Endocrine Journal 2001, 48 (2), 255-260

NOTE

Coexistence

Case Report

of Graves' Disease and

and Literature Review

Struma Ovarii:

YUKARI MIMURA, MASAYUKI KISHIDA*, HIsAsHI MASUYAMA**, NAOKO SUWAKI**,

JUNICHI KODAMA**, FUMIo OTSUKA*, HIDEO KATAOKA*, TAKAYOSHI YAMAUCHI*,

TosHlo OGURA***, TAKAFUMI KUDO** AND HIROFUMI MAKINO*

Faculty of Education, Okayama University, Okayama 700-8530, Japan * Department of Medicine 111, Okayama University, Medical School, Okayama 700-8558, Japan

**Department of Obstetrics and Gynecology , Okayama University, Medical School, Okayama 700-8558, Japan ***Health and Medical Center , Okayama University, Okayama 700-8530, Japan

Abstract. We report a rare case of Graves' disease associated with struma ovarii. A 26-year-old Japanese woman

had preexisting Graves' disease and was positive for TSH receptor antibody. She had been on antithyroid medication

at presentation. She noted a mass in the lower left abdomen, which was diagnosed as a left struma ovarii by

radiological work-up including computed tomography, magnetic resonance imaging and scintigraphy. The surgically

excised teratomatous tumor, containing cystic spaces with thyroid tissue, was histologically proved to be struma

ovarii. Since thyroid function tests and TSH receptor antibody did not change after surgery, her hyperthyroidism

was considered to be due to Graves' disease. Our case was diagnosed as struma ovarii before surgery using various

imaging studies.

Key words: Hyperthyroidism, TSH receptor antibody, Ovarian tumor

(Endocrine Journal 48: 255-260, 2001)

STRUMA ovarii (SO) is a rare teratomatous ovarian tumor in which thyroid tissue surpasses other tissue elements. Benign cystic teratomas constitute 10% of all ovarian tumors [1]. Although thyroid tissue is found in 1.5-28.5% of cystic teratomas [1] and is a major constituent in 1-2% of all teratomas, it is usually present in small and clinically insignificant

quantities [1]. SO rarely produces sufficient thyroid hormone to cause hyperthyroidism [2]. It is often difficult to diagnose SO before surgery in the absence of hyperthyroidism. In general, the cause of hyper-thyroidism is commonly Graves' disease rather than the ectopic thyroid tissue in the ovary. According to the previous studies, the cause of hyperthyroidism

associated with SO could be 1) hyperfunctioning SO

tissue alone, 2) both hyperfunctioning SO and cervi-

cal goiter, or 3) hyperfunctioning cervical goiter with incidental presence of non-functioning SO. So far,

however, it is difficult to determine the precise cause

of hyperthyroidism because of inadequate data on

thyroid function in the articles concerning SO with

hyperthyroidism [1 , 3-8] . We here report a patient

with SO coexisting Graves' disease, in whom SO was

diagnosed before surgery based on a battery of diag-

nostic procedures. We also discuss the cause of

hyperthyroidism shown in SO with Graves' disease

through the clinical features of previous reports.

Received: June 13, 2000

Accepted: December 27, 2000

Correspondence to: Yukari MIMURA, M.D., Faculty of Edu-

cation, Okayama University, 1-1, Naka 3-chome, Tsushima,

Okayama 700-8530, Japan

Case Report

A 26-year-old female was referred to our hospital

in May 1998 for evaluation of thyroid function. She

had been treated for Graves' disease with antithyroid

256 MIMURA et al.

drugs for four years. Although she had previously noticed a mass in the lower abdomen, she had not undergone further examination for about 3 years. In April 1998, the patient was diagnosed with an ovari-an tumor, and admitted to our hospital for surgery. The family history was negative for thyroid and ovarian diseases. Physical examination revealed she had a diffuse goiter, which was enlarged 3-fold in comparison with normal, but no tachycardia, thyroid bruit, or fine finger tremors. A large firm mass was identified on palpation, which extended from mid to lower abdomen. There was no evidence of Graves'

ophthalmopathy or infiltrative dermopathy. Although thyroid hormones measured by electro-chemical immunoassays (ECLIA) in the Elecsys 2010 immunoassay system (HITACHI Seisakusho, Tokyo, Japan) were within the normal ranges (free T3; 3.33 pg/ml; normal: 1.71-3.71, free T4; 1.29 ng/dl; normal: 0.97-1.69) on treatment with 10 mg thiamazole, TSH measured by ECLIA was not detectable (< 0.01 pU/ml; normal: 0.33-4.05) and TSH binding inhibitor immunoglobulin (TBII, TRAb kit Cosmic III; Cosmic Corp., Tokyo, Japan) and thyroid stimulating antibody (TSAb, TSAb kit Yamasa; Yamasa shoyu, Chiba, Japan) were 46%

(normal: < 10) and 141% (normal: < 180), respec-tively. Anti-thyroid peroxidase antibody (TPOAb, TPOAb kit Cosmic; Cosmic Corp.) was 2.6 U/ml

