Predominant Brenner Tumor Combined with Struma Ovarii Containing a Papillary Microcarcinoma Associated with Benign Peritoneal Strumosis: Report of a Case and Histologic Features

Brenner tumor and struma ovarii, two uncommon ovarian tumors arising alone or together with dermoid cysts or adenomas, are both rare entities. Both tumors rarely become malignant and rarely metastasize. Few published reports describe coexisting Brenner tumor and malignant struma ovarii. Patients in whom these malignancies coexist only occasionally have peritoneal spreading, strumosis, or a history of thyrotoxicosis. The patient we describe, a 74-year-old woman, presented with a 2 months’ history of lower abdominal pain and episodic intestinal subocclusion due to a complex pelvic mass. The mass consisted predominantly of a Brenner tumor associated with struma ovarii containing a single small island of thyroid tissue that had undergone malignant transformation into a well-differentiated papillary carcinoma and also normal thyroid tissue that had spread to the peritoneum. The patient underwent radical surgical treatment and after 7 years follow-up is disease free.     

Ovarian epithelial dysplasia after ovulation induction: time and dose effects

BACKGROUND: Ovarian epithelial dysplasia was first described after prophylacticoophorectomies for genetic risk. Ovarian stimulation has beenconsidered as a risk factor of ovarian cancer by Fathalla'sincessant ovulation theory. In this study, we have investigatedthe risk of ovarian dysplasia after ovulation induction. METHODS: We reviewed 99 oophorectomies or cystectomies between 1990 and2005 divided them into two groups: previous in vitro fertilization(n = 37) and a panel of fertile controls (n = 62). Eleven epithelialcytological and architectural features were defined and an ovarianepithelial dysplasia score was calculated to quantify the degreeof ovarian epithelial abnormalities. RESULTS: All the ovaries were macroscopically non-cancerous except intwo patients (one endometrioid cancer and one borderline tumour).The mean ovarian dysplasia score was significantly higher inthe ovulation induction group than in the control group (7.64versus 3.62, P = 0.0002). We also found a relationship betweenthe number of ovulation-inducted cycles and the severity ofovarian dysplasia (‘dose-effect’) and a relationshipbetween time after the end of ovulation induction (over 7 years)and the severity of ovarian dysplasia (‘time-effect’). CONCLUSIONS: There is probably a relationship between ovarian epithelialdysplasia and either ovulation inducing drugs or infertility.By Fathalla’s incessant ovulation theory, ‘the doseeffect and the time effect’ of ovarian stimulation mayexplain ovarian dysplasia formation.     

Coexisting Brenner tumor and struma ovarii in the right ovary: case report and review of the literature

A bilateral ovarian tumor composed of mixed Brenner tumor and struma ovarii in the right ovary and mature cystic teratoma in the left ovary, is described. Mixed Brenner tumor and struma ovarii is rare; eight cases are reviewed. In this case, in addition to the typical Brenner tumor and struma ovarii, some nests composed of both Brenner tumor and struma ovarii in one nest were found in the right ovarian tumor. Immunohistochemically, the struma ovarii is stained for thyroglobulin, and Brenner nests showed various degrees of positive stain for thyroglobulin, which is a specific finding. Brenner tumor, in this case, may produce thyroglobulin or have a receptor to thyroglobulin or analog of thyroglobulin. The origin of mixed Brenner tumor and struma ovarii may be germ cell, as described in some literature, or the Brenner tumor may be of a metaplastic nature, although the Brenner tumor is fourfold the size of struma ovarii in the case presented.     

