coexistence of graves' disease and struma ovarii: case
TRANSCRIPT
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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