(normal: < 0.3), while anti-thyroglobulin antibody (TgAb, TgAb kit Cosmic; Cosmic Corp.) was nega-tive (normal: <0.3 U/ml). Serum thyroglobulin

(Tg, Tg IRMA Pasteur, Daiichi Radioisotope, Tokyo, Japan) level was increased to 420 ng/ml

(normal: < 30). Cervical ultrasonography showed diffuse enlargement of the thyroid gland but no tumor. Pelvic ultrasonography showed a left pelvic fluid-filled mass. Magnetic resonance imaging

(MRI) and computed tomography (CT) of the pelvis are shown in Fig. 1. MRI scan (Fig. lA and B) showed a multilobular cystic tumor measuring 16 x 11 x 11 cm in the left ovary. The solid compo-nents appeared as a low-intensity area in T2WI MRI

(Fig. 1B) and as a high-density area on CT scan (Fig. 1C). These radiological features indicated that the

solid part of mass was composed of follicles with io-dine-containing fluid [9]. Scintigraphy with 99mTc-

pertechnetate (99mTc04-) showed a high uptake in the thyroid gland (Fig. 2A) and lower abdomen, the lat-ter being consistent with the MRI and CT findings of the solid part of the tumor (Fig. 2B). Therefore, the tumor was diagnosed as SO before surgery. The ovarian tumor was excised surgically in May

1998. The left ovarian tumor weighed 1,340 g (Fig. 3A) and contained cystic spaces and multiple thyroid tissues. Microscopic examination revealed that a large part of the tumor consisted of a follicular tis-sue, with each follicle lined with flat or cuboidal epithelium and filled with a dense eosinophilic sub-stance (Fig. 3B). There were no other teratomatous or germ cell elements. The final tissue diagnosis was benign SO with thyroid tissue comprising 95% of the whole solid tumor. Although serum free T4 level transiently increased after operation, thyroid func-tion was well controlled at the same dose of thiama-zole as that used before operation (free T3, 2.38 pg/mi; free T4,1.81 ng/dl; TSH, <0.01 pU/ml;

Fig. 1. Abdominal imaging showed a multilobular cystic ovarian tumor measuring 16 x 11 x 11 cm. imaging (T1WI), B: magnetic resonance imaging (T2WI), C: computed tomography.

A: Magnetic resonance

GRAVES' DISEASE AND STRUMA OVARII 257

Tg, 450 ng/ml). Postoperative titers of TBII (42%) and TSAb (160%) did not change compared to the

preoperative levels. At the last follow-up visit to the outpatient clinic, 20 months after surgery, the pa-tient was well and no sign of recurrence was noted.

Discussion

SO is generally diagnosed as an ovarian tumor containing mainly thyroid tissue in more than 50% of the solid tumor [4, 9] or as a tumor accompanying clinically evident hyperthyroidism due to significant

production of thyroid hormone from the tumor [1, 4]. Twenty-three cases of hyperthyroidism, which

are probably caused by the excessive hormone

produced in SO, are reported to date [8, 10, 11]. Smith [11] indicated that the incidence of cervical

goiter in patients with SO is 16.3/, suggesting that the incidence was higher than that expected by

chance. Brown et al. [8] reported a high incidence of cervical goiter (41.7%) among patients with SO ac-

companying overt hyperthyroidism. Among the 233 cases of SO, the incidence of hyperthyroidism of in-distinct origin is also reported to be 5-15°/ [10, 12]. However, the actual incidence remains obscure be-

Fig. 2. TcO4- scintigram of the thyroid (A) and abdomen (single photon emission computed tomography: SPECT; B). Arrow indicates the uptake of the ovarian tumor, which is the solid part of the tumor. The other cystic part of the tumor

shows no uptake.

Fig. 3. The surgically excised ovarian tumor that weighed 1,340g (A) tumor (B) (hematoxylin and eosin, x 400).

, and histopathological examination of the solid part of the

258 MIMURA et al.

cause of the lack of precise data on thyroid function

[4, 13]. Since Graves' disease is the commonest cause of hyperthyroidism, a number of previous cases with thyrotoxicosis due to SO were incorrectly treated by thyroidectomy [1, 3]. Contrary to the reports of functional SO, the SO accompanying Graves' disease is very rare. Since 1970, the total number of cases of hyper-

thyroidism due to SO coexisting with Graves' disease that have been reported in the literature is 5 including the present case (Table 1) [3-6]. The age of these cases ranged from 26 to 48 yrs (mean ± SD: 38.0±9.7 years) and our patient was the youngest case. Interestingly, the age of patients with com-bined Graves' disease and SO is similar to that of

patients with Graves' disease alone, although the age of patients with SO ranged from 6 to 74 years (mean: 42 years) [11]. As shown in Table 1, all patients had S0, which was confirmed histologically to contain thyroid tissue obtained at the time of surgery. These

patients also had a cervical goiter due to Graves' disease, which was considered responsible for excess

production and secretion of thyroid hormones, based on detectable TSH-receptor antibodies (Cases 2, 3 and 5), increased 1231 or 99mTcO4 - thyroid uptake