RAS Mutation-Positive Follicular Variant of Papillary Thyroid Carcinoma Arising in a Struma Ovarii

Struma ovarii is an ovarian mature teratoma composed exclusively or predominantly of thyroid tissue. Malignant transformation of struma ovarii is rare and poorly understood, although this process is thought to be similar to carcinogenesis in malignant tumors of differentiated thyroid tissue originating in the thyroid gland. Genetic alterations in the mitogen-activated protein kinase pathway, including mutations of BRAF, RAS, and RET genes, have been implicated in the development of differentiated thyroid carcinoma arising in the thyroid gland. We report here a case with RAS mutation detected in a malignant struma ovarii. The patient is a 38-year-old female who had a 2.4 cm ovarian cyst noted incidentally on a first trimester ultrasound. She proceeded to ovarian cystectomy post-delivery, with pathologic examination detecting a papillary thyroid carcinoma, follicular variant, arising in a cystic teratoma. The tumor was tested for BRAF, RAS, and RET/PTC mutations. HRAS codon 61 mutation was identified. This is the first report of RAS mutation detected in the follicular variant of papillary carcinoma arising in a struma ovarii. It provides evidence that tumors developing in this setting involve molecular mechanisms similar to those implicated in tumors developing in the thyroid gland.     

Unilateral malignant struma ovarii in a case of bilateral ovarian teratoma with raised CA-125 level: a rare case with treatment dilemmas

Struma ovarii are specialized form of mature ovarian teratoma comprised predominantly of thyroid tissue (>50%). Most of the struma ovarii are benign; rarely can they undergo malignant transformation. Elevated CA-125 levels with benign struma ovarii have been seen in only 5 cases in literature. The association of malignant struma ovarii and high CA-125 levels with pseudo-Meig syndrome has been reported in only 2 cases in English literature. We describe a case of a 46-year-old multigravida who presented with an abdominal mass and raised CA-125 levels. Radiological investigations revealed bilateral cystic adnexal masses with ossified elements on left side suggesting a teratoma. Intraoperative frozen section and final pathology revealed bilateral teratoma with follicular variant of papillary thyroid carcinoma arising in the left ovary. To the best of our knowledge, this is the first case of malignant struma ovarii in combination with bilateral teratoma. The dilemmas related to preoperative diagnoses with elevated CA-125 levels, mimicking an epithelial ovarian neoplasm; intraoperative frozen section consultation; management and follow-up issues in this rare malignancy are discussed.     

Ovarian cystic tumor composed of Brenner tumor and struma ovarii

Ovarian tumor composed only of Brenner tumor and struma ovarii is very rare; only 6 cases have been reported in the English literature, to the best of the author's knowledge. A 66-year-old woman underwent right oophorectomy because of torsion of right ovarian cyst. Macroscopically, the ovarian cyst was hemorrhagic and red. Cystic content was hemorrhagic fluid. Microscopically, the cyst walls were composed only of Brenner tumor (50% in area) and struma ovarii (50% in area). Hemorrhage and ischemic changes were seen. Other elements were not recognized. No malignant transformation was noted. These two elements were separately present, and no mergers between them were recognized. Immunohistochemically, the Brenner tumor element was positive for cytokeratins (AE1/3 and CAM5.2) and Ki67 (labeling=3%), but negative for thyroglobulin, TTF-1, p53, CA125, and vimentin. The struma ovarii element was positive for cytokeratins (AE1/3 and CAM5.2), thyroglobulin, TTF-1 and Ki67 (labeling=5%), but negative for p53, CA125 and vimentin. The findings suggests that there were cases of ovarian cyst composed only of Brenner tumor and struma ovarii, that such a case may be monodermal mature cystic teratoma or the Brenner tumor element was derived from surface epithelium in the preexisting struma ovarii, and that such a tumor manifest as cystic torsion.     

BRAF T1799A mutation occurring in a case of malignant struma ovarii

Struma ovarii is an extremely rare tumor that occasionally undergoes malignant transformation. Because struma ovarii is composed of thyroid tissue, it is conceivable that the pathogenetic events involved in thyroid follicular transformation may take place also in struma ovarii. The authors describe a case of a classical variant of papillary thyroid carcinoma arising in a struma ovarii of a 22-year-old female. The tumor was heterozygous for BRAF T1799A mutation. No ret/ PTC-1 or ret/PTC-3 rearrangements were detected. This finding would suggest that malignant struma ovarii is similar histologically and genetically to primary papillary thyroid carcinoma.     

