gorlin, 1987
), ovarian fibromas which are often bilateral (Clendenning, 1963) and cardiac fibromas (Coffin, 1992
).
There have only been two previous reports of recurrent ovarian fibromas in Gorlin syndrome in the gynaecological literature. The purpose of this case report is to describe an additional case identified in adolescence and to review the most appropriate surgical treatment.
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Case report |
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Following the diagnosis, other relatives were examined. Her 19 and 16 year old sisters showed no evidence of the syndrome; however her father and mother have suggestive, but not diagnostic signs of NBCC (thyroid adenoma and polydactyly).
She then developed a numerous basal cell nevoid, especially on the trunk. Physical examination documented that the circumference of the head was slightly enlarged with frontal bossing, scoliosis and palmar pits.
Previous magnetic resonance imaging had not shown signs of CNS tumours nor had X-ray studies shown lytic or blastic lesions of the skull, ribs, ankles, heels or feet.
In 1995 at the age of 17 years she developed more severe, frequent and prolonged menses but without any symptoms related to abdominal masses. Pelvic ultrasound showed several right and left adnexal masses with calcification bilaterally, and moderate peritoneal fluid in the pouch of Douglas. Pelvic resonance magnetic imaging documented bilateral solid masses measuring about 78 cm. The CA 125 plasma concentration was elevated (76 IU/ml; normal value <35 IU/ml), and the other tumoural markers were negative. She was referred to the Center for Reconstructive Pelvic Endosurgery of Bologna, to undergo conservative surgical treatment of the ovarian fibromas.
At laparoscopy, nine stony, hard, calcified ovarian masses (three masses of about 15 cm, four of about 8l0 cm and two of about 24 cm), which filled the entire pelvis, were found. No mesenteric cysts were seen. The uterus and the tubes appeared normal. A conservative resection of the ovaries was performed. The histopathological examination showed fibromas with scattered areas of mixoid calcification. The post-operative course was unremarkable. Regular menses returned but with increasing dysmenorrhoea.
In 1999 in the Department of Genetics, Yale University School of Medicine, the DNA analysis of the patient was tested by the PCR amplification. This technique identified the exact mutation involved in the syndrome: direct sequencing revealed a frameschift mutation in exon 16 of the patched gene (2582delG). This mutation is typical of NBCC.
A second surgical procedure was required in January 2000, because of a recurrence of several ovarian fibromas. Pelvic ultrasound showed a 5x5 cm left adnexal mass and a 6.5 cm right adnexal mass which appeared hypoechoic with numerous calcifications. Pelvic magnetic resonance imaging documented bilateral solid masses measuring about 5 cm and peritoneal fluid in the pouch of Douglas. The CA 125 and the other tumoural markers were negative. No symptoms related to the abdominal mass were present.
She was again referred to our centre to undergo surgical treatment. The patient wanted to preserve her childbearing potential and therefore we decided to perform conservative surgical treatment.
Laparoscopic surgery was initially performed and then modified into an abdominal minilaparotomy owing to the numerous large pelvic masses present. Bilateral multiple ovarian fibromas (eight in the right ovary between 28 cm and two in the left ovary between 12 cm) (Figure 1) were found and were conservatively resected, preserving both ovaries, leaving about 90% of tissue in the left and 70% in the right ovary. The uterus appeared to be of irregular aspect with four small fibromas (between 0.52 cm) which were excised; the oviducts were fibrosed. One peritoneal fibroma (0.5 cm) was removed. All the fibromas were similar in microscopic appearance to those removed in 1995. The patient made an excellent post-operative recovery.
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Discussion |
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However, a review of the literature has shown only five previously reported bilateral ovarian fibromas in premenarchal females (Johnson et al., 1986). Two of these cases occurred in children who were subsequently discovered to have NBCC (Raggio et al., 1983
; Johnson et al., 1986
). In both of these patients, the fibromas were the first sign of this syndrome to be discovered.
