Resolution of hyperthyroidism and thyroid antibodies following struma ovarii resection: an uncommon entity

Abstract

We report a case of 34-year-old clinically asymptomatic woman who had been followed for 6 years for hyperthyroidism with thyroid stimulating hormone <0.006 uIU/mL, free T4 1.98 ng/mL, free T3 5.3 pg/mL, elevated thyroid stimulating immunoglobulin 1.70 IU/L, thyroid peroxidase antibody 38 IU/mL and thyroglobulin antibody 9.3 IU/mL. Radioiodine thyroid scan showed minimal uptake in both thyroid lobes (24-hour uptake was 0.3%). She subsequently underwent evaluation for lower abdominal pain and menstrual irregularities, which revealed a large left ovarian cyst measuring 15.9 cm × 10.8 cm × 13.2 cm and right-sided ovarian cyst measuring 2.7 cm × 3.3 cm × 3.5 cm. Laparoscopic bilateral ovarian cystectomy was performed and the final pathology revealed struma ovarii of the left ovarian cyst with the entire ovarian tumour made up of benign thyroid tissue. Thyroid function tests performed 3 months after surgical removal of struma ovarii showed euthyroidism. We present a rare case with detailed laboratory and immunological data before and after ovarian extirpation with resolution of hyperthyroidism associated with functional struma ovarii.

Background

Struma ovarii, also known as ‘goitre of the ovary’, is a rare teratomatous tumour constituting less than 1% of all ovarian tumours. It is defined by the presence of mature thyroid tissue occupying at least 50% of the entire tumour mass.^{1 2} Hyperthyroidism in this circumstance may be associated with ascites, abdominal discomfort or irregular menstrual bleeding and occurs in about 5%–15% of all struma ovarii cases. We present a case of hyperthyroidism with elevated thyroid antibodies associated with hyperfunctioning thyroid tissue in Struma ovarii.

Case presentation

A 34-year-old woman with no known medical history presented to endocrine clinic in August 2014 with a history of mildly abnormal thyroid function test (TFT) during routine blood work at her primary care clinic. She denied any change in weight, heat or cold intolerance, change in bowel movements, anxiety, palpitations, fatigue or changes in hair or skin. When her TFTs were repeated in our clinic, it showed low normal thyroid stimulating hormone (TSH 0.494 uIU/mL), free T4 (FT4 1.09 ng/mL) but elevated thyroid peroxidase antibodies (TPO Abs 46 IU/mL). The patient was reassured but was asked to repeat blood work particularly TFTs in 1 year due to the presence of TPO Ab and low normal TSH. The patient continued to be asymptomatic however, TSH in 2016 was now overtly low at 0.287 uIU/mL (table 1) with normal FT4 (1.02 ng/mL) and free T3 (FT3 3.0 pg/mL) and elevated TPO Ab (38 IU/mL). At this time, thyroid stimulating immunoglobulin (TSI) and thyroglobulin antibody (Tg Ab) were absent (table 1). Thyroid ultrasound showed normal appearing right thyroid lobe, left lobe and isthmus without increased vascularity or nodules. The patient was told that she could have subclinical thyroid disease due to underlying autoimmune process and was recommended to undergo further work but was lost to follow-up. She later presented 2 years later at an urgent care with increased episodes of headache and panic attacks and with symptoms of hyperthyroidism with suppressed TSH (<0.006 uIU/mL), elevated FT4 (1.99 ng/mL) and FT3 (5.2 pg/mL) (table 1).

Table 1.

Thyroid function tests and thyroid antibodies

	Normal range	9/2014	6/2016	10/2018	8/2019	12/2019	5/2020
TSH (uIU/mL)	0.450–4.500	0.494	0.287	<0.006	<0.006	<0.006	1.340
FT4 (ng/mL)	0.82–1.77	1.09	1.02	1.99	1.98	1.62	0.97
FT3 (pg/mL)	2.0–4.4	–	3.0	5.2	5.3	4.4	2.9
Tg (ng/mL)	<40	–	–	–	164	–	9.0
Tg Ab (IU/mL)	<1.0 = absent	–	<1.0	–	9.3	–	66
TSI (IU/L)	0.00–0.55	–	<0.10	–	1.70	–	<0.10
TPO antibody (IU/mL)	0–34	46	38	–	–	–	14

FT3, free T3; FT4, free T4; Tg, thyroglobulin; Tg Ab, thyroglobulin antibody; TPO, thyroid peroxidase; TSH, thyroid stimulating hormone; TSI, thyroid stimulating immunoglobulin.

