European Journal of (2004) 150 119–123 ISSN 0804-4643

CASE REPORT Precocious secondary to massive ovarian oedema in a 6-month-old girl Anuja Natarajan, Jeremy K H Wales, 1Sean S Marven and Neil P Wright Departments of Paediatric Endocrinology and 1Surgery, Sheffield Children’s Hospital, Western Bank, Sheffield S10 2TH, UK (Correspondence should be addressed to N P Wright; Email: [email protected])

Abstract A 6-month-old girl was referred with and development. Investigations excluded an adrenal or central cause for her precocity. Ovarian ultrasound scans showed bilaterally enlarged with both solid and cystic changes. A follow-up examination suggested progression of the precocity and in view of the young age of the child, and concerns regarding underlying malignancy, she underwent laparotomy. Histology showed no evidence of neoplasia but there was stromal oedema consistent with a diagnosis of massive ovarian oedema. This entity is poorly recognised in the paedia- tric literature as a cause of sexual precocity, and has never previously been described in such a young patient. This is an unusual cause of precocity in a young child and its recognition and management are reviewed.

European Journal of Endocrinology 150 119–123

Introduction (DHEAS) 0.8 mmol/l (normal ranges for a pre-pubertal child are testosterone ,0.5 nmol/l and DHEAS A 6-month-old girl was referred with a 3-month ,0.5 mmol/l). estimation by the Tanner– history of pubic hair and breast development. She was Whitehouse 2 method (2) was advanced by 6 months. a non-identical twin, born at 36 weeks’ gestation to Ultrasound scans of her ovaries showed bilaterally non-consanguineous Caucasian parents following an enlarged ovaries with cystic and solid components and uncomplicated pregnancy. There was no history of con- some follicles seen bilaterally (right 3.2 ml, left sumption of any hormonal preparations during preg- ovary 9 ml (Fig. 1A and B); normal ovarian volumes nancy. Her father, paternal grandfather and paternal up to 5 years of age vary between 0.75 and 0.85 ml great uncle suffered from multiple lipomas. Her twin (3–5)). The left ovary was described as having a more brother was healthy. As far as we can ascertain his solid central component than the right ovary. The testicular size and consistency was normal. Her birth uterine volume was 1.7 ml (normal pre-pubertal weight, length and head circumference plotted at the volume ,2 ml). Tumour markers were normal (alpha- 98th, 75th and 98th centile respectively compared fetoprotein 30 kU/l and beta-human chorionic gonado- with current UK standards (1). trophin ,2 U/l). Clinically she had Tanner stage 2 and pubic Follow-up examination 2 weeks later suggested hair development. There was no but her further progression of puberty with an increased labia were slightly rugose with a normal looking intro- breast volume and pubic hair but no change in clinical itus with thin red mucosa. No were palpable. staging. Her extremely young age, progression of physi- Chromosomes were normal (46XX). Gonadotrophins cal signs and concerns regarding underlying malig- were in the normal pre-pubertal range (serum luteinis- nancy prompted surgical referral and she underwent ing ,0.5 IU/l, serum follicle-stimulating hor- laparoscopy, which identified a degree of bilateral tor- mone 2.2 IU/l). Oestradiol was below the lower limit of sion, worse on the left side. She then underwent open our assay (,73 pmol/l). It is possible that oestrogen left oophorectomy. At operation both ovarian pedicles levels were higher than normal; certainly there was showed torsion, with preservation of the blood supply. clinical evidence of oestrogenisation, but not detected The right ovarian pedicle was un-twisted but it was because of the limitations of our assay. There was no evi- decided to defer right oophorectomy until histology dence of congenital adrenal hyperplasia or Cushing’s was available. Microscopic examination of the enlarged syndrome (17-hydroxyprogesterone ,1.6 nmol/l, ovary (3.5 £ 2.2 £ 1.2 cm, weight 5.1 g (normal values 0900 h cortisol 233 nmol/l, 0900 h adrenocorticotro- at birth are about 1.3 £ 0.5 £ 0.3 cm, weight ,0.3 g phin 25 ng/l). were elevated, with testoster- and in adults about 4 £ 2 £ 1 cm, weight 5–8 g) one 0.5 nmol/l and dehydroepiandrosterone sulphate showed pronounced stromal oedema with sections