Ovarian fibromas are reported to be unilateral in 90% of the cases (Dockerty and Masson, 1944). Calcification in ovarian fibromas has been reported to occur rarely (Raggio et al., 1983
). Kraemer et al. (1984) have documented radiographical or pathological evidence of calcification especially in cases reported in premenarchal females. When present, calcification in ovarian fibromas should be considered as a cause of amorphous pelvic calcification in female patients. When they are bilateral, calcified, and nodular, the possibility of NBCC is suggested (Tytle and Rosin, 1984
). Because of their rarity, especially in prepubertal girls, ovarian fibromas should raise the diagnostic possibility of NBCC and should prompt a careful evaluation of the patient for abnormalities characteristic of the disease.
Most ovarian fibromas are asymptomatic (Kimonis et al., 1997) but when sufficiently large, they present with symptoms related to an abdominal mass; generally these symptoms are chronic and related to the gastrointestinal or genitourinary symptoms (Huffman et al., 1981
). Rarely, a patient may present with acute symptoms secondary to torsion of the fibroma, as has occurred in other studies (Raggio et al., 1983
; Johnson et al., 1986
; Howell et al., 1990
).
The decision to perform conservative surgery with preservation of ovarian function is problematic. Although ovarian malignancies have not been reported with this syndrome, Abel and Holtz have reported two ovarian fibrosarcomas in a review of 170 adolescents with ovarian tumours (Abel and Holtz, 1965). The recurrence of ovarian fibromas is uncommon (Raggio et al., 1983
): in reports we have reviewed the only recurrences occurring in two patients with Gorlin syndrome (Howell et al., 1990
). In the absence of gynaecological symptoms, it seems wisest to preserve ovarian function in young patients, as there is no reason to sacrifice childbearing capacity. Moreover, fertility does not appear to be affected in NBCC (Raggio et al., 1983
).
The management of this lesion should be the excision of the fibromas leaving only the normal appearing ovarian tissue. The risk of recurrence requires periodic follow-up (ultrasound pelvic evaluation).
The decision to perform bilateral oophorectomy and total hysterectomy should be made after considerable time and thought, in accordance with the request of patient and the severity of symptoms. In the literature, bilateral oophorectomy and total hysterectomy were performed only on one young woman (22 years) because of the severe gynaecological symptoms and her request for sterilization (Burket and Rauh, 1976).
In our case, we decided upon a conservative ovarian treatment, considering the young age of the patient, the absence of important gynaecological symptoms and her future plans to become pregnant.
However, genetic counselling should be offered because of the autosomal dominant inheritance pattern.
The recurrence of ovarian fibromas lead the young patient to undergo several surgical treatments with the risk, in the future, of losing ovarian function, resulting in early menopausal disease and infertility. In our centre (Fabbri et al., 1999) cryopreservation of ovarian tissue is performed for oncology patients: when they are in remission, fertility and/or steroidogenesis could, theoretically, be restored by autografting the thawed tissue at the orthotopic site or by growing enzymatically and/or mechanically isolated follicles to maturity in vitro. This method has been offered to this patient for the future because fecundity and steroidogenesis are preserved.
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Notes |
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References |
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Anderson, D.E., Taylor, W.B., Falls, H.F. et al. (1967) The nevoid basal cell carcinoma syndrome. Am. J. Hum. Genet., 19, 1222.[ISI][Medline]
Burket, R.L. and Rauh, J.L. (1976) Gorlin's syndrome: ovarian fibromas at adolescence. Obstet. Gynecol., 47, 43s46s.[Abstract]
Clendenning, W.E., Herdt, J.R., Block, J.B. et al. (1963) Ovarian fibromas and mesenteric cysts: their association with hereditary basal cell cancer of the skin. Am. J. Obstet. Gynecol., 87, 10081012.[ISI][Medline]
Coffin, C.M. (1992) Congenital cardiac fibroma associated with Gorlin syndrome. Pediatr. Pathol., 12, 255262.[ISI][Medline]
Dockerty, M.D. and Masson, J.C. (1944) Ovarian fibromas: a clinical and pathologic study of two hundred and eighty-three cases. Am. J. Obstet. Gynecol., 47, 741752.