She was asymptomatic except for the history of increased anxiety. She was not on any treatment except for over-the-counter biotin supplement, which she was taking for 1-month duration (she denied using biotin during any of her previous blood work). Physical examination was unremarkable; thyroid was non-tender, not enlarged and Graves’ associated eye signs were not present. Patient was asked to discontinue her biotin (2500 mcg daily) for at least 1 week and repeat blood work.

Investigations

Repeat TFTs continued to show suppressed TSH (<0.006 uIU/mL), elevated FT4 (1.98 ng/mL) and FT3 (5.3 pg/mL) (off biotin for >72 hours). She also had developed elevated thyroglobulin level (164 ng/mL), Tg Ab (9.3 IU/mL) and TSI (1.70 IU/L). Thyroid ultrasound showed the right lobe measuring 4.4 cm × 1.2 cm × 2 cm, the left lobe measuring 4.2 cm × 1.3 cm × 1.6 cm and normal appearing isthmus. Thyroid uptake/scan performed with 228 microcuries of I-123 revealed minimal uptake in both lobes of the thyroid. Her 24-hour uptake was 0.3% (normal 10%–30%) (figure 1). Unfortunately, nuclear medicine did not scan over the abdomen and urinary iodine was not done.

Figure 1.

Thyroid uptake scan showing scant I-123 uptake in both thyroid lobes.

Concurrently, the patient was seeing a gynaecologist for the history of breakthrough bleeding using an intrauterine device with left lower abdominal intermittent pain and discomfort for over a year. Transvaginal ultrasound showed a large left ovarian cyst and a right ovarian cyst with associated small collection of fluid in cul-de-sac. MRI of pelvis showed a 15.9 cm × 10.8 cm × 13.2 cm T1 hypointense, T2 hyperdense cystic lesion in the left ovary with septation. There was a 2.7 cm × 3.3 cm × 3.5 cm T1 hyperintense lesion in the right adnexa. None of the lesions demonstrated contrast enhancement.

Differential diagnosis

Our patient presented with hyperthyroidism but with low radioactive iodine uptake. Differential diagnosis for conditions causing low RAIU (Radioactive Iodine Uptake) of thyroid include factitious hyperthyroidism, subacute thyroiditis, silent thyroiditis and struma ovarii. Given that patient had increased thyroglobulin levels, factitious hyperthyroidism was ruled out and she was being worked up for endogenous causes of hyperthyroidism causing low RAIU as discussed.

Treatment

The Ca-125 level was slightly elevated (48.7 U/mL; normal range 0.0–38.1) and the patient underwent laparoscopic bilateral ovarian cystectomy without any complications. She was discharged home on post-operative day 1.

Outcome and follow-up

At pathology, the left ovarian tissue appeared white-tan, cystic with cut surface showing patchy blood clots. The right ovarian tissue appeared to be granular, white and the presence of hair. The final pathology was struma ovarii of left ovarian cyst with entire ovarian tumour made of benign thyroid tissue with epithelial cells staining positive for thyroglobulin (figure 2). The right ovarian cyst was reported as mature cystic teratoma (ie, dermoid cyst). The TFTs 3 months postoperatively off biotin for 1 week showed euthyroidism with TSH 1.340 uIU/mL, FT4 0.97 ng/mL, FT3 2.9 pg/mL along with normal levels of TSI (<0.10 IU/L) and TPO Ab (14 IU/mL). Her thyroglobulin level (9.0 ng/mL) had normalised but she still had elevated Tg Ab (66 IU/mL) (table 1). The patient continued to be asymptomatic.

Figure 2.

Struma ovarii of left ovarian cyst: the entire ovarian tumour was made of benign thyroid tissue with follicles of various sizes, lined by cuboidal cells and vacuoles filled with colloid.

Discussion

Thyroid tissue is present in about 20% of all ovarian teratomas but <5% fit the criteria for struma ovarii.³ Struma ovarii is a rare, specialised variant of ovarian teratoma defined by the presence of mature thyroid tissue occupying at least 50% of the entire tumour mass. Boettlin⁴ was the first to comment on the presence of thyroid follicular cells in ovaries and the subsequent term ‘teratoma strumoides ovari’ was based on thyroid tissue in an ovarian dermoid and it was postulated that ovarian tumours containing thyroid tissue must be teratomatous in origin.⁵ In one of the largest studies involving 152 cases of struma ovarii, the average age of patients was 42 years and an association of cervical goitre with struma ovarii was seen in 16.3%.⁶ We now know that thyroid tissue in struma ovarii is architecturally, biologically and physiologically similar to the thyroid gland and hyperthyroidism is directly related to the mass of thyroid tissue in struma ovarii.^{7 8} Symptoms associated with this tumour are often non-specific, which poses a challenge to the preoperative diagnosis. They are generally slow growing tumours and take many years to develop symptoms, such that the diagnosis can be delayed up to 26 years.⁹ The most common symptoms include abdominal pain, menstrual irregularities, ascites or an incidental ovarian mass. Hyperthyroidism occurs in about 5%–15% of all struma ovarii cases.¹⁰ Malignant transformation of thyroid tissue is rare and represents 5%–10% of all struma ovarii cases. Distant metastasis involving predominantly abdominal cavity and rarely bones, liver, lungs, brain have been reported.