Ovarian stimulation for in-vitro fertilization combining administration of gonadotrophins and blockade of the pituitary with D-Trp6-LHRH microcapsules: pilot studies with two protocols

In women undergoing in-vitro fertilization and embryo transfer(TVF-ET), a total of 408IVF cycles were stimulated using humanmenopausal gonadotrophin (HMG) or pure follicle stimulatinghormone (FSH) plus HMG in combination with a single injectionof D-Trp⁶-LHRH microcapsules in order to enhance the ovarianresponse to gonadotrophins and to avoid spontaneous LH surges.Sixty-seven pregnancies were achieved. Two protocols were employed.In protocol 1 (‘blocking protocol’, n = 268), thepituitary was first inhibited with a full dose (3.75 mg) ofD-Trp⁶-LHRH in microcapsules and ovarian stimulation was startedafter the hypogonadotrophic hypogonadal state was ascertained(Ej >50 pg/ml). In protocol 2 (‘flareup protocol’,n = 140), the treatment with D–Trp⁶LHRH microcapsules(half-dose = 1.80 mg) and the ovarian stimulation with gonadotrophinswere started at the same time. Higher doses of gonadotrophinswere needed (39.5 11.2 ampoules FSH and/or HMG) in protocol1, in which the pituitary was blocked prior to and during thestimulation, than in protocol 2 (209 ampoules) where the exogenousgonadotrophin stimulation appeared to be augmented by the initialagonistic effect of the injection of D-Trp⁶LHRH microcapsules.In patients with purely tubal infertility, under 38 years oldand no male factor, the results obtained with protocols 1 and2 were similar in terms of pregnancy rate per cycle or per embryotransfer: 22.6 versus 20.5% and 28.3 versus 27.4%, respectively.However, considering the cost benefit, ‘flare-up’protocols appeared to be a better choice and could be recommended.     

Endocrinology: von Willebrand factor: an endothelial marker to monitor in-vitro fertilization patients with ovarian hyperstimulation syndrome

A retrospective study was conducted to evaluate the possiblerole of endothelial and extracellular factors in the pathophysiologyof ovarian hyperstimulation syndrome (OHSS). Plasma changesin von Willebrand—Jürgen factor were correlated withthe clinical condition of hyperstimulated patients, since therise of capillary permeability is the central event in all subsequentmorbidity. The corresponding oestradiol levels and ultrasoundparameters were assessed. In-vitro fertilization patients designatedas ‘high responders’ and with oestradiol values>2500 pg/ml and >8 pre-ovulatory follicles at the timeof human chorionic gonadotrophin (HCG) injection were assessed.Among 62 patients, 37 fulfilled these criteria and 18 developedOHSS, indicating the low predictive ability of ultrasound andoestradiol values alone. The remaining 19 patients served ascontrol group. von Willebrand factor-associated antigen in plasmawas measured using enzyme-linked immunosorbent assay and ristocetinco-factor activity by an aggregatometric test. Basal valuesof the two groups of patients did not differ but there werelarge inter-individual variations. A slight increase occurredin the control group until the day of HCG although individualcycles showed ‘no change of pattern’ or a ‘decreasingtendency’ from the start. Some patients allocated to thenon-hyperstimulated type showed a steep increase of values followedby a decline. A consistent increase in the OHSS group lastedafter embryo transfer even to the late corpus luteum phase.These subtle changes of capillary permeability or damage alwayspreceded the clinical signs, such as ascites, haemoconcentration,hypoproteinaemia and pleural effusion. Mean values differedin the two groups from the day preceding ovum retrieval. Thistest may therefore provide an additional ‘prognostic marker’for early recognition and monitoring of OHSS.     