Fabbri, R., Marsella, T., Diano, C. et al. (1999) Ovarian tissue cryopreservation for oncology patients. Abstract of the Seventh Biennial Meeting of the International Gynecologic Cancer Society, Rome, Italy, pp. 2630.
Farndon, P.A., Del Mastro, R.G., Evans, D.G.R. et al. (1992) Location for gene for Gorlin syndrome. Lancet, 339, 581582.[ISI][Medline]
Gorlin, R.J. (1987) Nevoid basal cell carcinoma syndrome. Medicine, 66, 98113.[ISI][Medline]
Gorlin, R.J. and Goltz, R.W. (1960) Multiple basal-cell epithelioma, jaw cysts and bifid ribs: a syndrome. N. Engl. J. Med., 262, 908912.[ISI]
Gorlin, R.J. and Sedano, H.O. (1971) The multiple basal cell carcinoma syndrome revisited. Birth defects. Original Article Series VII, 8, 140148.
Griffiths, C.T. and Parker, L. (1986) Cancer of the ovary. In Knap, R.C. and Berkowitz, T.S. (eds) Gynecologic oncology. Macmillan, New York, pp. 317376.
Hahn, H., Wicking, C., Zaphiropoulus, P.G. et al. (1996) Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell, 85, 841845.[ISI][Medline]
Hertzberg, J.J. and Wiskeman, A. (1963) Die fune phakomatose, basalzell naevus mit familarer belastung und medulloblastom. Dermatologica, 126, 106123.[ISI][Medline]
Howell, C.G., Devid, A.R., Donna, S.G. et al. (1990) Bilateral ovarian fibromas in children. J. Pediatr. Surg., 25, 690691.[ISI][Medline]
Huffman, J.W., Dewhurst, C.J. and Capraro, V.J (1981) The gynecology of childhood and adolescence, 2nd edn, Saunders, Philadelphia, pp. 277349.
Johnson, A.D., Hebert, A.A. and Esterly, N.B. (1986) Nevoid basal cell carcinoma syndrome: bilateral ovarian fibromas in a 3.5 year old girl. J. Am. Acad. Dermatol., 14, 371374.[ISI][Medline]
Kimonis, V.E., Goldstein, A.M., Pastakia, B. et al. (1997) Clinical manifestation in 105 persons with nevoid basal cell carcinoma syndrome. Am. J. Med. Gen., 69, 299308.[ISI][Medline]
Kraemer, B.B., Silva, E.G. and Sneige, N. (1984) Fibrosarcoma of ovary. A new component in the nevoid basal cell carcinoma syndrome. Am. J. Surg. Pathol., 8, 231236.[ISI][Medline]
Petrikovsky, B.M., Bialer, M.G., McLaughlin J.A. et al. (1996) J. Ultrasound. Med., 15, 493495.[ISI][Medline]
Raggio, M., Kaplan, A.L. and Harberg, J.F. (1983) Recurrent ovarian fibromas. Obstet. Gynecol., 61 (suppl.), 95s96s.[Medline]
Shanley, S., Ratcliffe, J., Hockey A. et al. (1994) Nevoid basal cell carcinoma syndrome: review of 118 affected individuals. Am. J. Med. Genet., 50, 282290.[ISI][Medline]
Strong, L.C. (1977) Theories of pathogenesis: mutation and cancer. In Mulvihill, J.J., Miller, R.V. and Fraumeni, J.R. Jr (eds) Genetics of human cancer. Raven Press, New York, pp. 401414.
Towne, B.H., Mahour, G.H., Woolley, M.M. et al. (1975) Ovarian cysts and tumors in infancy and childhood. J. Pediatr. Surg., 10, 311320.[ISI][Medline]
Tytle, T. and Rosin, D. (1984) Bilateral calcified ovarian fibromas. South Med. J., 77, 11781180.[ISI][Medline]
Wicking, C., Berkman, J., Wainwright, B. et al. (1994) Fine genetic mapping of the gene for nevoid basal cell carcinoma syndrome. Genomics, 22, 505511.[ISI][Medline]
Submitted on November 9, 2000; accepted on March 7, 2001.