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Figure 1 (A) Ultrasound scan of the enlarged right ovary with a volume of 3.2 ml. (B) Ultrasound scan of the much larger left ovary with a 9 ml volume and a more solid central component than the right ovary. (C) Ultrasound scan of the right ovary 6 months after treatment. The scan shows an ovarian volume of 1.3 ml and normal small follicles. showing normal numbers of oocytes and occasional occur in pregnancy (7, 8). It was initially described cystic follicles (Fig. 2A and B). There was no evidence by Gustafson et al. (9) in 1954, and characterised by of stromal luteinisation or neoplasia. The findings Kalstone et al.(10) in 1969. It is a rare ‘tumour-like’ were consistent with massive stromal oedema of the condition of the ovary and defined in the World ovary. In an attempt to prevent further progression of Health Organisation’s Histological Classification (11) her sexual maturation our patient subsequently under- as ‘An accumulation of oedema fluid within the ovarian went elective laparoscopic right oophoropexy and right stroma separating normal follicular structures. In some inguinal herniotomy. A year later she remains well with cases the stroma contains lutein cells and the patient is no further progression of her physical signs and a virilised’. reduction in her right ovarian swelling (ovarian It typically presents with abdominal pain and a volume 1.3 ml, Fig. 1C). Her hormone levels have pelvic/adnexal mass. Menstrual irregularities are pre- returned to normal (testosterone ,0.3 nmol/l, andros- sent in many of the post-pubertal women and resolve tenedione ,0.3 nmol/l and DHEAS ,0.8 mmol/l). after treatment. Virilisation occurs in about 25% of the cases (6). There have been few reported cases of Discussion or early puberty (12, 13). It has been associated with Meig’s syndrome and, in a single We describe the youngest patient reported in the case, with retroperitoneal and omental nodules of literature with massive ovarian oedema (MOO) as a fibroma-like proliferations (14). cause of precocious puberty. MOO is a rare but now The aetiology of this condition is thought to relate to well-recognised condition that occurs predominantly intermittent or partial torsion of the ovarian pedicle in adolescents and young women (5–33 years, with (8, 10, 15). One half of the cases show evidence of tor- a mean age of 21 years) (6). It has been reported to sion at surgery. Torsion results in venous and lymphatic

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Figure 2 (A) Microscopic section of the left ovary showing normal oocytes (thin arrows) alongside an area of pronounced stromal oedema (large arrow). (B) Section of the ovary showing massive stromal oedema. ( £ 40). obstruction, but not arterial occlusion so there is no evi- stromal hyperplasia result in an increase in ovarian dence of haemorrhage or infarction seen in the ovaries and oestrogen production, which is respon- of these patients (16). The resulting lymphoedema sible for the virilisation and pubertal signs seen in leads to proliferation of the stromal cells and in some some of the patients (17). For this reason de-torsion to conversion to lutein cells. This luteinisation and and pexy was performed in our patient, with subsequent