Endocrinology: Follicular fluid insulin-like growth factor-I and insulin-like growth factor-II concentrations vary as a function of day 3 serum follicle stimulating hormone

We determined follicular fluid concentrations of insulin-likegrowth factor (IGF)-I, IGF-II and inhibin as a function of day3 serum follicle stimulating hormone (FSH) in 16 women undergoingfollicular fluid aspiration in preparation for in-vitro fertilizationand embryo transfer. Follicular fluid concentrations of IGF-Iand IGF-II were significantly less in the ‘low’FSH group as compared to the ‘high’ FSH group. Themean IGF-I concentration was 67.6 ng/ml [confidence intervals(CI) 51.6–92.5] in the ‘low’ FSH group comparedto 87.1 ng/ml (CI 72.8–104.2; P < 0.025) in the ‘high’FSH group. Mean IGF-II concentrations were 354.8 ng/ml (CI 297.8–422.9)in the ‘low’ FSH group compared to 489.8 ng/ml (CI384.6–624.5; P < 0.05) in the ‘high’ FSHgroup. Follicular fluid inhibin concentrations did not differbetween groups. These differences in follicular fluid IGF asa function of day 3 FSH may raise questions regarding the rolegrowth factors play in the physiological processes of the ageingfollicle.     

Imprint cytology of strumal carcinoid of the ovary: A case report with immunocytochemical analysis

Strumal carcinoid is a rare ovarian tumor defined as carcinoid associated with struma ovarii. We report here the second cytological case of strumal carcinoid and performed immunocytochemical analysis for the first time. A 68‐year‐old Japanese female was found to have a solid tumor with small cystic components in the left ovary, and bilateral salpingo‐oophorectomy was performed. The Papanicolaou smear of the imprint cytological specimen of the left ovarian tumor revealed presence of two distinct components. The first component included thyroid follicles, which was composed of flat sheets of polygonal epithelial cells without nuclear groove and intranuclear inclusion. The other component was composed of trabecular clusters of columnar cells containing round to slender nuclei with “salt and pepper” chromatin. Immunocytochemical analysis revealed that synaptophysin was expressed in the latter component. Therefore, a cytodiagnosis of strumal carcinoid was made. Histopathological analyses confirmed the diagnosis of strumal carcinoid. Albeit rare, carcinoid tumor occurs in the ovary, and the recognition of characteristic nuclear features and cellular arrangement leads to correct cytodiagnosis. Presence of struma ovarii component suggests an ovarian origin. Moreover, immunocytochemical analysis for neuroendocrine markers aids its differential diagnosis from granulosa cell tumor and carcinoma arising from struma ovarii.     

Suppression of maternal pituitary thyroid-stimulating hormone during pregnancy

Maternal serum thyroid-stimulating hormone (TSH) has been estimatedin 38 pregnant women with three new specific non-radioactivemonoclonal immunoassays which can measure very low concentrations.Values for the Pharmacia-LKB ‘DELFIA’ fluoroimmunoassayand for the Amersham ‘Amerlite’ luminescence immunoassaywere statistically identical over the range 0.15–1.5 uIU/mlWHO 2nd IRP 80/558, but thereafter the Amersham values wereslightly lower. The Abbott ‘IMx’ assay system gaveslightly higher results commensurate with the quoted highernon-pregnant normal values. The Amersham assay was preferredon practical grounds. There was no relationship of TSH levelsto HCG levels, or to the length of pregnancy. Four women hadapparently zero TSH levels by the Amersham and Pharmacia-LKBassays, although the Abbott assay could detect very low concentrations.Together with women whose TSH levels were below the normal non-pregnantrange for each assay, there were a total of eight women (21%)with TSH levels below ‘normal’. This suppressionof maternal pituitary TSH levels during pregnancy was consideredto be due to the central feedback inhibitory thyrotrophic activityof HCG, as a separate placental thyrotrophic hormone is believednot to exist. The enlargement of the maternal thyroid glandand the increased production of thyroid hormones during normalpregnancy is likewise to be attributed to HCG rather than toan increase in TSH production.     

Malignant struma ovarii: a case report

Malignant struma ovarii is a rare form of the ovarian germ cell tumors. Hence, diagnosis and management of malignant struma ovarii have not been clearly defined. We present the case of a 34-year-old woman with papillary carcinoma arising in struma ovarii. The malignant component of this tumor was detected after laparoscopic removal, and a re-staging operation was performed afterwards. There was no evidence of clinical malignancy or metastases. In this paper, clinical features, treatment guidelines, diagnostic features, and immunohistochemical characteristics of this tumor are reviewed.     