(Cases 4, 5), histologically confirmed Graves' disease (Case 1), and failure of serum thyroid hormone con-centrations to decrease following resection of SO

(Cases 1, 3-5). Concerning Case 2, hyperthyroidism was treated by subtotal thyroidectomy 20 years ago and the iodine uptake of the cervical goiter was sup-

pressed when the ovary was resected [3]. Strictly

speaking, Case 2 may not be actual coexistence of SO

with Graves' disease. Although the guidelines for

the diagnosis of Graves' disease itself remain to be

established, we would propose that at least two pos-

sible criteria are necessary for the diagnosis of com-

bined Graves' disease and SO; 1) scans of both the

neck and the ovarian tumor are positive, and 2)

thyroid function is not normalized after ovarian sur-

gery. With regard to the pathogenesis of hyper-

thyroidism in patient with SO, two possible clinical conditions can be considered. Firstly, the ovarian

tumor itself autonomously produces a significant

amount of thyroid hormone and causes hyper-

thyroidism, similar to Plummer's disease, without

the existence of Graves' disease [8]. In this situation 1231 scintigraphy of SO shows high uptake , while the uptake of cervical thyroid is suppressed. This theory

does not apply to the pathogenesis in the present

case. Secondly, hyperthyroidism is caused by the

concomitant Graves' disease. In this situation, the

significance of TSH receptor antibody on the growth

of thyrocytes in SO should be considered. Kasagi

et al. [13] reported that the occurrence of hyper-

thyroidism was preceded by detection of both TBII

and TSAb, which may play a crucial role in the de-

velopment of hyperthyroidism due to Graves' dis-

ease. Although it is not confirmed whether TSH

receptor antibody is produced in SO or in the cervical

goiter [4, 5, 14] and there is no report in which TSH receptor in SO tissues was examined, we speculate

that TSH receptor antibody could stimulate the

Table 1. Literature review of cases of coexistence of struma ovarii and Graves' disease

GRAVES' DISEASE AND STRUMA OVARII 259

thyroid tissue of SO. Because several in vitro ex-

periments show that serum IgG fraction purified from the patients with Graves' disease significantly induces thyroid cell proliferation [15, 16]. The IgG fraction associated with thyroid growth could be

thyroid growth-promoting immunoglobulin (TGI), which binds to TSH receptor and exerts its growth effect on thyrocytes [16]. In the present case, we considered that Graves'

disease preceded SO based on the medical history and the positive TSH receptor antibody. Because 99mTcO4- scintigraphy of cervical thyroid was posi-

tive and thyroid function remained stable on the same dose of antithyroid drugs even after ovarian surgery, we concluded that the main cause of hyper-thyroidism was Graves' disease.

The thyroid tissue present in SO is chemically,

pharmacologically, biologically, and microscopically identical to the cervical thyroid tissue [17, 18]. However, thyroid tissue derived from hyperfunc-tional SO was reported to be different from that of Graves' disease [3]. Histopathological examination of the thyroid in Graves' disease often shows paren-chymal hypertrophy and hyperplasia characterized by increased height of the epithelium and redundancy of the follicular walls, and follicles of variable size. In contrast, no such characteristic findings of thyroidal follicular cells are found in SO, even when the SO produced excess thyroid hormone. The thyroid tissue of SO also lacks the features seen in Plummer's disease [4]. In our case, histopathologi-cal examination of SO, which was regarded as an endocrinologically silent tumor, resembled those described in the above reports.

Joja et al. [19] described three characteristic MRI and CT features of SO based on analysis of 13 pa-

tients with SO. These included: 1) the presence of

both cystic and solid components with a multilobu-

lated surface and thickened septa, 2) various signal

intensities seen on both T 1 WI and T2WI, and 3)

high-density of the solid components on CT images,

which appears as low signal intensity on T2WI. These investigators suggested that the characteristic

appearance of SO indicated the presence of viscid

material containing iodine [19]. The MRI and CT findings of our case were essentially consistent with

the above characteristics. 99mTcO4- scintigraphy was

performed in our case instead of 1231 scintigraphy, since the patient had been treated with thiamazol and

we planned to perform surgery as soon as pos-

sible. The findings on 99mTcO4- scintigraphy of high

uptake in both SO and cervical goiter supported

those of MRI and CT findings. Although we could

not evaluate the iodine uptake by 1231 scintigraphy

before operation, the lack of change in thyroid hor-

mone levels and TSH receptor antibody after opera-

tion indicated that the cervical struma was the main

cause of hyperthyroidism.

In summary, we described a rare case of SO and

Graves' disease who was successfully treated with

ovarian surgery. Our report indicates that careful

assessment of thyroid function is necessary in pa-

tients with both SO and cervical struma. To deter-

mine the cause of excess thyroid hormone, morpho-logical and functional assessments using MRI, CT

and scintigram are essential. Possible role of pre-

existing TSH receptor antibody on the growth of

SO was considered. We hope to accumulate more

cases of this endocrinologically interesting condition

to enhance our understanding of SO combined with

Graves' disease.

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