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Downloaded from Bioscientifica.com at 10/01/2021 01:52:27PM via free access 122 A Natarajan and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004) 150 remission of her clinical and biochemical abnormalities. girls and women of childbearing age. Ovarian tumours Alternatively it has been suggested that stromal prolifer- account for approximately 1% of childhood malignan- ation or stromal can occur with resultant cies (24). They are rare in early childhood with the ovarian enlargement (6). The enlarged ovary is sub- median age for most ovarian tumours being greater sequently more prone to undergo torsion and oedema. than 8 years (25, 26). Consideration should be given This hypothesis is supported by the fact that MOO has to pre-operative ovarian tumour markers and to also been described in a previously fixed ovary (18), frozen-section biopsy to help with intraoperative man- but would not account for the improvement seen in agement and pathological diagnosis. Traditionally this case. oophorectomy has been the commonest treatment for Fifteen per cent of cases are bilateral, 85% unilateral MOO (27, 28). Conservative management should be and 75% affect the right ovary (8). The predisposition considered in younger patients. Wedge resection to of the right ovary may be due to elevated right ovarian debulk the ovary followed by ovarian suspension may vein pressure relative to the left reducing the tolerance be more appropriate in young patients if the histology of the right ovary to partial torsion (8). Alternatively it on frozen section is suggestive of MOO rather than of may be because the sigmoid colon decreases mobility of malignancy. Because of our lack of awareness of this the left adenexae (19). condition and its possible reversibility our patient The definitive diagnosis of MOO cannot reliably be underwent oophorectomy. With hindsight we would made pre-operatively. Ultrasound (US) scanning and have adopted a more conservative approach with pres- magnetic resonance imaging (MRI) have both been ervation of the left ovary. reported to help in establishing the diagnosis. The sono- graphic findings are variable, but multiple ovarian fol- licles located in the peripheral cortex of an enlarged Conclusion ovary have been suggested as an important diagnostic indicator of MOO (20). There are only four reports in MOO is a rare but well-recognised ‘benign tumour-like’ the literature discussing the MRI findings in MOO. condition that is a potentially reversible cause of sexual Two report a heterogeneous low-intensity lesion on precocity. It has not previously been described in such a T1-weighted images (8, 21). The third reports multiple young girl. Increased awareness of this condition is non-enlarged follicular lesions located in the peripheral important to prevent unnecessary oophorectomy and ovarian regions detected using phase-array pelvic coil concomitant ovarian loss especially in young patients. MRI (22). The fourth case reports diffuse ovarian Laparoscopic assessment of the ovaries followed by enlargement with low intensity in T1-weighted frozen-section histology to rule out malignancy may images, with multiple follicles located peripherally in be helpful before proceeding to any form of definitive the enlarged ovary (23). The diameter of the enlarged surgery. ovaries has been reported to vary from 5 to 35 cm and averages 11 cm. Hence use of the term ‘massive’ may be somewhat misleading. Acknowledgements As no single test is diagnostic of MOO, we recommend that besides investigation of the pituitary–ovarian axis, The authors thank Prof. Michael Wells and Dr S Variend, US scanning of the ovaries with or without an MRI Department of Pathology, Royal Hallamshire Hospital (depending on the local facility), ovarian tumour and Sheffield Children’s Hospital respectively, for their markers (alpha-feto protein, beta-human chorionic gon- valuable advice on the histopathological report of our adotrophin, oestrogen, progesterone, androgens, thyrox- patient. ine) (24, 25) and laparoscopic assessment of the ovaries followed by frozen-section histology, be performed. Macroscopically the ovaries in MOO are typically References opaque and white, resembling those of an oedematous 1 Freeman JV, Cole TJ, Chinn S, Jones PRM, White EM & Preece MA. fibroma or Krukenberg tumour (6), but identification of Cross sectional stature and weight reference curves for the UK, cystic follicles and sometimes corpora lutea within the 1990. Archives of Disease in Childhood 1995 73 17–24. oedematous tissue strongly suggests the diagnosis of 2 Tanner JM, Whitehouse RH, Cameron N, Marshall WA, Healy MJR MOO. Microscopic examination reveals oedematous, & Goldstein H. Assessment of Skeletal Maturity and Prediction of hypocellular stroma in the central portion of the ovary Adult Height, edn 2. London: Academic Press, 1983. 3 Cohen HL, Tice HM & Mandel FS. Ovarian volumes measured by surrounding rather than displacing follicles and their US: bigger than we think. Radiology 1990 177 177–189. derivatives. The peripheral cortex is typically composed 4 Comstock CH & Boal DK. Pelvic sonography of the paediatric of dense collagenous tissue and does not participate in patient. Seminars in Ultrasound, CT, and MR 1984 5 54–67. the oedema (6). 5 Eisenberg P, Cohen HL & Mandel F. US analysis of premenarchal gynaecological structure [Abstract]. Journal of Ultrasound in Neoplasia is usually the principal concern when an 1991 10 30. ovarian mass is diagnosed. MOO should be considered 6 Young RH & Scully RE. Non-neoplastic disorders of the ovary. In in the differential diagnosis particularly in pre-pubertal Haines and Taylor Obstetrical and Gynaecological Pathology, edn 5,