Hyperthyroidism in struma ovarii is thought be caused by one of the three mechanisms¹¹: (1) from hyperfunctioning struma ovarii; (2) from both hyperfunctioning struma ovarii and thyroid gland; (3) from hyperfunctioning thyroid gland with co-incidental presence of struma ovarii. Thus, most of these patients lack the detailed data of TFT preoperatively. To our knowledge, this is the first case report with detailed biochemical and immunological information in a patient with hyperthyroidism due to functional struma ovarii and evidence of resolution after treatment.

Symptoms associated with this tumour are most common with size >6 cm. In one study, 8 out of 25 patients had hyperthyroidism and in 5 out of 8 patients with struma ovarii and hyperthyroidism, hyperfunctioning thyroid tissue in the ovary played a contributing role to the degree of hyperthyroidism and correlated with amount of thyroid tissue.¹² It was hypothesised that the expression of TSH receptor in struma ovarii in the presence of circulating TSI could stimulate the growth of thyroid tissue and increase thyroid hormone production leading to hyperthyroidism.^{13 14} Indeed, in a patient with functioning struma ovarii and co-existing Graves’ disease, the TSH receptor staining in struma ovarii was established.⁸ Thus, the presence of TSH receptors in struma ovarii could be the determining factor in the functional status.^{15 16} Our patient had elevated TSI between 2016 and 2019, most likely from developing struma ovarii. It is unclear why the presence of TSI in the current case did not stimulate significant cervical growth and secretion unless the TSI affinity for the TSH receptor was enhanced in the ovarian tissue compared with the thyroid gland. To what degree struma ovarii may function autonomously has not been studied yet and remains unknown.⁶ The intensity of TSH receptor staining, however, does not seem to play a role in differentiating between functioning and non-functioning tumours. Thyroid tissue from struma ovarii, even when producing excess thyroid hormone, lacks the findings of parenchymal hypertrophy or hyperplasia seen in Graves’ disease.¹⁷ Radioiodine scan of pelvis could be useful in preoperative diagnosis of struma ovarii but is infrequently done due to its rarity.¹⁸ Surgical removal of benign tumour is almost always curative. The normalisation of TFTs and disappearance of thyroid antibodies after removal of tumour in this patient confirm ectopic cause of hyperthyroidism due to struma ovarii.

Patient’s perspective.

I have been dealing with abnormal thyroid test for the past 6 years. It was initially diagnosed on routine blood work. I never felt any symptoms from hyperthyroidism. Once I had to go to urgent care due to headache and was told it could be related to my thyroid. I did not follow up with Endocrine routinely as I was symptom free but continued to do blood work and imaging from time to time as recommended. What bothered me most in the recent years was my abdominal discomfort. I’m glad I took care of that. When the doctors told me the size of the ovarian cyst and that there is a possibility it could be cancer, I was very upset. I’m relieved that the results came back benign. But from what my Endocrinologists have told me it seems that the cyst in my ovary was producing excess thyroid hormones and now that it is removed, my thyroid blood work is normal. I’m amazed how an organ in the abdomen can produce thyroid hormone. I’m glad it is out and to be feeling better. My doctor showed me a picture of the pathology slide of the cyst and said I’m looking at thyroid tissue in the cyst but all I could see was pink seas and blue shores. It looked like an art.

Learning points.

• Struma ovarii is a rare ovarian teratoma defined by the predominant presence of thyroid tissue.

• Most patients with struma ovarii are asymptomatic such that the diagnosis is typically significantly delayed.

• Hyperthyroidism occurs in about 5%–15% of all struma ovarii cases. Malignant transformation of thyroid tissue is rare and represents 5%–10% of all struma ovarii cases.

• Although hyperthyroidism from struma ovarii is rare, it should be in the differential diagnosis of hyperthyroidism with low thyroid radioiodine uptake and abdominal scintigraphy should be considered in such patients.