Highly differentiated follicular carcinoma of ovary: Use of imprint cytology at intraoperative consultation

Highly differentiated follicular carcinoma of ovary (HDFCO) is a rare entity known to arise in struma ovarii. Clinical presentation and radiological features mimic other cystic ovarian neoplasm. Thus, intraoperative diagnosis of this entity can be challenging. We hereby report a HDFCO case of a 52‐year‐old woman, who presented with significant abdominal bloating for 3 months. Imaging showed a 11.7 cm left adnexal‐mixed cystic and solid mass, adhering to the bowel with ascites. The mass was examined intraoperatively and showed multilocular cysts filled with straw or red brown‐colored gelatinous fluid. Microscopically, the tumor consisted of small and large follicles with proteinous material and bland‐looking cuboidal cells, suspicious for struma ovarii or granulosa cell tumor with extensive cystic changes, while imprint cytology slides showed watery colloid with cracking artifact favoring the former. However, the adherence to the bowel suggested HDFCO, and prompted surgical staging. The histology of the ovarian mass in the permanent section resembled goiterous thyroid tissue with invasion of endocervical stroma, uterine wall and colonic serosa, and presence of tumor nodules in omentum leading to the diagnosis of HDFCO. Due to striking resemblance of HDFCO to benign thyroid goiter, searching for invasive and metastatic foci is crucial for correct diagnosis. In addition, intraoperative imprint cytology revealing colloid with cracking artifact is helpful for differentiating struma ovarii and/or HDFCO from other ovarian lesions.     

Long-term gonadotrophin-releasing hormone agonist therapy: the evolving issue of steroidal 'add-back' paradigms

The introduction of steroid ‘add-back’ regimensdraws on the recognition that several clinical entities targetedfor treatment with gonadotrophin-releasing hormone agonist (GnRHa)are not ‘6-month diseases’. Included under thisheading are individuals suffering from symptomatic endometriosis(not desires of pregnancy), uterine fibroids (ineligible ordisinterested in definitive surgical therapy), ovarian hyperandrogenism,premenstrual syndrome, menopausal transition, or dysfunctionaluterine bleeding. A 6-month course of therapy with a GnRHa doesnot adversely affect lipoprotein economy and therefore presumablythe corresponding cardiovascular risk. A 6-month course of GnRHatherapy appears to be associated with a substantial decrease(of up to 8.2%) in lumbar bone density, a phenomenon which maynot be entirely reversible 6 months after discontinuation oftherapy. In principle, steroid ‘add-back’ therabyshould diminish some or all of the side-effects associated withGnRHa therapy, may provide a medical treatment option for patientsrepresenting a high surgical risk, and may delay surgical interventionif desired. On the other hand, a steroid ‘add-back’theraby may delay tissue diagnosis, be associated with a substantialcost as well as with the need for parenteral route of administration.Norethindrone-only (but not medroxyprogesterone acetate-only)‘add-back’ regimens have proved promising in thecontext of endometriosis. Non-concurrent oestrogen/progestin‘add-back’ regimens proved promising in the contextof uterine fibroids. Substantial additional studies would haveto be carried out to validate the utility of steroid ‘add-back’regimens. Special emphasis will have to be placed on the evaluationof long-term utility with an eye towards assessing clinicalefficacy, impact on lipoprotein economy, impact on bone density,impact on urogenital tissues, and impact on the hot flush. Theconcurrent or non-concurrent use of non-steroid ‘add-back’regimens will also most likely constitute a major componentof future studies.     

Benign and malignant struma ovarii

Three cases of struma ovarii are reported, two of which were benign, and one which was malignant. Immunoperoxidase studies confirmed that the tumors secreted triiodothyronine and thyroxine, but no carcinoembryonic antigen nor alpha-fetoprotein. In the case of the malignant struma ovarii, the patient's thyroid was histologically normal, and thus the possibility of a metastasis to the ovary from a primary thyroid carcinoma was excluded.