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ch 17, pp 663–692. Eds H Fox & M Wells. Edinburgh: Churchill 20 Umesaki N, Tanaka T, Miyama M & Kawamura N. Sonographic Livingstone, 2002. characteristics of massive ovarian edema. Ultrasound in Obstetrics 7 Lambert B & Lessard M. Massive ovarian edema in a twin preg- and Gynecology 2000 16 479–481. nancy. Canadian Journal of Surgery 1987 30 40–41. 21 Lee AR, Kim KH, Lee BH & Chin SY. Massive edema of the ovary: 8 Hall BP, Printz DA & Roth J. Massive ovarian edema: ultrasound imaging findings. American Journal of Roentgenology 1993 161 and magnetic resonance characteristics. Journal of Computer 343–344. Assisted Tomography 1993 17 477–479. 22 Kramer LA, Lalani T & Kawashima A. Massive edema of the 9 Gustafon FW,Gardiner SH & Stout FE. Ovarian tumours complicat- ovary: high resolution MR findings using a phased-array pelvic ing pregnancy: a review of 45 surgically proved cases. American coil. Journal of Magnetic Resonance Imaging 1997 7 758–760. Journal of Obstetrics and Gynecology 1954 67 1210–1220. 23 Umesaki N, Tanaka T, Miyama M, Nishimura S, Kawamura N & 10 Kalstone CE, Jaffe RB & Abell MR. Massive edema of the ovary Ogita S. Successful preoperative diagnosis of massive ovarian simulating fibroma. Obstetrics and Gynecology 1969 34 564–571. edema aided by comparative imaging study using magnetic res- 11 Serov SF, Scully RE & Sobin LM. Histological Classification of onance and ultrasound. European Journal of Obstetrics, Gynecology, Tumours no. 9, p 52. Geneva: World Health Organization, 1973. and Reproductive Biology 2000 89 97–99. 12 Roth LM. Massive ovarian edema with stromal luteinization. 24 Young JL Jr, Ries LG, Silverberg E, Horm JW & Miller RW. Cancer American Journal of Clinical Pathology 1971 55 757–760. incidence, survival, and mortality for children younger than age 13 Kanumakala S, Warne GL, Stokes BK, Chan YF & Grover S. 15 year. Cancer 1986 58 598–602. Massive ovarian edema causing early puberty. Journal of Pediatric 25 Bulun SE & Adashi EY. The physiology and pathology of the female Endocrinology and Metabolism 2002 15 861–864. reproductive axis. In Williams’ Textbook of Endocrinology, edn 10, 14 Lacson AG, Alrabeeah A, Gillis DA, Salisbury S & Grantmyre EB. ch 16, pp 587–664. Eds PR Larsen, HM Krokenberg, S Melmed & Secondary massive ovarian edema with Meig’s syndrome. KS Polonsky. Philadelphia, PA: WB Saunders, 2002. American Journal of Clinical Pathology 1989 91 597–603. 26 Castleberry RP, Kelly DR, Joseph DB & Cain WS. Gonadal and 15 VanWingen T, Upton RT, Cloherty MG, Irwin JR & Linn JG. extragonadal germ cell tumours. In Clinical Pediatric Oncology. Bilateral massive ovarian edema. Journal of Reproductive Medicine edn 4, pp 577–594. Eds DJ Fernbach & T Vietti. St Louis, MO: 1984 29 875–877. Mosby Year Book, 1991. 16 Kapadia R, Sternhill V & Schwartz E. Massive edema of the ovary. 27 Tiltman AJ & Nel CP. Massive oedema of the ovary. South African Journal of Clinical Ultrasound 1982 10 469–471. Medical Journal 1984 66 924–926. 17 Van den Brule F, Bourque J, Gaspard UJ & Hustin JF. Massive ovar- 28 Young RH & Scully RE. Fibromatosis and massive edema of the ian edema with androgen secretion. A pathological and endocrine ovary, possibly related entities: a report of 14 cases of fibromatosis study with review of the literature. Hormone Research 1994 41 and 11 cases of massive edema. International Journal of Gynecolo- 209–214. gical Pathology 1984 13 153–178. 18 Hill LM, Pelekanos M & Kanbour A. Massive edema of an ovary previously fixed to the pelvic sidewall. Journal of Ultrasound in Medicine 1993 12 629–632. 19 McCrea RS. Uterine adnexal torsion with subsequent contralateral Received 22 July 2003 recurrence. Journal of Reproductive Medicine 1980 25 123–124. Accepted 23 October 2003

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